OXADIAZOLE COMPOUNDS, THEIR PREPARATION AND USE

FIELD OF THE INVENTION
The present invention relates to oxadiazole compounds, to processes for their
preparation, pharmaceutical compositions containing them, and their use in the
treatment of cancer.
BACKGROUND OF THE INVENTION
Cancer is an uncontrolled growth and spread of cells that may affect almost
any tissue of the body. Cancer can be defined as abnormal growth of tissues
characterized by a loss of cellular differentiation. It is caused due to a deregulation of
the signaling pathways involved in cell survival, cell proliferation and cell death.
Current treatments for cancer and related diseases have limited effectiveness
and a number of side effects. Cancer therapy currently falls under the following
categories including surgery, radiation therapy, chemotherapy, bone marrow
transplantation, stem cell transplantation, hormonal therapy, immunotherapy,
antiangiogenic therapy, targeted therapy, gene therapy and others.
In the treatment of cancer, chemical compounds are used to reduce, inhibit, or
diminish the proliferation of tumor cells, and thereby assist in reducing the size of a
tumor. These compounds, which exhibit antitumor activity, find use in the treatment
of cancers.
Chronic myeloid leukemia (CML) is a type of cancer characterized by the
clonal proliferation of malignant myeloid progenitor cells resulting in excessive
number of myeloid cells in all stages of maturation. Development of CML is
associated with a specific chromosomal translocation known as the Philadelphia (Ph)
chromosome. A molecular consequence of this translocation is the generation of a
fusion protein Bcr-Abl, a constitutively activated tyrosine kinase that is detectable
throughout the course of the disease. The Ph chromosome produces an enzyme, a
fusion protein (Bcr-Abl) that plays a central role in aberrant cell growth and division.
This aberrant enzyme sends out signals through multiple pathways within the cell,
resulting in the overproduction of white blood cells in the body. The result is that,
while a healthy cubic millimetre of blood contains 4,000 to 10,000 white blood cells,
blood from a patient with CML contains 10 to 25 times this amount. The massive
increase in the number of white blood cells characterises CML. In addition to CML,
Acute lymphoid leukemia (ALL) and acute myeloid leukaemia (AML) are Ph positive
Leukaemias.
The median survival of patients after diagnosis with CML is 4-6 years, with a
range of less than one year to more than 10 years (National Cancer Institute:
Chronic Myeloid Leukemia: Treatment: Health Professional Version: General
Information 2006). Treatment options for patients with CML are limited and are
based on the stage of leukaemia, and the patient's age and health. The disease may
be treated with bone marrow transplant (BMT) therapy or with drug therapy.
Interferon-alpha has been used for the treatment of CML and has shown improved
survival in CML patients. However, there are reports of patients showing resistance
to the treatment with Interferon-alpha (Leukemia Research, 2003, 27, 5, 405-41 1).
Recent reports have shown that ectopic Bcr-Abl expression dramatically
increases TGF /Smad-dependent transcriptional activity in Cos1 cells, and that this
may be due to enhancement of Smad promoter activity (FEBS Letters, 2007, 581 , 7,
1329-1 334; Leukemia, 2007, 2 1 , 494-504). Bcr-Abl expressing TF-1 myeloid cells
are more potently growth arrested by TGF compared to the parental TF-1 cell line.
The expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGF ,
and that this novel cross-regulatory mechanism might play an important role in
maintaining the transformed progenitor cell population in CML. A small pocket of
haemopoietic stem cells, which are resistant to imatinib mesylate, in part because
they are non-cycling, also hinders the complete eradication of CML. Therefore, TGF
is a prime candidate for maintaining these CML stem cells in a non-cycling state. An
upregulation or prolongation of TGF signaling by Bcr-Abl, suggests that one of the
mechanisms by which Bcr-Abl promotes the transformation of haemopoietic
progenitor cells, is by influencing the level of TGF signaling activity. TGF plays a
vital role in the preservation of the malignant progenitor population, and is partially
responsible for the resistance to treatments targeting Bcr-Abl that is observed in a
proportion of CML patients.
CRKL protein [V- crk sarcoma virus CT1 0 oncogene homolog (avian)- like]
belongs to the SH2-SH3 family of adaptor proteins. It is a 39-kD protein and is
constitutively heavily phosphorylated in Philadelphia-chromosome positive CML
cells. It is a prominent substrate for Bcr-Abl kinase. It is also stably phosphorylated in
neutrophils from patients in chronic phase of CML at a point in maturation when the
Bcr-Abl kinase activity is downregulated as measured by autophosphorylation. CRKL
and Bcr-Abl form a complex suggesting a significant role for this adaptor protein in
Bcr-Abl transformation. Phospho-CRKL monitoring has been recognized as a
prognostic marker in CML patients treated with first and second generation Bcr-Abl
inhibitors (Haematologica, 2008, 93, 5, 765-769; The Journal of Biological
Chemistry, 1994, 269, 37, 16, 22925-22928).
Imatinib mesylate (gleevec® or glivec®; Novartis India Ltd.) is currently the
most specific drug for the treatment of CML and is regarded as a very effective
therapy. Imatinib mesylate inhibits the Bcr-Abl tyrosine kinase and the effectiveness
of imatinib mesylate in CML patients is based on overall hematologic and
cytogenetic response rates. Despite significant hematologic and cytogenetic
responses, resistance to imatinib mesylate has also been observed in CML patients,
particularly in patients who have progressed to either the accelerated or blastic
phase of the disease. US Patent 7521 175 describes possible mechanisms
associated with imatinib mesylate resistance in CML patients and discloses a
number of Bcr-Abl mutants associated with resistance to imatinib mesylate. Attempts
have been made to find new therapeutic strategies to prevent or overcome this
resistance.
Recently, two experimental drugs namely nilotinib (AMN-107; Novartis India
Ltd.) and dasatinib (BMS-354825; Bristol Myers Squibb) were found to be effective in
circumventing some but not all forms of imatinib mesylate resistance (Expert
Reviews, Anticancer Then, 2008, 8, 9, 1387-1 398). The T315I mutant is one of the
more predominant mutations seen in imatinib mesylate-resistant patients. This T315I
mutation was shown to preserve kinase activity resulting in ineffective binding of
imatinib mesylate to Bcr-Abl. Another drug, Homoharringtonine (ChemGenex
Pharmaceuticals) which is in the Phase ll/lll stage has been found to be useful for
patients with imatinib mesylate resistant CML, including those containing the T315I
mutation (Expert Reviews, Anticancer Therapy, 2008, 8, 9, 1387-1 398). However,
despite these developments, there still exists a continuing need for agents which are
effective against the imatinib mesylate- resistant CML.
Blood, 2003, 101 , 690-698, describes the K-562-R resistant cell line. K-562 is
one of the human leukemic cell lines which contains a wild type Bcr-Abl protein,
while K-562-R is a K-562 cell line which is made resistant to imatinib mesylate by
continuous exposure to imatinib mesylate (2 g/mL).
Cancer Research, 2005, 65, 11, 4500-4505 describes various imatinib
mesylate resistant cell lines- Ba/F3 Bcr-Abl/ T315I, Ba/F3 Bcr-Abl/ E255K, Ba/F3
Bcr-Abl/ H396P, Ba/F3 Bcr-Abl/ M351T, Ba/F3 Bcr-Abl/ F359V, Ba/F3 Bcr-Abl/
E255V, Ba/F3 Bcr-Abl/ F317L, Ba/F3 Bcr-Abl/ H396R, Ba/F3 Bcr-Abl/ M244V, Ba/F3
Bcr-Abl/ Q252H, Ba/F3 Bcr-Abl/ Y253F and Ba/F3 Bcr-Abl/ Y253H.
Cancer Letters, 1996, 108, 2 11-214, describes the inhibitory effect of caffeic
acid phenethyl ester on human leukaemia HL-60 cells.
PCT publication WO2008026125 describes the use of caffeic acid and its
derivatives for the treatment of CML, which is resistant to treatment with imatinib
mesylate.
There is an urgent need for medicaments for treating cancer, in particular
chronic myeloid leukaemia (CML) and more particularly, chronic myeloid leukaemia
that is resistant to treatment with imatinib mesylate due to Bcr-Abl mutation.
SUMMARY OF THE INVENTION
The present invention relates to oxadiazole compounds, processes for their
preparation and their use in the treatment of cancer.
According to one aspect of the present invention, there are provided
compounds of formula 1 (as provided herein below), stereoisomers and tautomers
thereof, pharmaceutically acceptable salts, solvates, prodrugs and polymorphs
thereof.
According to another aspect of the present invention, there are provided
processes for producing compounds of formula 1.
According to yet another aspect of the present invention, there is provided the
use of compounds of formula 1 in the treatment of cancer.
According to another aspect of the present invention, there is provided the
use of compounds of formula 1 for the inhibition of TG (Transforming Growth
Factor-) .
According to a further aspect of the present invention, there is provided a
method for the treatment of cancer, particularly CML (Chronic myeloid leukaemia), the
method including administering to a mammal in need thereof a therapeutically
effective amount of a compound of formula 1.
According to another aspect of the present invention, there are provided
pharmaceutical compositions including one or more compounds of formula 1 as
active ingredient(s).
According to still another aspect of the present invention, there is provided
use of compounds of formula 1 for the manufacture of medicaments, which are
useful for the treatment of cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows inhibitory concentrations (IC5o) for compounds of the present
invention in imatinib mesylate sensitive (Ba/F3 Bcr-AbI/ Wild Type) and imatinib
mesylate resistant (Ba/F3 Bcr-AbI/ T31 51) cell lines.
Figure 2 shows inhibitory concentrations (IC5o) for compounds of the present
invention in imatinib mesylate resistant cell lines.
Figure 3 elucidates the mechanism of action of compounds of the present
invention in imatinib mesylate resistant T31 5 1cell line.
Figure 4 shows the effect of compounds of the present invention on
autophosphorylation of Bcr-AbI protein.
Figure 5 shows the CRKL phosphorylation analysis of imatinib resistant CML
cells (E255V) on treatment with compounds of the present invention.
Figure 6A shows the basal levels of phospho-CRKL (Tyr 207) in normal
neutrophils and CML cell lines
Figure 6B shows the CRKL phosphorylation analysis of imatinib resistant
CML cells on treatment with compound of Example 3.
Figure 7 shows the relative tumor weight profile for compounds of the present
invention in imatinib mesylate resistant T31 5 1cell line.
Figure 8 shows the relative tumor weight profile for compounds of the present
invention in imatinib mesylate sensitive cell line (Ba/F3).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides oxadiazole compounds of formula 1;
Formula 1
in all their stereoisomeric and tautomeric forms, their pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs
and pharmaceutically acceptable polymorphs;
wherein,
R is selected from hydroxy, (CrCi 2)-alkoxy or aryloxy;
R2 is selected from hydroxy, nitro, (Cerci 2)-alloy, aryloxy, NH-S02-(Ci-Ci 2)-alkyl,
NH-S0 2-aryl or NRaRb; wherein Ra and R are independently selected from
hydrogen, (Ci-Ci 2)-alkyl, aralkyl, aryl or heterocyclyl;
R3 is selected from hydrogen, (Cerci 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3;
wherein,
(Ci-Ci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, (Ci-Ci 2)-alloy, unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclyl, COORa, C(0)Ra, SRa, NRaRb and
C(0)NRaRb;
alkyl of (Ci-Ci 2)-alloy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclyl, COORa, C(0)Ra, SRa, NRaRb and
C(0)NRaR ;
(C3-Ci 2)-cycloalkyl is unsubstitued or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl, (C
C 2)-alloy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)Ra,SRa, NRaRb and C(0)NRaR ;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, (Cerci 2)-alkyl, (C2-Ci 2)-alkenyl, (C2-Ci 2)-alkynyl, (C1-C12)-
alloy, unsubstituted or substituted heterocyclyl, COORa, C(0)R a, SRa, NRaRb and
C(0)NR aRb;
aryl of aryloxy is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl, (C2-Ci 2)-
alkenyl, (C2-Ci 2)-alkynyl, unsubstituted or substituted heterocyclyl, COORa, C(0)R a,
SRa, NRaRb and C(0)NR aRb;
aryl of aralkyi is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl, (C2-Ci 2)-
alkenyl, unsubstituted or substituted heterocyclyl and (C2-Ci 2)-alkynyl ;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl, (C1-C12)-
alloy, unsubstituted or substituted aralkyi, unsubstituted or substituted aryl, COORa,
C(0)R a, SRa, NRaR , (C C 2)-alkyl-NR aRb and C(0)NR aR ; and
Ra and R are independently selected from hydrogen, (Cerci 2)-alkyl, aralkyi, aryl or
heterocyclyl.
Definitions
As used herein, the term "alkyl" whether used alone or as part of a substituent
group, refers to the radical of saturated aliphatic groups, including straight or
branched-chain alkyl groups. An alkyl group can have a straight chain or branched
chain containing 1 to 12 carbon atoms. Alkyl groups include methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl,
neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
A substituted alkyl refers to a (Ci-Ci 2)-alkyl substituted with one or more
groups selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted
(Ci-Ci 2)-alloy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)R a, SRa, NRaR and C(0)NR aR ; wherein Ra and Rb are
independently selected from hydrogen, unsubstituted or substituted (C1-C12) alkyl,
unsubstituted or substituted aralkyi, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl. Examples of substituted alkyls include
benzyl, hydroxymethyl, hydroxyethyl, 2-hydroxyethyl, N-morpholinomethyl, Nindolomethyl,
piperidinylmethyl, trifluoromethyl and aminoethyl.
As used herein, the term "alkenyl" whether used alone or as part of a
substituent group, refers to a straight or branched chain hydrocarbon radical
containing the indicated number of carbon atoms and at least one carbon-carbon
double bond (two adjacent sp2 carbon atoms). For example, (C2-Ci 2)-alkenyl refers
to an alkenyl group having 2 to 6 carbon atoms. Depending on the placement of
double bond and substituents if any, the geometry of the double bond may be
entgegen (E), or zusammen (Z), cis or trans. Examples of alkenyl include, but are
not limited to, vinyl, allyl and 2-propenyl.
A substituted alkenyl refers to an alkenyl group substituted with one or more
groups selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted
(Cerci 2)-alloy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)R a, SRa, NRaRb or C(0)NR aRb; wherein Ra and Rb are
independently selected from hydrogen, unsubstituted or substituted (C1-C12) alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl.
As used herein, the term "alkynyl" whether used alone or as part of a
substituent group, refers to a straight or branched chain hydrocarbon radical
containing the indicated number of carbon atoms and at least one carbon-carbon
triple bond (two adjacent sp carbon atoms). For example, (C2-Ci 2)-alkynyl refers to
an alkynyl group having 2-1 2 carbon atoms. Examples of alkynyl include, but are not
limited to, ethynyl, 1-propynyl, 3-propynyl and 3-butynyl.
A substituted alkynyl refers to an alkynyl group substituted with one or more
groups selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted
(Ci-Ci 2)-alloy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)R a, SRa, NRaRb or C(0)NR aR ; wherein Ra and Rb are
independently selected from hydrogen, unsubstituted or substituted (C C 2) alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl.
As used herein, the term "alkoxyl" or "alloy" refers to a (Ci-Ci 2)-alkyl having
an oxygen radical attached thereto. Representative alloy groups include methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
A substituted alloy refers to an alloy group in which the alkyl is substituted
with one or more groups selected from halogen, hydroxy, cyano, nitro, unsubstituted
or substituted aryl, unsubstituted or substituted heterocyclyl, COORa, C(0)R a, SRa,
NRaRb or C(0)NR aRb; wherein Ra and R are independently selected from hydrogen,
unsubstituted or substituted (C1 -C12) alkyl, unsubstituted or substituted aralkyl,
unsubstituted or substituted aryl or unsubstituted or substituted heterocyclyl.
Examples of substituted alloy are chloromethoxy, 2-cyanoethoxy, trifluoromethoxy
and benzyloxy group. A benzyloxy group refers to a benzyl having an oxygen radical
attached thereto.
The term "(C3 -C12) cycloalkyl" or "cycloalkyl" refers to monocyclic or polycyclic
hydrocarbon groups of 3-1 2 carbon atoms, which may be optionally bridged such as
adamantyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cycloctyl and cyclononyl.
A substituted (C3 -C12) cycloalkyl refers to a "(C3 -C12) cycloalkyl" substituted by
one or more substituents such as halogen, hydroxy, cyano, nitro, unsubstituted or
substituted (Ci -Ci 2)-alkyl, (Ci -Ci 2)-alloy, unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclyl, COOR a, C(0) Ra, SRa, NRaRb or
C(0)NR aRb; wherein Ra and R are independently selected from hydrogen,
unsubstituted or substituted (C1 -C12) alkyl, unsubstituted or substituted aralkyl,
unsubstituted or substituted aryl and unsubstituted or substituted heterocyclyl.
The term "aryl" as used herein refers to monocyclic or polycyclic hydrocarbon
groups having 6 to 14 ring carbon atoms in which the carbocyclic ring(s) present
have a conjugated pi electron system. Examples of (C6-Ci 4)-aryl residues are
phenyl, naphthyl, fluorenyl or anthracenyl. Examples of (C6-Ci 0)-aryl residues are
phenyl or naphthyl. Aryl groups can be unsubstituted or substituted by one or more,
for example 1, 2, 3, 4 or 5, identical or different substituents selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (C1 -C12) alkyl, unsubstituted or
substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-alkynyl,
unsubstituted or substituted (Ci -Ci 2)-alloy, unsubstituted or substituted
heterocyclyl, COOR a, C(0)R a, SRa, NRaR or C(0)NR aR ; wherein Ra and Rb are
independently selected from hydrogen, unsubstituted or substituted (C1 -C12) alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl. In monosubstituted phenyl residues the
substituent can be located in the 2-position, the 3-position or the 4-position. If the
phenyl carries two substituents, they can be located in 2,3-position, 2,4-position, 2,5-
position, 2,6-position, 3,4-position or 3,5-position. Examples of monosubstituted
phenyl groups are 3-trifluoromethylphenyl, 4-chlorophenyl and 4-cyanophenyl.
Examples of disubstituted phenyl groups are 3,5-difluorophenyl and 3,4-
dimethoxyphenyl.
As used herein, the term "aryloxyl" or "aryloxy" refers to an aryl group having
an oxygen radical attached thereto. The aryl of aryloxy group may be unsubstituted
or substituted as explained in the definition of substituted aryl herein above.
Representative aryloxy groups include phenoxy, 4-chlorophenoxy, 3,4-dimethoxy
phenoxy, etc.
The term "aralkyl" refers to an aryl group bonded directly through an alkyl
group, such as benzyl. The aryl of the aralkyl group may be unsubstituted or
substituted as explained in the definition of substituted aryl herein above.
The term "heteroatom" as used herein includes nitrogen, oxygen, and sulfur.
Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to
satisfy the valency.
Heterocyclyl includes saturated heterocyclic ring systems, which do not
contain any double bonds within the rings, as well as unsaturated heterocyclic ring
systems, which contain one or more, for example, 3 double bonds within a ring,
provided that the resulting mono, bi or tricyclic ring system is stable. In monocyclic
heterocyclyl groups, heterocyclyl preferably is a 4-membered, 5-membered, 6-
membered or 7-membered ring, more preferably a 5- or 6-membered ring. The
heterocyclyl group may, for example, have 1 or 2 oxygen atoms and/or 1 or 2 sulfur
atoms and/or 1 to 3 nitrogen atoms in the ring. Aromatic heterocyclyl groups may
also be referred to by the customary term "heteroaryl" for which all the definitions
and explanations relating to heterocyclic apply. Examples of heterocyclyls include
pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyrazinyl, piperazinyl, oxazolyl, isoxazolyl,
thiazolyl, fury, thienyl, pyridyl, pyrimidyl, piperidyl, benzothiazolyl, purinyl,
benzimidazolyl, benzoxazolyl, indolyl, isoindolyl, isoquinolyl, isoquinolyl, morpholinyl,
quinoxalinyl, and quinolyl.
A substituted heterocyclic refers to a heterocyclic substituted with one or more
groups selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted
(Cerci 2)-alkyl, unsubstituted or substituted (Cerci 2)-alloy, unsubstituted or
substituted aralkyl, unsubstituted or substituted aryl, COORa, C(0)R a, SRa, NRaRb,
(Ci-Ci 2)-alkyl-NR aRb or C(0)NR aRb; wherein Ra and R are independently selected
from hydrogen, unsubstituted or substituted (C1-C12) alkyl, unsubstituted or
substituted aralkyl, unsubstituted or substituted aryl and unsubstituted or substituted
heterocyclic. The substituents may be present on either the ring carbon or the ring
nitrogen atoms. The substituents can be present at one or more positions provided
that a stable molecule results.
The term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.
The term "solvate" describes a complex wherein the compound is coordinated
with a proportional amount of a solvent molecule. Specific solvates, wherein the
solvent is water, are referred to as hydrates.
The term "tautomer" refers to the coexistence of two (or more) compounds
that differ from each other only in the position of one (or more) mobile atoms and in
electron distribution, for example, keto-enol tautomers.
It will be understood that "substitution" or "substituted with" includes the
implicit proviso that such a substitution is in accordance with permitted valence state
of the substituted atom and the substituent, and represents a stable compound,
which does not readily undergo undesired transformation such as by rearrangement,
cyclization, or elimination.
As used herein, the term "compound of formula 1" includes all the
stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and their
pharmaceutically acceptable salts, solvates, prodrugs and polymorphs.
Aspects of the invention
In one aspect, the present invention provides compounds of formula 1;
Formula 1
wherein,
R is selected from hydroxy, (Cerci 2)-alloy or aryloxy;
R2 is selected from hydroxy, (Cerci 2)-alloy or aryloxy;
R3 is selected from hydrogen, (Cerci 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclic; and
n is an integer from 0-3;
wherein,
(Cerci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclic;
alkyl of (Cerci 2)-alloy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclic;
(C3-Ci 2)-cycloalkyl is unsubstituted or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl,
unsubstituted or substituted aryl and unsubstituted or substituted heterocyclic;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl, unsubstituted or
substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-alkynyl and
unsubstituted or substituted heterocyclic;
aryl of aryloxy is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclic;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclic;
heterocyclic is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl, (Ci-Ci 2)-
alloy, unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclic.
In another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (Ci-Ci 2)-alloy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is hydrogen or (CrCi 2)-alkyl; and
n is 0 or 1;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclic;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclic;
heterocyclic is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyi, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (Ci-Ci 2)-alkyl-NR aR ; and
Ra and R are independently selected from hydrogen, (C1-C12) alkyl, aralkyi, aryl or
heterocyclic.
In yet another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is hydrogen or unsubstituted (Ci-Ci 2)-alkyl; and
n is 0 or 1.
In a further aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is hydroxy or (Ci-Ci 2)-alkoxy;
R3 is (Ci-Ci2)-alkyl; and
n is O;
wherein,
(Ci-Ci 2)-alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,
sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl,
2-hexyl, 3-hexyl, n-heptyl, n-octyl and n-nonyl.
In another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is (C3-Ci 2)-cycloalkyl; and
n is 0 or 1;
wherein,
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclic;
(C3-Ci 2)-cycloalkyl is unsubstituted or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclic;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclic;
heterocyclic is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclic.
In yet another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is unsubstituted (C3-Ci 2)-cycloalkyl; and
n is 0 or 1.
In another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is aryl; and
n is 0 or 1;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclic;
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclic;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclic;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclic;
heterocyclic is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb; and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclic.
In yet another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is phenyl; and
n is 1.
In a further aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is heterocyclic; and
n is 0 or 1;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclic;
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclic;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclic;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclic;
heterocyclic is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (Cerci 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR arc; and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclic.
In another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is heterocyclic; and
n is 1;
wherein,
heterocyclic is unsubstituted or substituted with one or more groups selected from
halogen, (CrCi 2)-alkyl, unsubstituted or substituted aralkyi, COORa, NRaRb and (C
C 2)-alkyl-NR aRb; and
Ra and R are independently selected from hydrogen, (C1-C12) alkyl, aralkyi, aryl or
heterocyclic.
In yet another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or unsubstituted (CrCi 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is piperidine or pyridine; and
n is 0 or 1;
wherein,
piperidine is unsubstituted or substituted with one or more groups selected from
halogen, (Cerci 2)-alkyl, unsubstituted or substituted aralkyi, COORa, NRaRb and (C
C 2)-alkyl-NR aRb; and
Ra and R are independently selected from hydrogen, (C1-C12) alkyl, aralkyi, aryl or
heterocyclic.
In a further aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH-S02-(C C 2)-alkyl, NH-S0 2-aryl or NRaR ; wherein Ra
and R are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyi, aryl or
heterocyclyl;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyi, aryl or
heterocyclyl; and
n is an integer from 0-3;
wherein,
(Ci-Ci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
(C3-Ci 2)-cycloalkyl is unsubstitued or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (C
C 2)-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)Ra,SRa, NRaRb and C(0)NRaRb;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclyl.
In another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH2, NH-S02-(C C 2)-alkyl, NH-S02-aryl or NRaR ;
wherein Ra and R are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyl,
aryl or heterocyclyl;
R3 is hydrogen or (Ci-Ci 2)-alkyl; and
n is 0 or 1;
wherein,
(Ci-Ci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (Ci-Ci 2)-alkyl-NR aR ; and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclyl.
In yet another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH2, NH-S02-(C C 2)-alkyl, NH-S02-aryl or NRaRb;
wherein Ra and Rb are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyl,
aryl or heterocyclyl;
R3 is hydrogen or unsubstituted (Ci-Ci 2)-alkyl; and
n is Oor l .
In a further aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH2, NH-S02-(C Ci 2)-alkyl, NH-S02-aryl or NRaRb;
wherein Ra and R are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyl,
aryl or heterocyclyl;
R3 is aryl; and
n is 0 or 1;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclyl.
In another aspect, the present invention provides compounds of formula 1;
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH2, NH-S02-(C C 2)-alkyl, NH-S02-aryl or NRaRb;
wherein Ra and R are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyl,
aryl, heterocyclyl, S0 2-alkyl or S0 2-aryl;
R3 is heterocyclyl; and
n is 0 or 1;
wherein,
(Ci-Ci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)R a, NRaRb and (Ci-Ci 2)-alkyl-NR aR ; and
Ra and R are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclyl.
Examples of compounds according to the present invention are listed below:
4-[2-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-ethyl-[1 ,2,4]oxadiazole;
4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-propyl-[1 ,2,4]oxadiazole;
4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-Benzyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-3-propyl-[1 ,2,4]oxadiazole;
2-Methoxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenylamine;
N-{2-Methoxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide;
N-{2-Hydroxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide;
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
3-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-5-propyl-[1 ,2,4] oxadiazole;
2-Amino-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidine-1 -
carboxylic acid tert-butyl ester;
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidine;
4-[2-(3-Piperidin-4-ylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-1 -isopropylpiperidine;
4-{2-[3-(1 -lsopropyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-benzene-1 ,2-
diol;
[2-(4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidin-1 -yl)-
ethyl]-dimethyl-amine;
4-(2-{3-[1 -(2-Dimethylamino-ethyl)-piperidin-4-ylmethyl]-[1 ,2,4]oxadiazol-5-yl}-vinyl)-
benzene-1 ,2-diol;
1-Benzyl-4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-
piperidine;
4-{2-[3-(1 -Benzyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-nonyl-[1 ,2,4]oxadiazole;
4-[2-(3-Nonyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2- diol;
3-Cyclopropyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Cyclopropyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-pentyl-[1 ,2,4]oxadiazole;
4-[2-(3-Pentyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-hexyl-[1 ,2,4]oxadiazole;
4-[2-(3-Hexyl-[1 ,2,4]oxadizol-vinyl]-benzyldiol;
3-Cyclohexylmethyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Cyclohexylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-octyl-[1 ,2,4]oxadiazole;
4-[2-(3-Octyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-heptyl-[1 ,2,4]oxadiazole;
4-[2-(3-Heptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-yl}-pyridine;
4-[2-(3-Pyridin-3-yl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-Cycloheptyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Cycloheptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-Cyclohexyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole; and
4-[2-(3-Cyclohexyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate, pharmaceutically acceptable prodrug or pharmaceutically
acceptable polymorph thereof.
In another aspect, the invention encompasses compounds:
4-[2-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
N-{2-Hydroxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide;
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
2-Amino-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
4-[2-(3-Piperidin-4-ylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-{2-[3-(1 -lsopropyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-benzene-1 ,2-
diol;
4-(2-{3-[1 -(2-Dimethylamino-ethyl)-piperidin-4-ylmethyl]-[1 ,2,4]oxadiazol-5-yl}-vinyl)
benzene-1 ,2-diol;
4-{2-[3-(1 -Benzyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-
benzene-1 ,2-diol;
4-[2-(3-Nonyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2- diol;
4-[2-(3-Cyclopropyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Pentyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Hexyl-[1 ,2,4]oxadizol-vinyl]-benzyldiol;
4-[2-(3-Cyclohexylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Octyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Heptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Pyridin-3-yl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Cycloheptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol; and
4-[2-(3-Cyclohexyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate, pharmaceutically acceptable prodrug or pharmaceutically
acceptable polymorph thereof.
The compounds of the present invention also include all stereoisomeric and
tautomeric forms and mixtures thereof in all ratios and their pharmaceutically
acceptable salts, solvates, prodrugs and polymorphs.
According to another aspect of present invention, the compound of formula 1
can be prepared in a number of ways including using methods well known to the
person skilled in the art. Examples of methods to prepare the present compounds
are described below and illustrated in Schemes 1 to 7 but are not limited thereto. It
will be appreciated by persons skilled in the art that within certain of the processes
described herein, the order of the synthetic steps employed may be varied and will
depend inter alia on factors such as the nature of functional groups present in a
particular substrate and the protecting group strategy (if any) to be adopted. Clearly,
such factors will also influence the choice of reagent to be used in the synthetic
steps.
The reagents, reactants and intermediates used in the following processes
are either commercially available or can be prepared according to standard literature
procedures known in the art. The starting compounds and the intermediates used for
the synthesis of compounds of the present invention, are referred to numerically (2-
31).
Throughout the process description, the corresponding substituent groups in
the various formulae representing starting compounds and intermediates have the
same meanings as that for the compound of formula 1 unless stated otherwise.
The schemes of the present invention are referred to numerically ( 1 -7). The
processes used in various schemes of the present invention, are referred to with
general symbols namely 1a, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 4a, 4b, 4c, 4d, 4e,
4f, 4g, 5a, 5b, 6a, 6b, 6c, 6d, 6e, 7a, 7b and 7c.
Processes for the preparation of compounds of the present invention are set
forth in the following schemes:
Scheme 1:
Scheme 1 depicts a process for the preparation of the compounds of formula 1
(referred in Scheme 1 as compound 6 (R = R2= (CrCi 2)-alkoxy) and compound 7
(R = R2=OH) wherein n and R3 are as defined in formula 1) . Said process includes
steps 1 to 5 as described below:
6 (R =R2=alkoxy) 7 (R =R2=OH)
(Corresponds to compounds of formula 1) (Corresponds to compounds of formula 1)
Step 1
Preparation of compound of formula 3 :
Compound of formula 2 (wherein and R2 are (CrCi 2)-alkoxy) can be subjected to
Knoevenagel condensation with malonic acid (European Journal of Medicinal
Chemistry, 2002, 37, 979 - 984) to yield compound of formula 3 (Reaction 1a);
3
wherein and R2 are (CrCi 2)alkoxy.
Step 2
Preparation of compound of formula 5 :
The method of preparation of compound of formula 5 has been adapted from
Bioorganic & Medicinal Chemistry Letters, 1999, 9, 209-212.
The compound of formula 3 (obtained in Step 1) can be activated with an activating
reagent such as 1, 1 '-carbonyldiimidazole (CDI) at temperature ranging from 20 °C
to 35 °C in a suitable solvent selected from toluene, DMF and THF. Preferably DMF
or toluene is used as solvent. The activated compound of formula 3 can be reacted
with commercially available compound of formula 4 :
HO ( H2)nR3
NH2
4
wherein n and R3 are as defined in formula 1;
to obtain the corresponding compound of formula 5 (Reaction 1b);
wherein and R2 are (CrCi 2)-alkoxy; n and R3 are as defined in formula 1.
Non-commercially available amidoximes can be prepared from corresponding nitrile
derivatives (Synthesis, 2000, 8, 1148-1 159).
Step 3
Preparation of compound of formula 6 :
The compound of formula 5 (obtained in Step 2) can be dehydrated by treatment
with a reagent such as CDI in a suitable solvent selected from toluene, DMF and
THF. Preferably, toluene or DMF is used as solvent. The dehydration can be carried
out at a temperature ranging from 50 °C to 120 °C for 6 to 12 h to effect the
formation of the compound
wherein and R2 are (CrCi 2)-alkoxy; and n and R3 are as defined in formula 1.
Step 4
Preparation of compound of formula 7 :
The dealkylation of the alkoxy groups of compound of formula 6 (obtained in Step 3)
can be effected with suitable dealkylating agents. For example, demethylation of
methoxy groups may be carried out using demethylating agents selected from
suitable Lewis acids such as boron tribromide in a suitable solvent such as
dichloromethane at a temperature ranging from -78 °C to 0 °C to obtain compound of
formula 7. Alternately, anhydrous AICI3/DMS or anhydrous AICI3/EtSH in a suitable
solvent such as dichloromethane at a temperature ranging from 0 °C to 30 °C may
be used.
wherein R = R2=OH; and n and R3 are as defined in formula 1(Reaction 1d).
Preferably, the demethylating agent used is boron tribromide.
Step 5
The compounds of formula 6 and 7 (corresponding to the compounds of formula 1)
can be optionally converted to their corresponding salts.
Scheme 2 :
Scheme 2 depicts a process for the preparation of compounds of formula 1 (referred
in Scheme 2 as compound 7 wherein and n and R 3 are as defined in
formula 1). Said process includes steps 1 to 5 as described below:
1)
Step 1
Preparation of compound of formula 9 :
Commercially available compound of formula 8 (wherein and R2 are OH) can be
converted to compound of formula 9 (wherein L refers to a protected hydroxy group
such as the t-butyldimethylsilyloxy group). For example, the OH groups can be
protected by treatment with t-butyldimethylsilyl chloride (TBDMSCI) in presence of a
suitable base such as imidazole (Tetrahedron Asymmetry, 1996, 8, 2371-2379) in a
suitable solvent such as dry DMF over a period of 40-1 00 h at a temperature ranging
from 20 °C to 35 °C to give a mixture of compound of formula 9 (wherein L is tbutyldimethylsilyloxy)
and its corresponding ester with TBDMS. The mixture of
compound of formula 9 and its TBDMS ester can be dissolved in a suitable solvent
such as a mixture of THF and methanol and treated with a base such as aqueous
potassium carbonate followed by treatment with an acid such as citric acid to give
compound of formula 9 as the major product (Reaction 2a);
9
wherein L is protected hydroxy such as the t-butyldimethylsilyloxy group;
Step 2
Preparation of compound of formula 10:
The compound of formula 9 (obtained in Step 1) can be converted to acid chloride
by any suitable method well known in the art. For example, compound of formula 9
may be dissolved in a suitable solvent such as dichloromethane and treated with
oxalyl chloride in the presence of catalytic amount of DMF at a temperature range of
20 °C to 35 °C to obtain the corresponding acid chloride as compound of formula 10
(Reaction 2b);
10
wherein L is protected hydroxy such as the t-butyldimethylsilyloxy group.
Step 3
Preparation of compound of formula 11:
The compound of formula 10 (obtained in Step 2) can be dissolved in a suitable
solvent such as xylene or toluene in the presence of a suitable base such as pyridine
and treated with compound of formula 4 :
4
wherein n and R3 are as defined in formula 1;
at a temperature ranging from 120 °C to 140 °C (Jounal of Medicinal Chemistry,
2004, 47, 6662 - 6665) to obtain compound of formula 11 (Reaction 2c);
wherein L is protected hydroxy such as the t-butyldimethylsilyloxy group; and n and
R3 are as defined in formula 1. Preferably, a mixture of xylene and pyridine is used
Step 4
Preparation of compound of formula 7 :
Compound of formula 7 can be obtained from compound of formula 11 (obtained in
Step 3) by deprotection (e.g. desilylation) of the L group by reacting with any suitable
deprotecting agent. For example, t-butyldimethylsilyloxy group may be deprotected
using 1.0 M TBAF solution in THF at a temperature ranging from 20 °C to 35 °C
(Reaction 2d).
wherein and n and R3 are as defined in formula 1.
Step 5
Compound of formula 7 (corresponding to the compound of formula 1) can be
optionally converted to its corresponding salt.
Scheme 3 :
Scheme 3 depicts a process for the preparation of compounds of formula 1 (referred
in Scheme 3 as compound 7 wherein ; n and R3 are as defined in formula
1) . Said process includes steps 1 to 4 as described below:
7 (R1= R2=OH)
(corresponds to compound of formula 1)
Step 1
Preparation of compound of formula 12 :
Commercially available compound of formula 8 (wherein R and R2 are OH) which is
also known as caffeic acid can be converted to the corresponding ester of formula 12
(wherein = R2 = OH; and X is alkyl) by any suitable method. For example, the methyl
ester of formula 12 (wherein X is methyl) may be prepared by the reaction of compound
of formula 8 with methanol in presence of oxalyl chloride at a temperature ranging from
20 °C to 35 °C (Reaction 3a);
wherein ; and X is alkyl such as methyl ;
Step 2
Preparation of compound of formula 13:
Compound of formula 12 (obtained in Step 1) can be treated with suitable protecting
agent such as TBDMSCI in the presence of a suitable base such as imidazole in a
solvent such as THF or methanol, at a temperature ranging from 20 °C to 35 °C to
obtain compound of formula 13 (Reaction 3b);
13
wherein L is protected hydroxy such as the t-butyldimethylsilyloxy group and X is
alkyl such as methyl.
Step 3
Preparation of compound of formula 7 :
Compound of formula 13 (obtained in Step 2) can be treated with compound of formula
4 :
4
wherein n and R3 are as defined in formula 1;
in the presence of suitable base such as sodium hydride in a suitable solvent such as
THF at a temperature ranging from 40 °C to 80 °C for 6 to 8 h to obtain compound of
formula 7 (Reaction 3c);
wherein and n and R3 are as defined in formula 1.
Step 4
Compound of formula 7 (corresponding to the compound of formula 1) can be
optionally converted to its corresponding salt.
Scheme 4 :
Scheme 4 depicts a process for the preparation of compound of formula 1 (referred
in Scheme 4 as compound 18 (C
C 2)-alkoxy; R2=NH2) , compound 20 (Ri= (C C 2)alkoxy; R2=NHS0 2-alkyl or
NHS0 2-aryl), compound 2 1 (R = hydroxy; R2= NHS0 2-alkyl or NHS0 2-aryl), wherein
n and R3 are as defined in formula 1). Said process includes steps 1 to 8 as
described below:
S0 -aryl)
(compound(s) 18, 19, 20 and 2 1 correspond to the compound of formula 1)
Step 1
Preparation of compound of formula 15:
Compound of formula 14 (wherein is (Ci-Ci 2)alkoxy) i.e. 4-alkoxy benzaldehyde
can be converted into compound of formula 15 (wherein is (Ci-Ci 2)alkoxy, and R2
is nitro) by nitration using a suitable nitrating agent such as ammonium nitrate and
trifluoroacetic anhydride (TFAA) at a temperature ranging from 25 °C to 30 °C.
Alternately, a mixture of HN0 3 and H2SO4 may be used as the nitrating agent
(Reaction 4a);
15
wherein R is (CrCi 2)alkoxy and R2 is nitro.
Step 2
Preparation of compound of formula 16:
The compound of formula 15 (obtained in Step 1) can be subjected to Knoevenagel
condensation with malonic acid to obtain compound of formula 16 (Reaction 4b);
16
wherein R is (CrCi 2)alkoxy and R2 is nitro.
Step 3
Preparation of compound of formula 17:
Compound of formula 16 (obtained in Step 2) can be dissolved in a suitable solvent
such as DMF or THF and activated with a suitable reagent such as 1, 1 '-
carbonyldiimidazole (CDI) or 1-hydroxybenzotriazole (HOBt) at a temperature
ranging from 20 °C to 35 °C. Activated compound of formula 16 can be further
treated with compound of formula 4 :
4
wherein n and R3 are as defined in formula 1;
to obtain the corresponding o-acyl amidoximes as compound of formula 17
(Reaction 4c);
wherein - is (CrCi 2)alkoxy, R2 is nitro, and n and R3 are as defined in formula 1.
Non-commercially available amidoximes can be prepared from corresponding nitrile
derivatives.
Step 4
Preparation of compound of formula 18:
The compound of formula 17 (obtained in Step 3) can be dehydrated by treatment
with a reagent such as CDI in a suitable solvent such as DMF or THF at a
temperature ranging from 50 °C to 120 °C, for 6 to 12 h leading to the formation of
compound of formula 18 (Reaction 4d);
(Corresponds to the compound of formula 1)
wherein is (CrCi 2)alkoxy, R2 is nitro, and n and R3 are as defined in formula 1.
Step 5
Preparation of compound of formula 19:
Compound of formula 18 (obtained in Step 4) can be treated with a reducing agent
such as stannous chloride in a suitable solvent such as ethyl acetate or methanol at
a temperature ranging from 50 °C to 100 °C to obtain compound of formula 19.
Alternately, Fe/HCI may be used. Preferably, stannous chloride is used as reducing
agent (Reaction 4e);
(corresponds to the compound of formula 1)
wherein is (CrCi 2)alkoxy, R2 is NH2, and n and R3 are as defined in formula 1.
Step 6
Preparation of compound of formula 20:
The compound of formula 19 (obtained in Step 5) can be reacted with alkyl
sulphonyl chloride (for example, methyl sulphonyl chloride) or aryl sulfonyl chloride in
a solvent such as dichloromethane in presence of a suitable base such as pyridine
or triethylamine at temperature ranging from 20 °C to 40 °C (Reaction 4f), to obtain
compound of formula 20;
wherein is (CrCi 2)alkoxy, R2 is NHS0 2-alkyl or NHS0 2-aryl, and n and R3 are as
defined in formula 1. Alternately, the reaction may be carried out in pyridine, which
may be used as both, solvent and base.
Step 7
Preparation of compound of formula 2 1 :
The dealkylation of the alkoxy groups of compound of formula 20 (obtained in Step
6) can be effected with suitable dealkylating agents. For example, demethylation of
methoxy groups may be carried out using demethylating agents selected from
suitable Lewis acids such as boron tribromide in a suitable solvent such as
dichloromethane at a temperature ranging from -78 °C to 0 °C to obtain compound of
formula 2 1 (Reaction 4g). Alternately, anhydrous AICI3/DMS or anhydrous
AICb/EtSH in a suitable solvent such as dichloromethane at a temperature ranging
from 0 °C to 30 °C may be used.
(Corresponds to the compound of formula 1)
wherein R is OH, R2 is NHS0 2-alkyl or NHS0 2-aryl, and n and R3 are as defined in
formula 1.
Preferably, the demethylating agent used is boron tribromide.
Step 8
Compounds of formula 18, 19, 20 and 2 1 (corresponding to the compounds of
formula 1) can be optionally converted to their corresponding salts.
Scheme 5 :
Scheme 5 depicts a process for the preparation of compound of formula 1 (referred
in Scheme 5 as compound 18 (Ri= (CrCi 2)alkoxy; R2=N0 2) , compound 22
R2=N0 2) and compound 23 R2=NH2) wherein n and R3
are as defined in formula 1) . Said process includes steps 1-3 as described below:
(Compounds 8, 22 and 23 correspond to the compounds of formula )
Step 1
Preparation of compound of formula 22:
Compound of formula 16 (wherein is (Ci-Ci 2)alkoxy and R2 is nitro) can be
activated using reagents such as 1, 1 '-carbonyldiimidazole (CDI) or a combination of
N, N'-dicyclohexyl carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) in DMF
over a period of 40 min at temperature ranging from 20 °C to 35 °C (Synthetic
Communications, 2004, 34, 10, 1863 - 1870). The activated acid can be refluxed
with compound of formula 4 ;
HO ( H2)nR3
N
N L
wherein n and R3 are as defined in formula 1;
at a temperature ranging from 120 °C to 160 °C for 3-5 h to obtain compound of
formula 18 (Reaction 5a);
wherein is (CrCi 2)alkoxy and R2 is nitro ;
as the major product along with minor amount of dealkylated compound of formula
22;
wherein R is hydroxy and R2 is nitro ;
Step 2
Preparation of compound of formula 23:
Compound of formula 22 (obtained in Step 1) can be reduced with a suitable
reducing agent such as stannous chloride in a suitable solvent such as ethyl acetate
or methanol at a temperature ranging from 50 °C to 100 °C to obtain compound of
formula 23 (Reaction 5b);
wherein R is hydroxy and R2 is NH2.
Step 3
Compounds of formula 22 and 23 (corresponding to the compounds of formula 1)
can be optionally converted to their corresponding salts.
Scheme 6 :
Scheme 6 depicts a process for the preparation of the compound of formula 1
(referred in Scheme 6 as compound 27 (R1= R2= (CrCi 2)alkoxy), compound 28
( wherein n=1 ; R3=
; wherein * is the point of attachment and R4 is selected from H, ( -
C 2)alkyl or benzyl). Said process includes steps 1, 2, 2A-2D and 3-7 as described
below:
R4=H R4=alkyl/benzyl) R4=alkyl/benzyl)
Step 1
Preparation of compound of formula 24:
Compound of formula 3 (wherein can be converted to
compound of formula 24, which is the corresponding alkyl ester by conventional
method (Reaction 6a);
wherein For example, compound of formula 3 can be converted to the
correponding methyl ester.
Step 2
Preparation of compound of formu
boc
Step 2A
Preparation of compound of formula 25B:
Commercially available compound of formula 25A,
HCI
25A
can be treated with f-butoxycarbamate in presence of a suitable base such as
aqueous sodium hydroxide in a suitable solvent such as THF or dichloromethane at
a temperature ranging from 20 °C to 35 °C to obtain compound of formula 25B
(Reaction 6f).
25B
Step 2B
Preparation of compound of formula 25C:
Compound of formula 25B can be refluxed with a cyanomethylating reagent such as
cyanomethyl phosphonic acid diethylester in presence of a suitable base such as
anhydrous potassium carbonate in a suitable solvent such as THF at a temperature
ranging from 20 °C to 50 °C to obtain compound of formula 25C (Reaction 6g).
Step 2C
Preparation of compound of formula 25D:
Compound of formula 25C can be reduced using a suitable reducing agent such as
H2/Pd-C in a suitable solvent such as methanol at a temperature ranging from 20 °C
to 35 °C at a pressure ranging from 40-60 psi to obtain compound of formula 25D
(Reaction 6h).
Step 2D
Preparation of compound of formula 25:
Compound of formula 25D can be treated with hydroxylamine hydrochloride in
presence of a suitable base such as anhydrous potassium carbonate in a suitable
solvent such as alcohol or aqueous alcohol at a temperature ranging from 20 °C to
35 °C (Reaction 6i) to obtain compound of formula 25.
25
Step 3
Preparation of compound of formula 26:
Compound of formula 24 (obtained in Step 1) can be treated with compound of
formula 25 (obtained in Step 2C); in the presence of suitable base such as sodium
hydride in a suitable solvent such as THF (Journal of Medicinal Chemistry, 1993, 22,
3397-3408) at a temperature ranging from 20 °C to 60 °C to obtain compound of
formula 26 (Reaction 6b);
wherein and R2 are (CrCi 2)alkoxy.
Step 4
Preparation of compound of formula 27:
Compound of formula 26 (obtained in Step 3) can be deprotected with suitable
deprotecting agent such as trifluoroacetic acid in a suitable solvent such as
dichloromethane at a temperature ranging from 20 °C to 35 °C to obtain compound
of formula 27 (Reaction 6c)
wherein R and R2 are (CrCi 2)alkoxy; and
Step 5
Preparation of compound of formula 28:
Compound of formula 27 (obtained in Step 4) can be alkylated by heating with alkyl
halide or benzyl halide in presence of a suitable base such as anhydrous K2C0 3 or
sodium hydride, in a suitable solvent such as dry DMF, at a temperature ranging
from 25 °C to 100 °C to obtain compound of formula 28 (Reaction 6d);
wherein and R2 are (CrCi 2)alkoxy; and n=1 ;
, wherein R4 is selected from alkyl and benzyl.
Step 6
Preparation of compound of formula 27A or compound of formula 29:
Compound of formula 28 (obtained in Step 5) can be treated with a suitable
dealkylating agent, for example, in order to carry out demethylation of methoxy
groups, compound of formula 28 can be treated with suitable Lewis acid such as
boron tribromide in a suitable solvent such as dichloromethane at a temperature
ranging from -78 °C to 0 °C to obtain compound of formula 29 (Reaction 6e).
Alternately, anhydrous AICI3/DMS or anhydrous AICI3/EtSH in a suitable solvent such
as dichloromethane at a temperature ranging from 0 °C to 30°C may be used.
wherein R and R2 are hydroxy; and n=1 ;
R3 is , wherein R4 is selected from alkyl and benzyl.
Preferably, the demethylating agent used is boron tribromide.
Similarly, compound of formula 27 (obtained in Step 4) can be converted to
compound of formula 27A;
wherein R and R2 are hydroxy; and n=1 ;
R3 is , wherein R4 is hydrogen.
Step 7
Compounds of formula 27, 27A, 28 and 29 (corresponding to the compounds of
formula 1) can be optionally converted to their corresponding salts.
Scheme 7 :
Scheme 7 depicts a process for the preparation of compound of formula 1 (referred
in Scheme 7 as compound 27 R4 is hydrogen), compound
27A R4 is hydrogen), compound 28 R4 is
alkyl or benzyl) and compound 29 R4 is alkyl or benzyl) wherein
n=1 R3=
; wherein * is the point of attachment. ) . Said process includes steps 1, 2,
2A-2D and 3-5 as described below:
(n=1 ; R1=R2=alkoxy;
3 = * R ;
4=H/alkyl/benzyl)
R4=H/alkyl/benzyl)
(Compounds 27, 27A, 28 and 29 correspond to the compounds of formula 1)
Step 1
Preparation of compound of formula 30:
Compound of formula 3 (wherein can be converted to
compound of formula 30, which is the corresponding acid chloride of the compound
of formula 3, by using a conventional method (Reaction 7a);
wherein R and R2 are (CrCi 2)alkoxy.
Step 2
Preparation of compound of formula 3 1 :
HO-N
H N
-(CH
3 1
wherein n=1 and R3 is ; w ere n s t e po nt o attac ment an 4
selected from hydrogen, alkyl and benzyl.
Step 2A
Preparation of compound of formula 3 1A:
Commercially available compound of formula 25A;
HCl
25A
can be treated with R4-X (wherein R4 is selected from alkyl and benzyl and X is
halide) in presence of suitable base such as anhydrous potassium carbonate in a
suitable solvent such as dry DMF at a temperature ranging from 20 °C to 35 °C to
obtain compound of formula 3 1A (Reac 7d).
3 1A
Step 2B
Preparation of compound of formula 3 1B:
Compound of formula 25A or 3 1A can be refluxed with a cyanomethylating reagent
such as cyanomethyl phosphonic acid diethylester in presence of a suitable base
such as anhydrous potassium carbonate in a suitable solvent such as THF at a
temperature ranging from 20 °C to 35 °C to obtain compound of formula 3 1B
(Reaction 7e).
Step 2C
Preparation of compound of formula 3 1C:
Compound of formula 3 1B in a suitable solvent such as methanol can be treated
with suitable reducing agent such as magnesium turnings (Journal of Medicinal
Chemistry, 1999, 42, 730-741 ) at a temperature ranging from 0 °C to 10 °C to obtain
compound of formula 3 1C (Reaction 7f).
3 1C
Step 2D
Preparation of compound of formula 3 1 :
Compound of formula 3 1C can be treated with hydroxylamine hydrochloride in
presence of a suitable base such as anhydrous potassium carbonate in a suitable
solvent such as alcohol or aqueous alcohol at a temperature ranging from 20 °C to
35 °C (Reaction 7g) to obtain compound of formula 3 1 ;
HO-N
^(CH )nR3 H N
3 1
N
wherein n=1 and R 3 is ' ; wherein * is the point of attachment and R4 is
selected from hydrogen, (CrCi 2)alkyl and benzyl.
Step 3
Preparation of compound of formula 27 or compound of formula 28:
Compound of formula 30 (obtained in Step 1) can be treated with compound of
formula 3 1(obtained in Step 2D) in a suitable solvent such as xylene or toluene in
presence of a suitable base such as pyridine at a temperature ranging from 120 °C
to 140 °C to obtain compound of formula 27 or compound of formula 28 (Reaction
7b);
wherein - and R2 are (CrCi 2)alkoxy; n=1 ;
R3 is , wherein in compound 27, R4 is hydrogen and in compound 28, R4
is selected from alkyl and benzyl.
Alternatively, base such as sodium acetate in a suitable solvent such as aqueous
ethanol may be used.
Step 4
Preparation of compound of formula 27A or compound of formula 29:
Compound of formula 27 (obtained in Step 3) can be treated with a suitable
dealkylating agent, for example, in order to carry out demethylation of methoxy
groups, compound of formula 27 can be treated with suitable Lewis acid such as
boron tribromide in a suitable solvent such as dichloromethane at a temperature
ranging from -78 °C to 0 °C to obtain compound of formula 27A (Reaction 7c).
Alternately, anhydrous AICI3/DMS or anhydrous AICI3/EtSH in a suitable solvent such
as dichloromethane at a temperature ranging from 0 °C to 30 °C may be used.
wherein R and R2 are hydroxy; n=1 ; and
R3 is , wherein R4 is hydrogen.
Similarly, compound of formula 28 can be converted to compound of formula 29
(Reaction 7c);
wherein R and R2 are hydroxy; n=1 ; and
R3 is , wherein R4 is selected from alkyl and benzyl.
Preferably, the demethylating agent used is boron tribromide.
Step 5
Compounds of formula 27, 27A, 28 and 29 (corresponding to the compounds of
formula 1) can be optionally converted to their corresponding salts.
The present invention also includes within its scope all isotopically labeled
forms of compounds of formula 1, wherein one or more atoms of compounds of
formula 1 are replaced by their respective isotopes. Examples of isotopes that may
be incorporated into the compounds disclosed herein include, but are not limited to,
isotopes of hydrogen such as H and H, carbon such as 1 1C, 1 C and 14C, nitrogen
such as 1 N and 15N, oxygen such as 150 , 170 and 1 0 , chlorine such as 6CI, fluorine
such as 1 F and sulphur such as 5S.
Substitution with heavier isotopes, for example, replacing one or more key
carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic
advantages, for example, longer metabolism cycles, improved safety or greater
effectiveness.
Isotopically labeled forms of compounds of formula 1, can be prepared by
conventional techniques known to those skilled in the art or by processes analogous
to those described above and in the subsequent section on examples by using an
appropriate isotopically labeled reagent instead of non-labeled reagent.
The compounds of the present invention can also be utilized in the form of
their pharmaceutically acceptable salts or solvates thereof. The pharmaceutically
acceptable salts of the compounds of the present invention are in particular salts,
which can be used physiologically.
The term "pharmaceutically acceptable salts" is meant to include salts of the
active compounds which are prepared with acids or bases, depending on the
particular substituents found on the compounds described herein. When compounds
of the present invention contain relatively acidic functionalities, base addition salts
can be obtained by contacting the compounds with a sufficient amount of the desired
base, either neat or in a suitable inert solvent. Examples of pharmaceutically
acceptable base addition salts include sodium, potassium, calcium, magnesium,
ammonium or organic base salt, or a similar salt. Examples of pharmaceutically
acceptable organic base addition salts include those derived from organic bases like
lysine, arginine, guanidine, diethanolamine and the like.
When compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting the compounds with
a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
Examples of pharmaceutically acceptable acid addition salts include those derived
from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric, sulfuric, monohydrogensulfuric or hydriodic acids and the
like, as well as the salts derived from organic acids like acetic, propionic, isobutyric,
oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or
galacturonic acids and the like. Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the compounds to be
converted into either base or acid addition salts.
The compounds may be regenerated by contacting the salt with a base or
acid and isolating the parent compound in the conventional manner. The compound
differs from the various salt forms in certain physical properties. An example of
physical properties that may differ is solubility in polar solvents.
Certain compounds of the present invention can exist in unsolvated forms as
well as solvated forms, including hydrated forms. Certain compounds of the present
invention may exist in multiple crystalline or amorphous forms. In general, all
physical forms are suitable for the uses contemplated by the present invention and
are intended to be within the scope of the present invention.
Various polymorphs of compounds of formula 1 can be prepared by
crystallization of the compounds under different conditions. The different conditions
are, for example, using different solvents or their mixtures for crystallization;
crystallization at different temperatures; various modes of cooling, ranging from very
fast to very slow cooling during crystallizations. Polymorphs can also be obtained by
heating or melting the compound followed by gradual or fast cooling. The presence
of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR
(Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry,
powder X-ray diffraction or such other techniques.
Those skilled in the art will recognize that stereocentres exist in compounds of
formula 1. Accordingly, the present invention includes all possible stereoisomers and
geometric isomers of formula 1 and includes not only racemic compounds but also
the optically active isomers as well. When a compound of formula 1 is desired as a
single enantiomer, it may be obtained either by resolution of the final product or by
stereospecific synthesis from either isomerically pure starting material or any
convenient intermediate. Resolution of the final product, an intermediate or a starting
material may be effected by any suitable method known in the art for example Chiral
reagents for Asymmetric Synthesis by Leo A. Paquette; John Wiley & Sons Ltd
(2003).
Additionally, in situations wherein tautomers of the compounds of formula 1
are possible, the present invention is intended to include all tautomeric forms of the
compounds.
The present invention also envisages prodrugs of the compound of formula
1. Prodrug derivatives of any compound of the invention are derivatives of said
compounds which following administration release the parent compound in vivo via
some chemical or physiological process, e.g., a prodrug on being brought to the
physiological pH or through enzyme action is converted to the parent compound.
The preferable prodrugs are those that are converted intracellularly, more preferably
where the cellular converting location is the site of therapeutic action. For instance,
preferred produgs are pharmaceutically acceptable ester derivatives convertible by
solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower
alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted
lower alkyl esters such as the pivaloyloxymethyl ester and the like
conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L.
Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges
and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald
T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley)
The present invention furthermore relates to pharmaceutical compositions
that contain an effective amount of at least one compound of formula 1 or its
physiologically tolerable salt in addition to a customary pharmaceutically acceptable
carrier, and to a process for the production of a pharmaceutical compositions, which
includes bringing at least one compound of formula 1, into a suitable administration
form using a pharmaceutically suitable and physiologically tolerable excipient and, if
appropriate, further suitable active compounds, additives or auxiliaries.
As used herein, the term "pharmaceutically acceptable carrier" refers to a
material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating
material or formulation auxiliary of any type which is compatible with a subject,
preferably a mammal, more preferably a human, and is suitable for delivering an
active agent to the target site without terminating the activity of the agent.
The present invention also envisages the use of a compound of formula 1 or a
pharmaceutically acceptable salt of the compound in combination with other
pharmaceutically active compounds. For instance, a pharmaceutical composition
including a compound of formula 1 or a pharmaceutically acceptable salt can be
administered to a mammal, in particular a human, with any other anti-cancer
compound, for instance, with first and second generation Bcr-Abl inhibitors such as
imatinib and dasatinib, in mixtures with one another or in the form of pharmaceutical
preparations.
The term, "therapeutically effective amount" as used herein means an amount
of compound or composition comprising compound of formula 1, effective in
producing the desired therapeutic response in a particular patient suffering from
cancer. The therapeutically effective amount of the compound or composition will
vary with the particular condition being treated, the age and physical condition of the
end user, the severity of the condition being treated, the duration of the treatment,
the nature of concurrent therapy, the specific compound or composition employed,
the particular pharmaceutically acceptable carrier utilized, and like factors.
The term "subject" as used herein refers to an animal, preferably a mammal,
and most preferably a human.
The term "mammal" used herein refers to warm-blooded vertebrate animals of
the class Mammalia, including humans, characterized by a covering of hair on the
skin and, in the female, milk-producing mammary glands for nourishing the young.
The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey,
deer, mouse, pig as well as human.
As used herein, the terms "treatment" "treat" and "therapy" and the like refer
to alleviate, slow the progression, attenuation or cure of existing disease or condition
(e.g., cancer). Treatment also includes treating the symptoms of the disease or
condition.
Representative cancer that can be treated by the compounds of the present
invention are selected from, but not limited to bladder cancer, breast cancer,
colorectal cancer, endometrial cancer, head and neck cancer, lung cancer,
lymphoma, melanoma, non-small-cell lung cancer, ovarian cancer, prostate cancer,
testicular cancer, renal cancer, uterine cancer, cervical cancer, thyroid cancer,
gastric cancer, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma,
glioblastoma, ependymoma, Ewing's sarcoma family of tumors, germ cell tumor,
extracranial cancer, Hodgkin's disease, leukemia, acute lymphoblastic leukemia,
acute myeloid leukemia, liver cancer, medulloblastoma, neuroblastoma, brain
tumors, non-Hodgkin's lymphoma, osteosarcoma, malignant fibrous histiocytoma of
bone, retinoblastoma, rhabdomyosarcoma, soft tissue sarcomas, supratentorial
primitive neuroectodermal and pineal tumors, visual pathway and hypothalamic
glioma, Wilms' tumor, acute lymphocytic leukemia, adult acute myeloid leukemia,
adult non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myeloid
leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, multiple myeloma,
oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin
cancer and small-cell lung cancer.
In another aspect, the cancer that can be treated by the compounds of the
present invention are selected from leukemia, acute lymphoblastic leukemia, acute
myeloid leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia,
chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.
In yet another aspect, the cancer that can be treated is chronic myeloid
leukemia.
In a further aspect, the cancer that can be treated by the compounds of the
present invention is chronic myeloid leukemia that is resistant to treatment with
imatinib mesylate.
In one aspect, the present invention provides a method of treatment of
cancer, comprising administering a therapeutically effective amount of a compound
of formula 1, to a mammal in need thereof.
In another aspect, the present invention provides a method of treatment of
cancer selected from leukemia, acute lymphoblastic leukemia, acute myeloid
leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia; comprising
administering a therapeutically effective amount of a compound of formula 1, to a
mammal in need thereof.
In yet another aspect, the present invention provides a method of treatment of
chronic myeloid leukemia; comprising administering a therapeutically effective
amount of a compound of formula 1, to a mammal in need thereof.
In a further aspect, the present invention provides a method of treatment of
chronic myeloid leukemia resistant to treatment with imatinib mesylate; comprising
administering a therapeutically effective amount of a compound of formula 1, to a
mammal in need thereof.
In another aspect, the present invention provides a method of reducing the
proliferation of cells that are resistant to treatment with imatinib mesylate; comprising
providing said cells with a therapeutically effective amount of the compound of
formula 1.
In another aspect, the present invention provides a method of reducing the
proliferation of cells that are resistant to treatment with imatinib mesylate; comprising
administering to a mammal in need thereof, a therapeutically effective amount of the
compound of formula 1.
In one aspect of the invention, the resistance of the cells to treatment with
imatinib mesylate is caused by Bcr-Abl mutation.
In another aspect of the invention, the cells resistant to imatinib mesylate are
selected from Ba/F3 Bcr-Abl/T31 5l, Ba/F3 Bcr-Abl/E255K, Ba/F3 Bcr-Abl/H396P,
Ba/F3 Bcr-Abl/M351T, Ba/F3 Bcr-Abl/F359V, Ba/F3 Bcr-Abl/E255V, Ba/F3 Bcr-
Abl/F317L, Ba/F3 Bcr-Abl/H396R, Ba/F3 Bcr-Abl/M244V, Ba/F3 Bcr-Abl/Q252H,
Ba/F3 Bcr-Abl/Y253F, and Ba/F3 Bcr-Abl/Y253H.
In another aspect, the present invention provides a method for inhibiting
TG comprising administering to a mammal in need thereof, a therapeutically
effective amount of a compound of formula 1.
In a further aspect, the present invention provides a method for reducing
proliferation of CML stem cells mediated by inhibition of ; comprising
administering to a mammal in need thereof, a therapeutically effective amount of a
compound of formula 1.
In another aspect, the present invention provides a method for reducing
proliferation of CML stem cells mediated by inhibition of ; comprising providing
said CML stem cells with a therapeutically effective amount of a compound of
formula 1.
In another aspect, the present invention provides use of a compound of
formula 1 for the treatment of cancer.
In another aspect, the present invention provides use of a compound of
formula 1 for the treatment of cancer selected from leukemia, acute lymphoblastic
leukemia, acute myeloid leukemia, acute lymphocytic leukemia, adult acute myeloid
leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell
leukemia.
In yet another aspect, the present invention provides use of a compound of
formula 1 for the treatment of chronic myeloid leukemia.
In a further aspect, the present invention provides use of a compound of
formula 1 for the treatment of chronic myeloid leukemia, that is resistant to treatment
with imatinib mesylate.
In another aspect, the present invention provides use of a compound of formula
1 for inhibition of GF .
In yet another aspect, the present invention provides use of a compound of
formula 1 for reducing proliferation of CML (chronic myeloid leukemia) stem cells
mediated by inhibition of TG .
In a further aspect, the present invention provides use of a compound of
formula 1; for the manufacture of a medicament for the treatment of cancer.
In another aspect, the present invention provides use of a compound of
formula 1; for the manufacture of a medicament for the treatment of cancer selected
from leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute
lymphocytic leukemia, adult acute myeloid leukemia, chronic lymphocytic leukemia,
chronic myeloid leukemia, and hairy cell leukemia.
In yet another aspect, the present invention provides use of a compound of
formula 1; for the manufacture of a medicament for the treatment of chronic myeloid
leukemia (CML).
In a further aspect, the present invention provides use of a compound of
formula 1; for the manufacture of a medicament for the treatment of chronic myeloid
leukemia (CML), that is resistant to treatment with imatinib mesylate.
In one aspect, the compounds of the present invention are used in a method
for reducing the population of imatinib mesylate sensitive (e.g., K-562 or Ba/F3 Bcr-
AbI/ WT) and imatinib mesylate resistant chronic myeloid leukemia (CML) cells invitro,
wherein said cells are selected from Ba/F3 Bcr-AbI/ T315I, Ba/F3 Bcr-AbI/
E255K, Ba/F3 Bcr-AbI/ M351T, Ba/F3 Bcr-AbI/ F359V, Ba/F3 Bcr-AbI/ E255V, Ba/F3
Bcr-AbI/ F31 7V, Ba/F3 Bcr-AbI/ H396R, Ba/F3 Bcr-AbI/ H396P, Ba/F3 Bcr-AbI/
M244V, Ba/F3 Bcr-AbI/ Q252H, Ba/F3 Bcr-AbI/ Y253F or Ba/F3 Bcr-AbI/ Y253H.
The in-vivo efficacy of the compounds of the present invention in imatinib
mesylate-sensitive and imatinib mesylate-resistant tumor models can be evaluated
by using cell lines such as Ba/F3 transfectants expressing full-length wild type Bcr-
AbI (Ba/F3 Bcr-AbI/ WT) or mutated Bcr-AbI (Ba/F3 Bcr-AbI/ T315I) in xenograft
models of SCID (Severely Combined Immune-Deficient) mice.
In another aspect, the treatment methods and methods for reducing cellular
proliferation described herein use the pharmaceutical compositions described above
can be administered by the following administration routes, modes, etc.
Pharmaceutical Compositions and Methods
The compositions can be administered orally, for example in the form of pills,
tablets, coated tablets, capsules, granules or elixirs. Administration, however, can
also be carried out rectally, for example in the form of suppositories, or parenterally,
for example intravenously, intramuscularly or subcutaneously, in the form of
injectable sterile solutions or suspensions, or topically, for example in the form of
ointments or creams or transdermal^, in the form of patches, or in other ways, for
example in the form of aerosols or nasal sprays.
As used herein, the term "pharmaceutically acceptable" means that the
carrier, diluent, excipients, and/or salt must be compatible with the other ingredients
of the formulation, and not deleterious to the recipient thereof.
The pharmaceutical preparations according to the invention are prepared in a
manner known and familiar to one skilled in the art. Pharmaceutically acceptable
inert inorganic and/or organic carriers and/or additives can be used in addition to the
compound(s) of formula 1, and/or its (their) physiologically tolerable salt(s). For the
production of pills, tablets, coated tablets and hard gelatin capsules it is possible to
use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia
or glucose, etc. Carriers for soft gelatin capsules and suppositories are, for example,
fats, waxes, natural or hardened oils, etc. Suitable carriers for the production of
solutions, for example injection solutions, or of emulsions or syrups are, for example,
water, physiological sodium chloride solution or alcohols, for example, ethanol,
propanol or glycerol, sugar solutions, such as glucose solutions or mannitol
solutions, or a mixture of the various solvents which have been mentioned.
The pharmaceutical preparations normally contain about 1 to 99 %, for
example, about 5 to 70 %, or from about 10 to about 30 % by weight of the
compound of the formula 1 or its physiologically tolerable salt. The amount of the
compound of the formula 1 or its physiologically tolerable salt in the pharmaceutical
preparations normally is from about 5 to 500 mg. The dose of the compounds of this
invention, which is to be administered, can cover a wide range. The dose to be
administered daily is to be selected to suit the desired effect. A suitable dosage is
about 0.01 to 100 mg/kg/day of the compound of formula 1 or their physiologically
tolerable salt, for example, about 0.1 to 50 mg/kg/day of a compound of formula 1 or
a pharmaceutically acceptable salt of the compound. If required, higher or lower daily
doses can also be administered.
The selected dosage level will depend upon a variety of factors including the
activity of the particular compound of the present invention employed, or the ester,
salt or amide thereof, the route of administration, the time of administration, the rate
of excretion of the particular compound being employed, the duration of the
treatment, other drugs, compounds and/or materials used in combination with the
particular compounds employed, the age, sex, weight, condition, general health and
prior medical history of the patient being treated, and like factors well known in the
medical arts.
In addition to the compound of the formula 1 or its physiologically acceptable
salt and carrier substances, the pharmaceutical preparations can contain additives
such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers,
flavors, preservatives, solubilizers or colorants. They can also contain two or more
compounds of formula 1 or their physiologically tolerable salts. Furthermore, in
addition to at least one compound of formula 1 or its physiologically tolerable salt,
the pharmaceutical preparations can also contain one or more other therapeutically
or prophylactically active ingredients.
It is understood that modifications that do not substantially affect the activity of
the various aspects of this invention are included. Accordingly, the following
examples are intended to illustrate but not to limit the present invention.
The following abbreviations or terms are used throughout the specification
and the appended claims:
AICb/DMS Aluminium chloride-dimethyl sulfide complex
AICI3/EtSH Aluminium chloride-ethanethiol complex
CD3OD Deuteriated methanol
CDCI3 Deuteriated chloroform
CDI 1, 1 '-Carbonyldiimidazole
C0 2 Carbon dioxide
°C degree Centigrade
DCC ,'-Dicyclohexyl carbodimide
DMF ,-Dimethylform amide
DMSO Dimethylsulfoxide
DMSO-de Deuteriated dimethylsulfoxide
Fe/HCI iron in hydrochloric acid
gram(s)
h : hour(s)
HCI : Hydrochloric acid
HN0 3 : Nitric acid
H2SO4 : Sulfuric acid
HOBt : 1-Hydroxybenzotriazole
K2C0 3 : Potassium carbonate
MeOH : Methanol
mg : milligram(s)
min: : minute(s)
mL : milliliter
- : microliter
mmol : millimole
: micromolar
NaCI : Sodium chloride
nM : nanometer
Pd/C : Palladium over activated carbon
Room temperature : 20-35 °C
TBAF : Tributyl ammonium fluoride
TBDMS-CI : Tetrabutyl dimethyl silyl chloride
THF : Tetrahydrofuran
Example 1:
4-[2-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
Step 1: Preparation of 3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic
acid methyl ester
A mixture of methyl ester of caffeic acid ( 13 g, 66.94 mmol) and imidazole (15.95 g,
23.43 mmol) was dissolved in dry DMF (70 mL) at room temperature. Tetrabutyl
dimethyl silyl chloride (TBDMS-CI) (35.31 g, 23.43 mmol) was dissolved in dry DMF
(40 mL) and added dropwise to the reaction mixture, which was stirred for about 16 -
18 h at room temperature. After completion of the reaction, approximately 200 mL of
ice water was added. The mixture was extracted with diethyl ether ( 100 mL) and the
combined organic layers were washed with water (2 x 50 mL) followed by brine (50
mL). The organic phase obtained was dried over anhydrous sodium sulphate and
concentrated to dryness. The crude product obtained was purified by crystallisation
using petroleum ether to afford the title compound.
Yield: 23.68 g (83.70 %); 1HNMR (CDCI3, 300 MHz): 7.57 (d, 1H), 7.01 (m, 2H),
6.83 (d, 1H), 6.23 (d, 1H), 3.79 (s, 3H), 0.99 (s, 9H), 0.98 (s, 9H), 0.21 (s, 6H), 0.20
(s, 6H).
Step 2 : Preparation of 4-[2-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1,2-
diol
A solution of N-hydroxy-acetamidine (0.17 g, 2.29 mmol) in dry tetrahydrofuran (5
mL) was added slowly into the suspension of 60 % sodium hydride (0.14 g, 3.5
mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at 0 °C to 10 °C. The
reaction mixture was stirred for 30 min at room temperature. 3-[3,4-Bis-(tert-butyldimethyl-
silanyloxy)-phenyl]-acrylic acid methyl ester (compound of Example 1, Step
1; 0.5 g, 1.18 mmol) in dry tetrahydrofuran (5 mL) was added into the reaction
mixture and heated at 60 °C for 8 h. The reaction mixture was cooled at 0 °C and
quenched with MeOH (2 mL) to destroy excess sodium hydride. The reaction mixture
was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were
washed with water (2 x 10 mL) followed by brine ( 10 mL). The organic phase
obtained was dried over anhydrous sodium sulphate and concentrated to dryness.
The crude product obtained was purified by column chromatography (silica gel,
chloroform - methanol) to afford the title compound.
Yield: 0.1 1 g (42.62 %); 1HNMR(CD 3OD, 300 MHz): 7.65 (d, 1H), 7.1 1 (d, 1H), 7.02
(dd, 1H), 6.83 (d, 2H), 6.80 (d, 1H), 2.36 (s, 3H).
Example 2:
4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
Method A:
Step 1 (Method a): Preparation of 3-(3,4-Dimethoxy-phenyl)-acrylic acid
3,4-Dimethoxybenzaldehyde (25 g, 0.15 mol), malonic acid (32.87 g, 0.31 mol) and
piperidine ( 1 mL) were dissolved in pyridine ( 100 mL) under stirring. The reaction
mixture was heated at 80 °C for 3 h, after which the temperature was further
increased to 120 °C and maintained at this temperature for 3 h. The reaction mixture
was cooled, diluted with water (70 mL) and pH of the solution was adjusted to 9 by
addition of 10 % aqueous sodium hydroxide solution. The mixture was extracted with
ethyl acetate (3 x 150 mL). The pH of the aqueous layer was adjusted to 2 by
addition of aqueous HCI ( 1 :1) and the resulting solid was filtered and dried to afford
the title compound.
Yield: 26 g (83.0 %); 1H NMR (DMSO-d 6, 300 MHz): 7.51 (d, 1H), 7.30 (s, 1H),
7.19 (d, 1H), 6.96 (d, 1H), 6.44 (d, 1H), 3.79 (s, 6H); MS (ES-): 207 (M-1).
Step 1 (Method b): Preparation of 3-(3,4-Dimethoxy-phenyl)-acrylic acid
To a solution of 1000 g (6.024 mol) of 3, 4-dimethoxybenzaldehyde in 3L pyridine,
1378.3 g ( 13.25 mol) of malonic acid and 100 mL of piperidine were added. The
resulting mixture was stirred at 105 °C to 110 °C for 6 - 8 h. After completion of the
reaction, the reaction mixture was cooled to 25 °C to 30 °C and slowly quenched the
reaction mixture into 10 L of 5 % sodium hydroxide solution at 25 °C to 30 °C (pH: 9-
10). The reaction mixture was washed with ethyl acetate (2 x 5 L) and the organic
layer separated was washed with 2 L of 5 % sodium hydroxide solution. The
aqueous layers were combined and cooled to 15 °C to 20 °C. The aqueous layer
was acidified slowly with 2.5 L of 50 % sulphuric acid below 20 °C (pH: 1-2). After an
additional 30 - 45 min stirring at 15 °C to 20 °C, the solid obtained was collected by
filtration, washed with 10 L of water followed by 4 L of n-hexane. The partially dried
compound was unloaded into trays and dried at 55 °C to 60 °C for 8-1 0 h to give
1110 g of the title compound.
Yield: 1110 g (88 %); 1H NMR (DMSO-d 6, 300 MHz): 7.51 (d, 1H), 7.30 (s, 1H),
7.19 (d, 1H), 6.96 (d, 1H), 6.44 (d, 1H), 3.79 (s, 6H); MS (ES-): 207 (M-1).
Step 2 : Preparation of 5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-ethyl-
[1 ,2,4]oxadiazole
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 4
g, 19.21 mmol) was dissolved in DMF (30 mL) to which 1, 1 '-Carbonyldiimidazole
(CDI) (4.04 g, 24.97 mmol) was added and the reaction mixture was stirred at room
temperature. At the end of 3 h, N-hydroxy-propionamidine (2.03 g, 23.05 mmol) was
added and the reaction mixture was stirred at room temperature for 8 h. After
completion of the reaction, additional CDI (4.04 g, 24.97 mmol) was added and the
reaction mixture was refluxed at 110 °C to120 °C for 8 h to effect cyclodehydration.
After evaporation of DMF, the residue obtained was cooled to room temperature
followed by addition of water (25 mL) and extracted with ethyl acetate (3 x 15 mL).
The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL),
dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Yield: 1.5 g (30.0 %); 1H NMR (CD3OD, 300 MHz): 7.73 (d, 1H), 7.28 (d, 1H), 7.21
(dd, 1H), 6.98 (m, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.74 (q, 2H), 1.31 (t, 3H).
Step 3 : Preparation of 4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-
diol
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-ethyl-[1 ,2,4]oxadiazole (compound of Example
2, Method A, Step 2; 0.3 g, 1. 1 5 mmol) was dissolved in dichloromethane (6 mL) and
cooled to -78 °C. A solution of boron tribromide (0.41 mL, 4.40 mmol) in
dichloromethane (4 mL), which was cooled to -50 °C, was added slowly over a
period of 30 min. After 3 h, the reaction mixture was allowed to warm to room
temperature and stirred for 12 h. After the completion of the reaction, the mixture
was quenched by dropwise addition of methanol (5 mL) at 0 °C and stirred for 30 min
at room temperature. The solvent was evaporated and the residue obtained was
redissolved in 10 % methanol in chloroform at 0 °C, and stirred with solid sodium
carbonate to obtain pH ~9. The solvent was evaporated and the crude product
obtained was purified by column chromatography (silica gel, 0.5 % methanol in
chloroform) to afford the title compound.
Yield: 0.06 g (23.0 %); MS (ES-): 231 (M-1 ) .
Method B:
Step 1: Preparation of 3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic
acid
A mixture of caffeic acid ( 100 g, 0.555 mol) and imidazole (340.09 g, 4.99mol) was
dissolved in dry DMF ( 1 L) at room temperature to which TBDMS-CI (376.48 g, 2.49
mol) was added. The reaction mixture was stirred at room temperature over a period
of 72 h. After completion of the reaction, approximately 700 mL of ice-water was
added. The mixture was extracted with diethyl ether (4 x 200 mL) and the combined
organic layers were washed with water (2 x 100 mL) followed by brine (50 mL). The
organic phase obtained was dried over anhydrous sodium sulphate and
concentrated to dryness. The crude product obtained was dissolved in methanol
(300 mL) and tetrahydrofuran (500 mL). Solid potassium carbonate was added and
the resulting mixture was stirred for 45 min at room temperature to adjust pH of the
solution obtained to ~8. The reaction mixture was cooled to 0 °C and pH was
adjusted to 6 by addition of saturated aqueous solution of citric acid. The reaction
mixture was extracted with diethyl ether (3 x 300 mL) and the combined organic
layers were washed with water (2 x 100 mL) and brine ( 1 x 50 mL). The organic
phase obtained was dried over anhydrous sodium sulphate and concentrated to
afford the title compound.
Yield: 222 g (97.86 %); 1HNMR (CDCI3, 300MHz): 7.64 (d, 1H), 7.04 (m, 2H), 6.85
(d, 1H), 6.24 (d, 1H), 1.00 (s, 9H), 0.98 (s, 9H), 0.22 (s, 6H), 0.20 (s, 6H); MS (ES+):
409 (M+1 ) .
Step 2 : Preparation of {2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-
vinyl}-3-ethyl-[1,2,4] oxadiazole
3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid (compound of Example
2, Method B, Step 1; 1 g, 2.44 mmol) was dissolved in dichloromethane ( 10 mL) and
oxalyl chloride (0.31 mL, 3.66 mmol) was added at room temperature in presence of
catalytic amount of DMF. The resulting mixture was stirred at room temperature for 3
h followed by evaporation of dichloromethane to afford the acid chloride. The crude
acid chloride and N-hydroxy-propionamidine (0.27 g, 3.17 mmol) were dissolved in
3:1 xylene / pyridine ( 15 mL: 5 mL) followed by reflux at 130 °C to 140 °C. After 4 h,
pyridine and xylene were evaporated and the resulting reaction mixture was cooled
to room temperature. The resulting mixture was extracted with ethyl acetate (10 mL)
and saturated sodium bicarbonate solution ( 10 mL). The organic phase obtained was
dried over anhydrous sodium sulphate and concentrated to obtain a crude product,
which was purified by column chromatography (silica gel, 0.5 % ethyl acetate in
petroleum ether) to afford the title compound.
Yield: 0.370 g (33.03 %); 1H NMR (CDCI3, 300 MHz): 7.66 (d, 1H), 7.06 (m, 2H),
6.84(d, 1H), 6.77 (d, 1H), 2.78 (q, 2 H), 1.36 (t, 3H), 0.99 (s, 9H), 0.98 (s, 9H), 0.227
(s, 6H), 0.220 (s, 6H); MS (ES+): 461 (M+1 ) .
Step 3 : Preparation of 4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-
diol
{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-vinyl}-3-ethyl-[1 ,2,4]oxadiazole
(compound of Example 2, Method B, Step 2; 0.35 g, 0.75 mmol) was dissolved in
THF (10 ml.) followed by addition of 1 M solution of TBAF (tetra butyl ammonium
fluoride) in THF (0.77 ml_, 2.25 mmol) at room temperature over a period of 5 min.
After stirring at room temperature for 3 h, the solvent was evaporated and the
reaction mixture was allowed to cool to room temperature. The reaction mixture was
diluted with water (5 ml.) and stirred for 10 min followed by extraction with ethyl
acetate (2 x 10 ml_). The combined organic layers were washed with water (2 x 10
ml.) and brine ( 10 ml_). The organic phase obtained was dried over anhydrous
sodium sulfate and concentrated to obtain a crude product, which was purified by
column chromatography (silica gel, 0.5 % methanol in chloroform) to afford the title
compound.
Yield: 0.030 g (17.04 %); 1H NMR (CD3OD, 300 MHz): 7.67 (d, 1H), 7.1 1 (d, 1H),
7.02 (dd, 1H), 6.83 (d, 1H), 6.80 (d, 2H), 2.74 (q, 2H), 1.32 (t, 3H); MS (ES-): 231 (M-
1) -
Example 3:
4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
Method A:
Step 1: Preparation of 5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-propyl-
[1 ,2,4]oxadiazole
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1;
3.5 g, 16.80 mmol) was dissolved in dry DMF (35 ml_). 1, 1 '-Carbonyldiimidazole
(CDI) (3.0 g, 18.48 mmol) was added and the reaction mixture was stirred at room
temperature. At the end of 3 h, N-hydroxy-butyramidine ( 1 .88 g, 18.48 mmol) was
added and the reaction mixture was stirred at room temperature for 8 h. After
completion of the reaction, additional CDI (2.99 g, 18.48 mmol) was added and the
reaction mixture was refluxed at 110 °C to 120 °C for 7 h to effect cyclodehydration.
DMF was evaporated and the residue obtained was cooled to room temperature
followed by addition of water (20 ml_). The resulting mixture was extracted with ethyl
acetate (3 x 15 ml_). The combined organic layers were washed with water (2 x 10
mL) and brine ( 10 mL). The organic phase obtained was dried over anhydrous
sodium sulfate and concentrated to afford the title compound.
Yield: 1.4 g (30.36 %); 1H NMR (CD3OD, 300 MHz): 7.74 (d, 1H), 7.29 (d, 1H), 7.22
(dd, 1H), 7.0 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.69 (t, 2H), 1.78 (m, 2H), 1.00 (t,
3H); MS (ES+): 275 (M+1 ) .
Step 2 : Preparation of 4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-
diol
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-propyl-[1 ,2,4]oxadiazole (compound of
Example 3, Method A, Step 1; 1.28 g, 4.66 mmol) was dissolved in dichloromethane
( 15 mL) and cooled to -78 °C. A solution of boron tribromide (4.42 mL, 4.66 mmol) in
dichloromethane (5 mL), which was cooled to 0 °C, was added slowly over a period
of 25 min. After 2 h, the reaction mixture was allowed to warm to room temperature
(25 °C) and stirred for 2 h. At the end of the reaction, the mixture was quenched by
dropwise addition of methanol ( 15 mL) at 0 °C and stirred for 20 min at room
temperature. The solvent was evaporated and the residue obtained was redissolved
in 10 % methanol in chloroform at 0 °C and stirred with solid sodium carbonate to
obtain pH ~ 8. The solvent was evaporated and the crude product obtained was
purified by column chromatography (silica gel, 0.5 % methanol in chloroform) to
afford the title compound.
Yield: 0.25 g (21 .92 %); 1H NMR (CD3OD, 300 MHz): 7.67 (d, 1H), 7.1 1 (d, 1H),
7.02 (dd, 1H), 6.83 (d, 1H), 6.80 (d, 1H), 2.69 (t, 2H), 1.78 (m, 2H), 0.99 (t, 3H); MS
(ES-): 245 (M-1 ) .
Method B:
Step 1: Preparation of 5-{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-
vinyl}-3-propyl-[1,2,4]oxadiazole
3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid (compound of Example
2, Method B, Step 1; 122 g, 298.51 mmol) was dissolved in dichloromethane (900
mL) followed by a catalytic amount of DMF and oxalyl chloride (38.60 mL, 447.76
mmol). The resulting mixture was stirred at room temperature for 4 h followed by
evaporation of dichloromethane to afford the acid chloride. The crude acid chloride
and N-hydroxy-butyramidine (42.68 g, 417.91 mmol) were dissolved in 2:1 toluene :
pyridine (800 mL : 400 mL) followed by heating at 110 °C to 120 °C. After heating for
about 16-18 h, pyridine and toluene were evaporated and the reaction mixture was
cooled to room temperature. The reaction mixture was diluted with water (300 mL)
and stirred for 10 min. The aqueous layer was extracted with ethyl acetate (3 x 250
mL). The combined organic layers were washed with water (2 x 10 mL) and brine ( 10
mL). The organic phase obtained was dried over anhydrous sodium sulfate and
concentrated to obtain a crude product, which was purified by column
chromatography (silica gel, 0.5 % ethyl acetate in petroleum ether) to afford the title
compound.
Yield: 38 g (26.81 %); 1H NMR (CDCI3, 300 MHz): 7.62 (d, 1H), 7.02 (m, 2H), 6.81
(d, 1H), 6.73 (d, 1H), 2.69 (t, 2H), 1.77 (m, 2H), 0.98 (t, 9H), 0.97 (s, 12H), 0.20 (s,
6H), 0.19 (s, 6H); MS (ES+): 475 (M+1 ) .
Step 2 : Preparation of 4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-
diol
5-{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-vinyl}-3-propyl-[1 ,2,4] oxadiazole
(compound of Example 3, Method B, Step 1; 38 g, 80.03 mmol) was dissolved in
THF (300 mL) followed by addition of 1 M solution of TBAF in THF ( 139 mL, 480.1 8
mmol) over a period of 10 min. After stirring at room temperature for 3 h, the solvent
was evaporated and the reaction mixture was allowed to cool to room temperature.
The reaction mixture was diluted with water ( 100 mL) and stirred for 10 min followed
by extraction with ethyl acetate (3 x 50 mL). The combined organic layers were
washed with water (2 x 50 mL) and brine (50 mL). The organic phase obtained was
dried over anhydrous sodium sulfate and concentrated to obtain a crude product,
which was purified by column chromatography (silica gel, 1.0 % methanol in
chloroform) to afford the title compound.
Yield: 9.5 g (48.22 %); 1H NMR (CD3OD, 300 MHz): 9.38 (bs, 2H), 7.62 (d, 1H),
7.12 (s, 1H), 7.07 (d, 1H), 6.91 (d, 1H), 6.77 (d, 1H), 2.64 (t, 2H), 1.68 (m, 2H), 0.91
(t, 3H); MS (ES+): 247 (M+1 ) .
Method C:
4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
A solution of N-hydroxy- butyramidine (0.24 g, 2.34 mmol) in tetrahydrofuran (5 mL)
was added slowly into the suspension of 60 % sodium hydride (0.14 g, 3.5 mmol) in
dry tetrahydrofuran (5 mL) under nitrogen atmosphere at 0 °C to 10 °C. The mixture
was stirred for 30 min at room temperature. 3-[3,4-Bis-(tert-butyl-dimethylsilanyloxy)-
phenyl]-acrylic acid methyl ester (compound of Example 1, Step 1; 0.5 g,
1.18 mmol) in dry tetrahydrofuran (5 mL) was added into the reaction mixture and
heated at 60 °C for 8 h. The reaction mixture was cooled at 0 °C and quenched with
methanol (2 mL) to destroy excess sodium hydride. The reaction mixture was
extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were
washed with water (2 x 10 mL) followed by brine ( 10 mL). The organic phase
obtained was dried over anhydrous sodium sulphate and concentrated to dryness.
The crude product obtained was purified by column chromatography (silica gel,
chloroform - methanol) to afford the title compound.
Yield: 0.12 g (41 .38 %); 1HNMR (CD3OD, 300 MHz): 7.68 (d, 1H), 7.1 1 (bs, 1H),
7.01 (d, 1H), 6.8 (m, 2H), 2.69 (t, 2H), 1.77 (q, 2H), 1.0 (t, 3H).
Example 4:
4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
Method A:
Step 1: Preparation of 3-Benzyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-
[1 ,2,4]oxadiazole
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1;
2.0 g, 9.6 mmol) was dissolved in DMF (20 mL) to which 1, 1 '-carbonyldiimidazole
(CDI) ( 1 .71 g, 10.56 mmol) was added and the reaction mixture was stirred at room
temperature. At the end of 3 h, N-hydroxy-2-phenyl-acetamidine ( 1 .58 g, 10.56
mmol) was added and the reaction mixture was stirred at room temperature for 8 h.
After the completion of the reaction, additional CDI ( 1 .71 g, 10.56 mmol) was added
and the reaction mixture was refluxed at 110 °C to 120 °C for 8 h to effect
cyclodehydration. DMF was evaporated and the residue obtained was cooled to
room temperature followed by addition of water ( 15 mL). The resulting mixture was
extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed
with water (2 x 10 mL) and brine (10 mL). The organic phase obtained was dried
over anhydrous sodium sulfate and concentrated to afford the title compound.
Yield: 1.2 g (38.83 %); 1H NMR (CD3OD, 300 MHz): 7.75 (d, 1H), 7.33 (m, 4H),
7.27 (m, 3H), 7.00 (m, 2H), 4.08 (s, 2H), 3.88 (s, 6H); MS (ES+): 345 (M+Na).
Step 2 : Preparation of 4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1,2-
diol
3-Benzyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole (compound of Example
4, Method A, Step 1; 0.180 g, 0.55 mmol) was dissolved in dichloromethane (7 mL)
and cooled to -78 °C. A solution of boron tribromide (0.41 mL, 4.40 mmol) in
dichloromethane (4 mL), which was cooled to 0 °C, was added slowly over a period
of 15 min. After 3 h, the reaction mixture was warmed to room temperature and
stirred for 3 h. After completion of the reaction, the mixture was quenched by
dropwise addition of methanol ( 15 mL) at 0 °C and stirred for 20 min at room
temperature. The solvent was evaporated and the residue obtained was redissolved
in 10 % methanol in chloroform at 0 °C, followed by stirring with solid sodium
carbonate to maintain pH ~8. The solvent was evaporated and the crude product
obtained was purified by column chromatography (silica gel, 0.5 % methanol in
chloroform) to afford the title compound.
Yield: 0.05 g (30.48 %); 1H NMR (CD3OD, 300 MHz): 7.66 (d, 1H), 7.31 (m, 4H),
7.24 (m, 1H), 7.09 (d, 1H), 7.00 (dd, 1H), 6.81 (d, 1H), 6.79 (d, 1H), 4.06 (s, 2H); MS
(ES-): 293 (M-1 ) .
Method B:
Step 1: Preparation of 3-Benzyl-5-{2-[3,4-bis-(tert-butyl-dimethyl-silanyloxy)-
phenyl]-vinyl}-[1,2,4]oxadiazole
3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid (compound of Example
2, Method B, Step 1; 17 g, 4 1.59 mmol) was dissolved in dichloromethane (150 mL)
and oxalyl chloride (5.38 mL, 62.38 mmol) was added at room temperature in
presence of catalytic amount of DMF. The resulting mixture was stirred at room
temperature for 3 h followed by evaporation of dichloromethane to afford the acid
chloride. The crude acid chloride and N-hydroxy-2-phenyl-acetamidine (7.49 g, 49.90
mmol) were dissolved in 2:1 xylene: pyridine ( 100 mL: 50 mL) followed by reflux at
130 °C to 140 °C. After heating for about 16-1 8 h, pyridine and xylene were
evaporated and the resulting mixture was cooled to room temperature. The resulting
mixture was diluted with water (50 mL) and stirred for 10 min. The aqueous layer
was extracted with ethyl acetate (3 x 35 mL). The combined organic layers were
washed with water (2 x 50 mL) and brine (50 mL). The organic phase obtained was
dried over anhydrous sodium sulfate and concentrated to obtain a crude product,
which was purified by column chromatography (silica gel, 0.5 % ethyl acetate in
petroleum ether) to afford the title compound.
Yield: 4.65 g (21 .38 %); 1H NMR (CDCI3, 300 MHz): 7.66 (d, 1H), 7.37 (m, 3H),
7.30 (m, 2H), 7.05 (m, 2H), 6.85 (d, 1H), 6.77 (d, 1H), 4.1 1 (s, 2H), 1.01 (s, 9H), 1.00
(s, 9H), 0.24 (s, 6H), 0.23 (s, 6H); MS (ES+): 523 (M+1 ) .
Step 2 : Preparation of 4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1,2-
diol
3-Benzyl-5-{2-[3,4-bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-vinyl}-[1 ,2,4]
oxadiazole (compound of Example 4, Method B, Step 1) (4.60 g, 8.79 mmol) was
dissolved in THF (30 mL) and cooled to 5 °C. This was followed by addition of 1 M
solution of TBAF in THF ( 12.72 mL, 43.95 mL) over a period of 15 min and allowed
to warm to room temperature. After 3 h stirring at room temperature, the solvent was
evaporated and the reaction mixture was allowed to cool to room temperature. The
reaction mixture was diluted with water (30 mL) and stirred for 10 min followed by
extraction with ethyl acetate (3 x 20 mL). The combined organic layers were washed
with water (2 x 10 mL) and brine (10 mL). The organic phase obtained was dried
over anhydrous sodium sulfate and concentrated to obtain a crude product, which
was purified by column chromatography (silica gel, 0.5 % methanol in chloroform) to
afford the title compound.
Yield: 1.62 g (62.79 %); 1H NMR (CD3OD, 300 MHz): 7.68 (d, 1H), 7.33 (d, 4H),
7.27 (m, 1H), 7.1 1 (d, 1H), 7.02 (dd, 1H), 6.82 (m, 2H), 4.07 (s, 2H); MS (ES-): 293
(M-1 ) .
Example 5:
4-Methoxy-3-nitro-benzaldehyde
4-Methoxy-benzaldehyde ( 1 g, 7.34 mmol) was added to a mixture of ammonium
nitrate (0.58 g, 7.34 mmol) and trifluoroacetic anhydride (3.56 mL, 25.69 mmol),
which was cooled to 0 °C. The reaction mixture was stirred at 0 °C for 15 min and
then allowed to stir at room temperature for about 7 h. Ice was added and stirred for
30 min. The solid obtained was filtered, washed with cold water (3 x 5 mL) and dried.
Yield: 1. 100 (82.70 %); 1H NMR (DMSO-d6, 300 MHz): 9.93 (s, 1H), 8.40 (d, 1H),
8.17 (dd, 1H), 7.55 (d, 1H), 4.02 (s, 3H).
Example 6:
3-(4-Methoxy-3-nitro-phenyl)-acrylic acid
4-methoxy-3-nitro-benzaldehyde (compound of Example 5; 1.05 g, 5.79 mmol) and
malonic acid ( 1 .32 g, 1.27 mmol) were dissolved in pyridine (20 mL) under stirring
and piperidine ( 1 mL) was added to the pyridine solution. The reaction mixture was
heated at 75 °C to 80 °C for 3 h, after which the temperature was further increased
to120 °C and maintained at this temperature for 6 h. At the end of the reaction,
pyridine was evaporated, followed by addition of aqueous HCI ( 1 :1) to obtain pH ~ 4.
The solid obtained was filtered, washed with cold water and dried.
Yield: 1.0 g (83.01 %); 1H NMR (DMSO-d6, 300 MHz): 12.37 (bs, 1H), 8.22 (d, 1H),
7.99 (dd, 1H), 7.57 (d, 1H), 7.37 (d, 1H), 6.54 (d, 1H), 3.94 (s, 3H); MS (ES-): 222
(M-1 ) .
Example 7:
5-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-3-propyl-[1,2,4]oxadiazole
3-(4-Methoxy-3-nitro-phenyl)-acrylic acid (compound of Example 6; 0.95 g, 4.25
mmol) was dissolved in DMF ( 15 mL) to which CDI (0.82 g, 5.1 0 mmol) was added
and the reaction mixture was stirred at room temperature. After 45 min, N-hydroxybutyramidine
(0.52 g, 5.1 0 mmol) was added. The reaction mixture was stirred at
room temperature for about 16-1 8 h. After completion of the reaction, additional CDI
(0.82 g, 5.10 mmol) was added and the reaction mixture was refluxed at 110 °C to
120 °C for 6 h to effect cyclodehydration. DMF was evaporated and the reaction
mixture was cooled to room temperature. Water (10 mL) was added to the reaction
mixture followed by extraction with ethyl acetate (2 x 10 mL). The combined organic
layers were washed with water (2 x 10 mL) and brine (10 mL). The organic phase
obtained was dried over anhydrous sodium sulfate and concentrated to obtain a
crude product, which was purified by column chromatography (silica gel, 0.25 %
ethyl acetate in petroleum ether) to afford the title compound.
Yield: 0.150 g ( 12.19 %); 1H NMR (CD3OD, 300 MHz): 8.14 (d, 1H), 7.92 (dd, 1H),
7.77 (d, 1H), 7.34 (d, 1H), 7.1 1 (d, 1H), 3.99 (s, 3H), 2.71 (t, 2H), 1.77 (m, 2H), 0.99
(t, 3H); MS (ES+): 290 (M+1 ) .
Example 8:
2-Methoxy-5-[2-(3-propyl-[1,2,4]oxadiazol-5-yl)-vinyl]-phenylamine
5-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-3-propyl-[1 ,2,4]oxadiazole (compound of
Example 7; 0.140 g, 0.48 mmol) was dissolved in ethyl acetate (10 mL) to which
stannous chloride (0.43 g, 1.93 mmol) was added and the reaction mixture was
stirred at room temperature. After 8 h, additional stannous chloride (0.32 g, 1.44
mmol) was added and the reaction mixture was stirred at room temperature for about
16-18 h. The pH of the reaction mixture was adjusted to 11 by addition of 10 %
sodium hydroxide and extracted with ethyl acetate (2 x 5 mL). The combined organic
layers were washed with water (2 x 10 mL) and brine (10 mL). The organic phase
obtained was dried over anhydrous sodium sulfate and concentrated to obtain a
crude product, which was purified by column chromatography (silica gel, 0.5 %
methanol in chloroform) to afford the title compound.
Yield: 0.1 00 g (80 %); 1H NMR (CD3OD, 300 MHz): 7.68 (d, 1H), 7.1 (d, 1H), 6.99
(dd, 1H), 6.86 (m, 2H), 3.89 (s, 3H), 2.69 (t, 2H), 1.77 (m, 2H), 1.00 (t, 3H); MS
(ES+): 260 (M+1 ) .
Example 9:
N-{2-Methoxy-5-[2-(3-propyl-[1,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-methane
sulfonamide
2-Methoxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenylamine (compound of
Example 8; 0.08 g, 3.08 mmol) was dissolved in dichloromethane (10 mL) followed
by addition of pyridine (0.047 mL, 0.60 mmol) and methanesulfonyl chloride (0.034
mL, 0.45 mmol) at room temperature. After stirring for 8 h, dichloromethane was
evaporated and the reaction mixture was cooled to room temperature. The crude
residue obtained was purified by column chromatography (silica gel, petroleum
ether) to afford the title compound.
Yield: 0.08 g (76.92 %); 1H NMR (CD3OD, 500 MHz): 9.29 (m, 2H), 9.08 (dd, 1H),
8.67 (d, 1H), 8.52 (d, 1H), 5.51 (s, 3H), 4.50 (s, 3H), 4.25 (t, 2H), 3.35 (m, 2H), 2.55
(t, 3H).
Example 10:
N-{2-Hydroxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide
N-{2-Methoxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-methane
sulfonamide (compound of Example 9; 0.08 g, 0.23 mmol) was dissolved in
dichloromethane (7 ml.) and cooled to -78 °C. A solution of boron tribromide in
dichloromethane (0.1 5 ml_, 1.61 mmol) was cooled to -78 °C and slowly added to
the reaction mixture. After 1.5 h, the reaction mixture was warmed to room
temperature and stirred for 3 h. At the end of 3 h, the mixture was quenched by
dropwise addition of methanol (5 ml.) at 0 °C and stirred for 20 min at room
temperature. The solvent was evaporated, and the residue was redissolved in a
mixture of 10 % methanol in chloroform at 0 °C. Solid sodium carbonate was added
to this solution to adjust pH to 8. The solvent was evaporated and the crude product
obtained was purified by column chromatography (silica gel, 0.5 % methanol in
chloroform) to afford the title compound.
Yield: 0.05 g (65.78 %); 1H NMR (CD3OD, 300 MHz): 7.69 (d, 1H), 7.63 (d, 1H),
7.38 (dd, 1H), 6.88 (m, 2H), 2.93 (s, 3H), 2.66 (t, 2H), 1.74 (m, 2H), 0.96 (t, 3H).
Example 11:
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol (minor)
and 3-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-5-propyl-[1,2,4] oxadiazole (major;
compound of Example 7)
3-(4-Methoxy-3-nitro-phenyl)-acrylic acid (compound of Example 6; 1 g, 4.48 mmol),
DCC ( 1 .01 g, 4.92 mmol) and HOBt (0.50 g, 4.92 mmol) were dissolved in DMF ( 15
ml.) and stirred at room temperature for 40 min. N-Hydroxy-butyramidine was added
to the reaction mixture at room temperature and the resulting slurry was stirred at
135 °C to 140 °C. After 18 h, DMF was evaporated and the reaction mixture was
cooled to room temperature. The mixture was diluted with water (7 mL) followed by
extraction with ethyl acetate (3 x 5 mL). The combined organic layers were washed
with water (2 x 10 mL) and brine (10 mL). The organic phase obtained was dried
over anhydrous sodium sulfate and concentrated to obtain a crude product, which
was purified by column chromatography (silica gel, 0.5 % ethyl acetate in petroleum
ether) to afford 3-[2-(4-methoxy-3-nitro-phenyl)-vinyl]-5-propyl-[1 ,2,4]oxadiazole
(compound of Example 7) as the major product and 2-nitro-4-[2-(5-propyl-
[ 1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol (compound of Example 11) as the minor product.
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol
Yield: 0.350 g (28.1 8 %); 1H NMR (CD3OD): 8.35 (d, 1H), 7.98 (dd, 1H), 7.80 (d,
1H), 7.21 (d, 1H), 7.1 3 (d, 1H), 2.71 (t, 2H), 1.78 (m, 2H), 1.00 (t, 3H).
3-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-5-propyl-[1,2,4]oxadiazole
Yield: 0.250 g ( 19.23 %); 1H NMR (CD3OD, 300 MHz): 8.14 (d, 1H), 7.92 (dd, 1H),
7.77 (d, 1H), 7.34 (d, 1H), 7.1 1 (d, 1H), 3.99 (s, 3H), 2.71 (t, 2H), 1.82 (m, 2H), 1.15
(t, 3H).
Example 12:
2-Amino-4-[2-(5-propyl-[1,2,4]oxadiazol-3-yl)-vinyl]-phenol
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol (compound of Example 11;
0.2 g, 0.72 mmol) was dissolved in ethyl acetate (5 mL) to which stannous chloride
was added and the reaction mixture was stirred at room temperature for 12 h. The
reaction mixture was cooled to 0 °C followed by addition of aqueous sodium
hydroxide solution to adjust pH to 10. The reaction mixture was extracted with ethyl
acetate (2 x 5 mL). The combined organic layers were washed with water (2 x 10
mL) and brine ( 10 mL). The organic phase obtained was dried over anhydrous
sodium sulfate and concentrated to obtain a crude product, which was purified by
column chromatography (silica gel, 0.5 methanol in chloroform) to afford the title
compound.
Yield: 0.1 30 g (73.86 %); 1H NMR (CD3OD, 300 MHz): 7.65 (d, 1H), 7.08 (d, 1H),
6.89 (dd, 1H), 6.81 (d, 1H), 6.72 (d, 1H), 2.68 (t, 2H), 1.78 (m, 2H), 0.99 (t, 3 H).
Example 13:
4-Oxo-piperidine-1-carboxylic acid ferf-butyl ester
Aqueous 2N sodium hydroxide (81 mL, 162.7 mmol) was added slowly at 0 °C into a
solution of 4-piperidonehydrochloride (10 g, 65 mmol) in THF (50 mL) and stirred for
15 min. f-Butoxycarbamate (17.04 g, 78 mmol) was added slowly into the reaction
mixture and stirred for 4 h. The reaction mixture was concentrated to dryness, diluted
with ethyl acetate (2 x 50 mL) and washed with water (2 x 50 mL) and brine (50 mL).
The organic phase obtained was dried over anhydrous sodium sulphate and
concentrated to afford the title compound.
Yield: 12.7 g (98.44 %); 1H NMR (CDCI3, 300 MHz): 3.68 (t, 4H), 2.40 (t, 4H), 1.45
(s, 9H); MS (ES+): 200 (M+1 ) .
Example 14:
4-Cyanomethylene-piperidine-1-carboxylic acid ferf-butyl ester
A mixture of 4-oxo-piperidine-1 -carboxylic acid ferf-butyl ester (compound of
Example 13; 13.5 g, 67 mmol), anhydrous potassium carbonate ( 1 1.22 g, 8 1 mmol)
and cyanomethyl phosphonic acid diethylester ( 15.6 g, 88 mmol) in THF (70 mL)
was heated at reflux for 12 h. THF was evaporated and the residue was dissolved in
chloroform (2 x 50 mL). The resulting solution was washed with water (2 x 50 mL)
and brine (50 mL). The organic phase obtained was dried over anhydrous sodium
sulphate and concentrated to afford the title compound.
Yield: 7.9 g (50.64 %); 1H NMR (DMSO-d 6, 300 MHz): 5.55 (s, 1H), 3.41 (t, 4H),
2.41 (t, 2H), 2.29 (t, 2H), 1.39 (s, 9H); MS (ES+): 223 (M+1).
Example 15:
4-Cyanomethyl-piperidine-1-carboxylic acid ferf-butyl ester
4-Cyanomethylene-piperidine-1 -carboxylic acid fe/t-butyl ester (compound of
Example 14; 6.9 g, 3 1 .0 mmol) and Pd/C (0.7 g) in ethanol ( 150 mL) was maintained
under hydrogen atmosphere for 8 h. The reaction mixture was filtered through Celite
and the solvent was evaporated to afford the title compound.
Yield: 6.4 g (91 .95 %); 1H NMR (MeOD, 300 MHz): 4.06 (m, 2H), 2.74 (m, 2H),
2.41 (d, 2H), 1.86 (m, 1H), 1.77 (m, 2H), 1.42 (s, 9H), 1.21 (m, 2H).
MS (ES+): 225 (M+1 ) .
Example 16:
4-(N-Hydroxycarbamimidoylmethyl)-piperidine-1 -carboxylic acid ferf-butyl
ester
4-Cyanomethyl-piperidine-1 -carboxylic acid ferf-butyl ester (compound of Example
15; 2.3 g, 10.2 mmol), anhydrous potassium carbonate (2.27 g, 16.4 mmol) and
hydroxylamine hydrochloride (2.14 g, 30.8 mmol) in ethanol: water (25 : 4 ml.) was
stirred at room temperature for 48 h. The reaction mixture was filtered, solvent
evaporated and the residue obtained was purified by column chromatography (silica
gel, 8 % ethyl acetate in petroleum ether) to afford the title compound.
Yield: 2.14 g (81 .36 %); 1H NMR (MeOD, 300 MHz): 4.04 (m, 2H), 2.73 (m, 2H),
1.99 (d, 2H), 1.77 (m, 1H), 1.67 (m, 2H), 1.44 (s, 9H), 1. 1 0 (m, 2H); MS (ES+): 258
(M+1).
Example 17:
3-(3,4-Dimethoxy-phenyl)-acrylic acid methyl ester
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2 (Step 1); 1.0 g, 4.8
mmol) was dissolved in methanol (10 ml.) in the presence of catalytic amount of
sulfuric acid. The reaction mixture was stirred at room temperature for 4 h. The
reaction mixture was cooled at 5 °C and quenched with saturated sodium carbonate
solution (2 ml_). The solid obtained was filtered and dried.
Yield: 1.0 g (93.72 %); 1HNMR (CDCI3, 300MHz): 7.65 (d, 1H), 7.23 (d, 1H), 7.18
(dd, 1H), 6.99 (d, 1H), 6.43 (d, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H); MS
(ES+): 223 (M+1 ) .
Example 18:
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine-1-
carboxylic acid tert-butyl ester
4-(N-Hydroxycarbamimidoylmethyl)-piperidine-1 -carboxylic acid ferf-butyl ester
(compound of Example 16; 5.0 g, 22.5 mmol) was added to a suspension of 60 %
sodium hydride (2.25 g, 56.3 mmol) in dry THF (25 ml.) and the reaction mixture was
stirred at 25 °C for 0.5 h. 3-(3,4-Dimethoxy-phenyl)-acrylic acid methyl ester
(compound of Example 17; 11.57 g, 45 mmol) was added into the reaction mixture
and the reaction mixture was refluxed for 12 h. The reaction mixture was quenched
with water (30 mL) and the solvent was evaporated. The residue obtained was
dissolved in chloroform (50 mL) and washed with water (2 x 30 mL). The organic
phase obtained was dried over anhydrous sodium sulfate and concentrated to afford
the title compound.
Yield: 4.9 g (53.48 %); MS (ES+): 452.2 (M+Na).
Example 19:
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine
Trifluoroacetic acid (5 mL) was added slowly into a solution of 4-{5-[2-(3,4-
dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidine-1 -carboxylic acid
tert-butyl ester (compound of Example 18; 4.5 g, 10.4 mmol) in dichloromethane (25
mL) and was stirred at 25 °C for 15 h. The solvent was evaporated and the residue
was extracted into chloroform (2 x 25 mL). The combined organic layers were
washed with saturated sodium carbonate solution (2 x 25 mL) and water ( 1 x 25 mL).
The organic phase obtained was dried over anhydrous sodium sulphate and
concentrated to afford the title compound.
Yield: 3.1 g (89.79 %); 1H NMR (CDCI3, 300MHz): 7.69 (d, 1H), 7.13 (dd, 1H), 7.06
(d, 1H), 6.86 (d, 1H), 6.80 (d, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.21 (m, 2H), 2.70 (m,
5H), 2.01 (m, 1H), 1.81 (m, 2H), 1.44 (m, 2H); MS (ES+): 330 (M+1).
Example 20:
4-[2-(3-Piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
Boron tribromide (0.43 mL, 4.55 mmol) was added dropwise to a cooled solution of
4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidine
(compound of Example 19; 0.25 g, 0.75 mmol) in dichloromethane (10 mL) at -78
°C. The reaction mixture was allowed to warm to room temperature and stirred for 6
h. The reaction mixture was quenched with methanol (5 mL) and the organic solvent
was evaporated. The residue obtained was dissolved in 8 % methanolic ammonia (5
mL) and the inorganic solid obtained was removed by filtration. The filtrate was
concentrated and purified by column chromatography (silica gel, 3 % methanol in
chloroform) to afford the title compound.
Yield: 0.050 g (21 .86 %); MS (ES+): 302 (M+1 ) .
Example 2 1 :
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-1-isopropylpiperidine
Isopropyl bromide (0.13 mL, 1.45 mmol) was added slowly into a mixture of 4-{5-[2-
(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidine (compound of
Example 19; 0.4 g, 1.21 mmol) and anhydrous potassium carbonate (0.25 g, 1.82
mmol) in dry DMF (10 mL). The reaction mixture was heated at 55 °C to 60 °C for 4
h. The reaction mixture was cooled to room temperature and ice water (5 mL) was
added into it. The solid obtained was filtered and dried.
Yield: 0.175 g (38.88 %); 1H NMR (CDCI3, 300MHz): 7.70 (d, 1H), 7.14 (dd, 1H),
7.08 (d, 1H), 6.89 (d, 1H), 6.83 (d, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.07 (m, 2H), 2.99
(m, 1H), 2.70 (d, 2H), 2.35 (m, 2H), 1.91 (m, 3H), 1.58 (m, 2H), 1.14 (d, 6H); MS
(ES+): 372 (M+1 ) .
Example 22:
4-{2-[3-(1-lsopropyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-benzene-
1,2-diol
Boron tribromide (0.229 mL, 2.42 mmol) was added dropwise to a cooled solution of
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-1 -isopropylpiperidine
(compound of Example 2 1; 0.15 g, 0.4 mmol) in dichloromethane (5 mL)
at -78 °C. The reaction mixture was warmed to room temperature and stirred for 6 h.
The reaction mixture was quenched with methanol (2 mL) and the organic solvent
was evaporated. The residue obtained was dissolved in 8 % methanolic ammonia (5
mL) and the inorganic solid obtained was removed by filtration. The filtrate was
concentrated and purified by column chromatography (silica gel, 3 % methanol in
chloroform) to afford the title compound.
Yield: 0.019 g ( 13.69 %); MS (ES+): 344 (M+1 ) .
Example 23:
[2-(4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidin-
1-yl)-ethyl]-dimethyl-amine
,-Dimethylethyl chloride (0.21 g, 1.45 mmol) was added slowly into a solution of
4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidine
(compound of Example 19; 0.4 g, 1.21 mmol) and anhydrous potassium carbonate
(0.37 g, 1.82 mmol) in dry DMF (10 mL). The mixture was heated at 55 °C to 60 °C
for 4 h. The reaction mixture was cooled to room temperature and ice water (5 mL)
was added into it. The solid obtained was filtered and dried to afford the title
compound.
Yield: 0.160 g (32.91 %); MS (ES+): 401 (M+1 ) .
Example 24:
4-(2-{3-[1-(2-Dimethylamino-ethyl)-piperidin-4-ylmethyl]-[1 ,2,4]oxadiazol-5-yl}-
vinyl)-benzene-1 ,2-diol
Boron tribromide (0.14 mL, 1.49 mmol) was added dropwise to a cooled solution of
[2-(4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-piperidin-1-yl)-
ethyl]-dimethyl-amine (compound of Example 23; 0.10 g, 0.25 mmol) in
dichloromethane (5 mL) at -78 °C. The reaction mixture was warmed to room
temperature and stirred for 6 h. The reaction mass was quenched with methanol (2
mL) and the organic solvent was evaporated. The residue obtained was dissolved in
8 % methanolic ammonia (5 mL) and the inorganic solid obtained was removed by
filtration. The filtrate was concentrated and purified by column chromatography (silica
gel, 3 % methanol in chloroform) to afford the title compound.
Yield: 0.050 g (53.78 %); 1H NMR (DMSO-d 6, 300MHz): 7.60 (d, 1H), 7.1 1 (d, 1H),
7.07 (dd, 1H), 6.91 (d, 1H), 6.75 (d, 1H), 2.84 (m, 2H), 2.58 (d, 2H), 2.35 (s, 4H),
2.14 (s, 6H), 1.95 (m, 3H), 1.69 (m, 2H), 1.41 (m, 2H); MS (ES+): 373 (M+1 ) .
Example 25:
Benzyl-piperidin-4-one
A mixture of 4-piperidone monohydrate hydrochloride (2.5 g, 14.56 mmol) and
anhydrous potassium carbonate (7 g, 50.64 mmol) in dry DMF (25 mL) was stirred
for 30 min at room temperature. Benzyl bromide (2 mL, 16.82 mmol) was added
dropwise into the reaction mixture and heated at 65 °C for 14 h. The reaction mixture
was cooled to room temperature, filtered and quenched with ice water (25 mL). The
resulting mixture was extracted in ethyl acetate (2 x 20 mL) and the combined
organic layers were washed with water (2 x 15 mL) followed by brine (20 mL). The
organic phase obtained was dried over anhydrous sodium sulphate and evaporated.
The crude product obtained was purified by crystallisation using 2 % methanol in
chloroform to afford the title compound.
Yield: 2.5 g (89.28 %); 1HNMR (CDCI3, 300MHz): 7.34 (m, 4H), 7.29 (m, 1H), 3.62
(S, 2H), 2.75 (t, 4H), 2.46 (t, 4H).
Example 26:
1-Benzylpiperidin- 4-ylideneacetonitrile
A mixture of diethyl cyanomethylphosphonate (2.06 g, 11.62 mmol) and anhydrous
potassium carbonate ( 1 .6 g, 11.62 mmol) in dry THF ( 10 mL) was stirred at room
temperature for 15 min and then refluxed for 20 min. After cooling to room
temperature, benzyl-piperidin-4-one (compound of Example 25; 2 g, 10.56 mmol)
was added and the mixture was heated at reflux for 16 h (-70 °C). The reaction
mixture was cooled to room temperature, filtered and quenched with ice water (25
mL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL) and the
combined organic layers were washed with water (2 x 15 mL) followed by brine (20
mL). The organic phase obtained was dried over anhydrous sodium sulphate and
concentrated to obtain a crude product, which was purified by crystallisation using 2
% ethyl acetate in hexane to afford the title compound.
Yield: 2.14 g (95.41 %); MS (ES+): 2 13 (M+1).
Example 27:
2-(1 -Benzylpiperidin-4-yl) acetonitrile
To a solution of benzylpiperidin- 4-ylideneacetonitrile (compound of Example 26; 1 g,
4.7 mmol) in methanol (50 mL), magnesium turnings (4.58 g, 188.3 mmol) was
added at 0 °C. The reaction mixture was stirred at 5 °C to 10 °C for 4 h. The
magnesium salts were dissolved by addition of concentrated hydrochloric acid, and
the mixture was basified with 10 N sodium hydroxide solution. The precipitate was
filtered and extracted with ethyl acetate (2 x 20 mL). The combined organic layers
were washed with water (2 x 15 mL) followed by brine ( 10 mL). The organic phase
obtained was dried over anhydrous sodium sulphate and evaporated to afford the
title compound.
Yield: 0.82 g (82 %); 1HNMR(CDCI 3, 300 MHz): 7.32 (m, 5H), 3.52 (s, 2H), 2.92
(bm, 2H , 2.30 (d, 2H , 2.0 (m, 2H), 1.80 (m, 2H), 1.69 (m, 1H), 1.43 (m, 2H).
Example 28:
2-(1-Benzyl-piperidin-4-yl)-N-hydroxy-acetamidine
Sodium metal (0.8 g, 34.78 mmol) was dissolved in dry methanol ( 10 mL) at 0-1 0°C
and this solution was added slowly into a suspension of hydroxylamine hydrochloride
(2.43 g, 34.96 mmol) in methanol ( 10 mL) at room temperature. The reaction mixture
was stirred for 10 min until a clear solution was obtained. 2-(1 -Benzylpiperidin-4-yl)
acetonitrile (compound of Example 27; 3 g, 13.99 mmol) in dry methanol (20 mL)
was added into the resulting reaction mixture and heated at 75 °C for 13 h. The
solvent was evaporated at 50 °C to 55 °C and the crude product obtained was
purified by column chromatography (silica gel, chloroform- methanol) to afford the
title compound.
Yield: 2.3 g (66.66 %); 1HNMR (CDCI3, 300 MHz,): 7.30 (d, 4H), 7.24 (m, 1H), 4.5
(s, 2H), 3.52 (s, 2H), 2.88 (d, 2H), 2.03 (d, 2H), 1.97 (t, 2H), 1.70 (d, 2H), 1.55 (m,
1H), 1.36 (m, 2H); MS (ES+): 248 (M+1 ) .
Example 29:
N-[2-(1-Benzyl-piperidin-4-yl)-1-hydroxyimino-ethyl]-3-(3,4-dimethoxy-phenyl)-
acrylamide
A solution of 3,4-dimethoxycinnamic acid (compound of Example 17; 0.484 g, 2.32
mmol) in dichloromethane (10 mL) was converted to its acid chloride using oxalyl
chloride (0.3 mL, 3.49 mmol). The organic solvent was evaporated. The resulting
acid chloride was redissolved in dry pyridine (5 mL) and 2-(1 -benzyl-piperidin-4-yl)-
N-hydroxy-acetamidine (compound of Example 28; 0.6 g, 2.55 mmol) was added to
the acid chloride solution. The reaction mixture was stirred at 25 °C for 12 h, pyridine
was evaporated and the residue was dissolved in ethyl acetate (2 X 10 mL). The
organic layer was washed with water (2 X 5 mL), dried over anhydrous sodium
sulphate and concentrated to obtain a crude product, which was purified by column
chromatography (silica gel, 2 % methanol in chloroform) to afford the title compound.
Yield: 0.120 g (21 .60 %); 1HNMR (CDCI3, 300MHz): 7.72 (d, 1H, 7.29 (m, 4H), 7.23
(m, 1H), 7.1 1 (dd, 1H), 7.04 (d, 1H), 6.86 (d, 1H), 6.38 (d, 1H), 4.70 (s, 1H), 3.90 (s,
6H), 3.48 (s, 2H), 2.87 (m, 2H), 2.21 (d, 2H), 1.95 (t, 2H), 1.74 (d, 2H), 1.64 (m, 1H),
1.37 (m, 2H); MS (ES+): 436 (M-1 ) .
Example 30:
1-Benzyl-4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-
piperidine
Sodium acetate (0.082 g, 1.005 mmol) was dissolved in water and added to a stirred
solution of N-[2-(1-benzyl-piperidin-4-yl)-1 -hydroxyimino-ethyl]-3-(3,4-dimethoxyphenyl)-
acrylamide (compound of Example 29; 0.4 g, 0.914 mmol) in ethanol (3 mL)
and water. The resulting mixture was heated at 80 °C to 85 °C for 5 h. Ethanol was
evaporated and the residue obtained was dissolved in chloroform (3 mL) and the
undissolved solid was filtered. The filtrate was evaporated to obtain a crude product,
which was purified by column chromatography (silica gel, chloroform-methanol) to
afford the title compound.
Yield: 0.06 g (15.64 %); 1HNMR (CDCI3, 300MHz): 7.72 (d, 1H), 7.30 (m, 4H), 7.23
(m, 1H), 7.12 (dd, 1H), 7.09 (d,1 H), 6.89 (d, 1H), 6.81 (d, 1H), 3.93 (s, 6H), 3.50 (s,
2H), 2.89 (m, 2H), 2.68 (d, 2H), 1.99 (t, 2H), 1.85 (m, 1H), 1.70 (m, 2H), 1.36 (m,
2H); MS (ES+): 420 (M+1 ) .
Example 3 1 :
4-{2-[3-(1 -Benzyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-benzene-1 ,2-
diol
Boron tribromide (0.056 mL, 0.595 mmol) was added drop wise to a cooled solution
of 1-benzyl-4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-
piperidine (compound of Example 30; 0.05 g, 0.12 mol) in dichloromethane (3 mL) at
-78 °C. The reaction mixture was warmed to room temperature and stirred for 6 h.
The reaction mixture was quenched with methanol (2 mL) and the organic solvent
was evaporated. The residue was suspended in methanolic ammonia (2 mL) and the
undissolved solid was filtered. The filtrate was evaporated to obtain a crude product,
which was purified by column chromatography (silica gel, 3 % methanol in
chloroform) to afford the title compound.
Yield: 0.01 5 g (32.15 %); 1HNMR (CDCI3, 300MHz): 7.67 (d, 1H), 7.46 (m, 5H),
7.22 (dd, 1H), 7.14 (d, 1H), 7.01 (m, 1H), 6.82 (d, 1H), 3.51 (m, 2H), 3.04 (m, 2H),
2.75 (m, 2H), 2.27 (t, 2H), 2.01 (m, 2H), 1.60 (m, 3H); MS (ES+): 392 (M+1).
Example 32:
N-hydroxy-decanimidamide
To a solution of 0.68 g (9.78 mmol) of hydroxylamine hydrochloride in 11 mL of
isopropyl alcohol, 1.206 g (14.3 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 1.0 g (6.52 mmol) of
decanitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After the reaction was
complete, the reaction mixture was cooled to 25 °C to 30 °C, filtered and the residue
was washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled
out completely to yield a residue which was washed with toluene to yield the title
compound.
Yield: 1. 1 g (90 %).
Example 33:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-nonyl-[1,2,4]oxadiazole
To a solution of 0.547 g (2.6 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 8 mL of toluene, 0.46 g (2.8 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thick mixture, 1 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of N-hydroxy-decanimidamide
(compound of Example 32; 1.0 g, 5.3 mmol) in 3 mL of toluene was added to the
above reaction mixture at 25 °C to 30 °C. The reaction mixture was stirred at 25 °C
to 30 °C under nitrogen for 12 - 14 h and further at 100 °C to 105 °C for 6 - 8 h. After
completion of the reaction, the mixture was cooled to 25 °C to 30 °C and quenched
with 10 mL of chilled water under stirring at 25 °C to 30 °C. The organic layer was
separated, and the aqueous layer was washed with 5 mL of toluene. The combined
organic layers was washed with 5 mL of 1N HCI solution, 5 mL of 5 % sodium
bicarbonate solution and 5 mL of 10 % sodium chloride solution. The organic layer
was distilled to yield a crude material, which was purified by column chromatography
(silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.2 g (23 %).
Example 34:
4-[2-(3-Nonyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2- diol
To a cooled solution of 0.06 mL of boron tribromide (0.6 mmol) in 2 mL
dichloromethane, 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-nonyl-[1 ,2,4]oxadiazole
(compound of Example 33; 0.1 g, 0.27 mmol) dissolved in 8 mL of dichloromethane
was added over a period of 15 - 20 min at - 45 °C to - 40 °C. The reaction mixture
was stirred at - 45 to - 40 °C for 15-20 min and allowed to attain a temperature of 25
°C to 30 °C over a period of 1h. The reaction mixture was further stirred at 25 °C to
30 °C for 4 - 5 h. After the completion of the reaction, the reaction mixture was
quenched in 20 mL of chilled 5 % sodium bicarbonate solution at a temperature
below 20 °C (pH = 8 - 9). 10 mL of ethyl acetate was added to the reaction mixture
to dissolve the solid and stirred for 10-15 min. The organic layer was separated and
the aqueous layer was washed with 10 mL of 10 % sodium chloride solution. The
organic layer was collected and distilled to obtain a crude material, which was
purified by column chromatography (silica gel, chloroform - methanol) to yield the
title compound.
Yield: 0.025 g (27 %); 1H NMR (DMSO-d 6, 300 MHz): 9.64 (s, 1H), 9.1 7 (s, 1H),
7.61 (d, 1H), 7.1 2 (s, 1H), 7.07 (d, 1H), 6.91 (d, 1H), 6.76 (d, 1H), 2.65 (t, 2H), 1.63
(m, 2H), 1.24 (m, 12H), 0.83 (t, 3H); MS (ES-): 329 (M-1).
Example 35:
N-Hydroxy-cyclopropanecarboximidamide
To a solution of 3.1 1 g (44.7 mmol) of hydroxylamine hydrochloride in 22 mL of
isopropyl alcohol, 5.50 g (65.5 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 2.0 g (29.8 mmol) of
cyclopropanecarbonitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After the
reaction was completed, the reaction mixture was cooled to 25 °C to 30 °C, filtered
and washed with 6 mL of isopropyl alcohol. The filtrate was collected and distilled out
completely to yield the title compound.
Yield: 2.1 g (70 %).
Example 36:
3-Cyclopropyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole
To a solution of 2.74 g ( 13.2 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 20 mL of toluene, 2.1 8 g (13.4 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 5 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of N-hydroxycyclopropanecarboximidamide
(compound of Example 35; 2.1 g, 26.9 mmol) in 10
mL of toluene was added to the above reaction mixture as one portion at 25 °C to 30
°C. The reaction mixture was stirred at 25 °C to 30 °C under nitrogen for 12 - 14 h,
followed by stirring at 100 °C to 105 °C for 6 - 8 h. After completion of the reaction,
the reaction mixture was cooled to 25 °C to 30 °C and quenched with 20 mL of
chilled water under stirring at 25 °C to 30 °C. The organic layer was separated, and
the aqueous layer was washed with 10 mL of toluene. The organic layers were
combined and washed with 20 mL of 1N HCI solution, 10 mL of 5 % sodium
bicarbonate solution and 10 mL of 10 % sodium chloride solution. The organic layer
was distilled completely to obtain a crude material, which was purified by column
chromatography (silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.1 g (3.6 %).
Example 37:
4-[2-(3-Cyclopropyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 0.79 mL of 1M boron tribromide (0.79 mmol) in 2 mL
dichloromethane, 0.1 g (0.34 mmol) of cyclopropyl-5-[2-(3,4-dimethoxy-phenyl)-
vinyl]-[1 ,2,4]oxadiazole (compound of Example 36) dissolved in 1 mL of
dichloromethane was added, over a period of 15 -20 min at - 40 °C to - 45 °C. The
reaction mixture was stirred at - 40 °C to - 45 °C for 30 - 45 min and allowed to attain
25 °C to 30 °C slowly, over a period of 1h. The reaction mixture was further stirred at
25 °C to 30 °C for 4 - 5 h. After the completion of the reaction, the reaction mixture
was quenched with 10 mL of chilled 5 % sodium bicarbonate solution, below 20 °C
(pH: 8 - 9). 10 mL of ethyl acetate was added to the reaction mass to dissolve the
solid and stirred for 10-1 5 min. The organic layer was separated and the aqueous
layer was washed with 10 mL of 10 % sodium chloride solution. The organic layer
was collected and distilled to obtain a crude material, which was purified by column
chromatography (silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.016 g (17.9 %); 1H NMR (DMSO-d6, 300 MHz): 9.46 (s, 2H), 7.56 (d, 1H),
7.10 (d, 1 H) 7.07 (d, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 2.08 (m, 1H), 1.04 (m, 2H), 0.89
(m, 2H); MS (ES-): 243 (M-1 ) .
Example 38:
N-hydroxy hexanimidamide
To a solution of 0.107 g ( 15.4 mmol) of hydroxylamine hydrochloride in 11 mL of
isopropyl alcohol, 1.90 g (22.64 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 1.0 g (10.2 mmol) of
hexanenitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After the reaction
period, the reaction mixtures was cooled to 25 °C to 30 °C, filtered and washed with
2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to
obtain a crude residue. The residue with chased with 5 mL of toluene, to yield the
title compound.
Yield: 1.0 g (74.6 %).
Example 39:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-pentyl-[1,2,4]oxadiazole
To a solution of 0.70 g (3.39 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 6 mL of toluene, 0.59 g (3.69 mmol) of 1,1-
carbonyldiimidazole was added in portions at 25 °C to 30 °C under an inert
atmosphere. To the thickened reaction mixture, 5 mL of toluene was added and the
resulting mixture was stirred at 25 °C to 30 °C for 60 to 90 min. A solution of Nhydroxy-
hexanimidamide (compound of Example 38; 0.9 g, 6.9 mmol) diluted with 5
mL of toluene was added to the above reaction mixture at 25 °C to 30 °C. The
reaction mass was stirred at 25 °C to 30 °C under nitrogen for 12 - 14 h, followed by
stirring at 100 °C to 105 °C for 6 - 8 h. After the completion of the reaction, the
reaction mixture was cooled to 25 °C to 30 °C and quenched with 10 mL of chilled
water under stirring at 25 °C to 30 °C. The organic layer was separated, and the
aqueous layer was washed with 5 mL of toluene. The organic layers were combined
and washed with 10 mL of 1N HCI solution, 10 mL of 5 % sodium bicarbonate
solution and 10 mL of 10 % sodium chloride solution. The organic layer was distilled
completely to obtain a crude material, which was purified by column chromatography
(silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.3 g (28.9 %).
Example 40:
4-[2-(3-Pentyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 1M boron tribromide ( 1 .52 mL, 1.5 mmol) in 2 mL
dichloromethane, 0.2 g (0.6 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-pentyl-
[ 1 ,2,4]oxadiazole (compound of Example 39) dissolved in 1 mL of dichloromethane
was added over a period of 15 -20 min at - 40 °C to - 45 °C. The reaction mixture
was stirred at - 40 to - 45 ° for 30 - 45 min and allowed to attain 25 °C to 30 °C
slowly, over a period of 1h. The reaction mixture was further stirred at 25 °C to 30 °C
for 4 - 5 h. After the completion of the reaction, the reaction mixture was quenched
with 10 mL of chilled 5 % sodium bicarbonate solution, below 20 °C (pH: 8 - 9). 10
mL of ethyl acetate was added to the reaction mixture to dissolve the solid and
stirred for 10-15 min. The organic layer was separated and the aqueous layer was
washed with 10 mL of 10 % sodium chloride solution. The organic layer was
collected and distilled to obtain a crude residue, which was purified by column
chromatography (silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.025 g (13.8 %); 1H NMR (CDCI3-d6, 300 MHz): 7.66 (d, 1H), 7.14 (s, 1H),
7.04 (m, 1H), 6.90 (d, 1H), 6.78 (d, 1H), 6.01 (s, 2H), 2.74 (t, 2H), 1.77 (m, 2H), 1.35
(m, 4H), 0.91 (t, 3H); MS (ES-): 273 (M-1 ) .
Example 4 1 :
N-hydroxy-heptanimidamide
To a solution of 0.93 g (13.4 mmol) of hydroxylamine hydrochloride in 11 mL of
isopropyl alcohol, 1.66 g (19.78 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 1.0 g (8.9 mmol) of
hexanenitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After completion of
the reaction, the reaction mixture was cooled to 25 °C to 30 °C, filtered and washed
with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely
to obtain a crude residue, which was chased with 5 mL of toluene, to yield the title
compound.
Yield: 1.0 g (77.5 %).
Example 42:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-hexyl-[1,2,4]oxadiazole
To a solution of 0.63 g (2.08 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 6 mL of toluene, 0.540 g (3.33 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 5 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of N-hydroxy-heptanimidamide
(compound of Example 4 1 ; 0.9 g, 6.2 mmol) in 5 mL of toluene was added to the
above reaction mixture at 25 °C to 30 °C. The reaction mixture was stirred at 25 °C
to 30 °C under nitrogen for 12 - 14 h, followed by stirring at 100 °C to 105 °C for 6 - 8
h. After completion of the reaction, the reaction mixture was cooled to 25 °C to 30 °C
and quenched with 10 mL of chilled water under stirring at 25 °C to 30 °C. The
organic layer was separated, and the aqueous layer was washed with 5 mL of
toluene. The organic layers were combined and washed with 10 mL of 1N HCI
solution, 10 mL of 5 % sodium bicarbonate solution and 10 mL of 10 % sodium
chloride solution. The organic layer was distilled completely to obtain a crude
residue, which was purified using column chromatography (silica gel, chloroform -
methanol) to yield the title compound.
Yield: 0.2 g (21 %)
Example 43:
4-[2-(3-Hexyl-[1,2,4]oxadizol-vinyl]-benzyldiol
To a cooled solution of 1.44 mL of 1M boron tribromide ( 1 .4 mmol) in 2 mL
dichloromethane, 0.2 g (0.6 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-hexyl-
[ 1 ,2,4]oxadiazole (compound of Example 42) dissolved in 2 mL of dichloromethane
was added over a period of 15 -20 min at - 40 °C to - 45 °C. The reaction mixture
was stirred at - 40 to - 45 °C for 30 - 45 min and allowed to attain 25 °C to 30 °C
slowly, over a period of 1h. The reaction mixture was further stirred at 25 °C to 30 °C
for 4 - 5 h. After the completion of the reaction, the reaction mixture was quenched
with 10 mL of chilled 5 % sodium bicarbonate solution, below 20 °C (pH: 8 - 9). 10
mL of ethyl acetate was added to the reaction mass to dissolve the solid and stirred
for 10-1 5 min. The organic layer was separated and the aqueous layer was washed
with 10 mL of 10 % sodium chloride solution. The organic layer was collected and
distilled to obtain a crude residue, which was purified by column chromatography
(silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.1 17 g (64 %); 1H NMR (CDCI3-d6, 300 MHz): 8.16 (s, 1H), 7.97 (s, 1H),
7.55 (d, 1H), 7.04 (d, 1H), 6.89 (m, 1H), 6.79 (d, 1H), 6.67 (d, 1H), 2.63 (t, 2H), 1.66
(m, 2H), 1.27 (m, 6H), 0.79 (t, 3H); MS (ES-): 287 (M-1).
Example 44:
2-cyclohexyl-N-hydroxyacetimidamide
To a solution of 0.846 g (8.1 mmol) of hydroxylamine hydrochloride in 11 mL of
isopropyl alcohol, 1.499 g (17.8 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 1.0 g (8.1 mmol) of 2-
cyclohexylacetonitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After
completion of the reaction, the reaction mixture was cooled to 25 °C to 30 °C, filtered
and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out
completely to obtain a crude residue. The residue was chased with 5 mL of toluene
to yield the title compound.
Yield: 0.6 g (47 %).
Example 45:
3-Cyclohexylmethyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazole
To a solution of 0.39 g ( 1 .88 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 6 mL of toluene, 0.333 g (2.00 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 5 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of 2-cyclohexyl-Nhydroxyacetimidamide
(compound of Example 44; 0.6 g, 3.8 mmol) in 5 mL of
toluene was added to the above reaction mixture at 25 °C to 30 °C. The reaction
mass was stirred at 25 °C to 30 °C under nitrogen for 12 - 14 h, followed by stirring at
100 °C to 105 °C for 6 - 8 h. After completion of the reaction, the reaction mixture
was cooled to 25 °C to 30 °C and quenched with 10 mL of chilled water under stirring
at 25 °C to 30 °C. The organic layer was separated, and the aqueous layer was
washed with 5 mL of toluene. The organic layers were combined and washed with
10 mL of 1N HCI solution, 10 mL of 5 % sodium bicarbonate solution and 10 mL of
10 % sodium chloride solution. The organic layer was distilled completely to obtain a
crude residue, which was purified by column chromatography (silica gel, chloroform
- methanol) to yield the title compound.
Yield: 0.22 g (35 %).
Example 46:
4-[2-(3-Cyclohexylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 0.14 mL of 1M boron tribromide ( 1 .5 mmol) in 2 mL
dichloromethane, 0.216 g (0.658 mmol) of 3-cyclohexylmethyl-5-[2-(3,4-dimethoxyphenyl)-
vinyl]-[1 ,2,4]oxadiazole (compound of Example 45) dissolved in 1 mL of
dichloromethane was added over a period of 15 - 20 min at - 45 °C to - 40 °C. The
reaction mixture was stirred at - 45 °C to - 40 °C for 30 - 45 min and allowed to attain
25 °C to 30 °C slowly, over a period of 1h. The reaction mixture was further stirred at
25 °C to 30 °C for 4 - 5 h. After the completion of the reaction, the reaction mixture
was quenched with 10 mL of chilled 5 % sodium bicarbonate solution, below 20 °C
(pH: 8 - 9). 10 mL of ethyl acetate was added to the reaction mass to dissolve the
solid and stirred for 10-1 5 min. The organic layer was separated and the aqueous
layer was washed with 10 mL of 10 % sodium chloride solution. The organic layer
was collected and distilled to obtain a crude residue, which was purified by column
chromatography (silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.1 0 g (50.8 %); 1H NMR (CDCI3-d6, 300 MHz): 9.38 (s, 2H), 7.62 (d, 1H),
7.12 (d, 1H), 7.08 (m, 1H), 6.92 (d, 1H), 6.77 (d, 1H), 2.55 (m, 2H), 1.64 (m, 6H),
1.17 (m, 3H), 0.97 (m, 2H); MS (ES-): 299 (M-1 ) .
Example 47:
N-hydroxynonanimidamide
To a solution of 0.74 g (10.7 mmol) of hydroxylamine hydrochloride in 11 mL of
isopropyl alcohol, 1.327 g (17.8 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 1.0 g (7.1 mmol) of
nonanenitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After the reaction
period, the reaction mixture was cooled to 25 °C to 30 °C, filtered and washed with 2
mL of isopropyl alcohol. The filtrate was collected and distilled out completely to
obtain a crude residue. The residue with chased with 5 mL of toluene below 45 °C,
under vacuum, to yield the title compound.
Yield: 1. 1 g (89.4 %).
Example 48:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-octyl-[1,2,4]oxadiazole
To a solution of 0.59 g (2.84 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 6 mL of toluene, 0.503 g (3.1 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 5 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of N-hydroxynonanimidamide
(compound of example 47; 1.0 g, 3.8 mmol) diluted with 5 mL of toluene was added
to the above reaction mixture at 25 °C to 30 °C. The reaction mixture was stirred at
25 °C to 30 °C under nitrogen for 12 - 14 h, followed by stirring at 100 °C to 105 °C
for 6 - 8 h. After completion of the reaction, the reaction mixture was cooled to 25 °C
to 30 °C and quenched with 10 mL of chilled water under stirring at 25 °C to 30 °C.
The organic layer was separated, and the aqueous layer was washed with 5 mL of
toluene. The organic layers were combined and washed with 10 mL of 1N HCI
solution, 10 mL of 5 % sodium bicarbonate solution and 10 mL of 10 % sodium
chloride solution. The organic layer was distilled to obtain a crude residue, which
was purified by column chromatography (silica gel, chloroform - methanol) to yield
the title compound.
Yield: 0.2 g (20.5 %)
Example 49:
4-[2-(3-Octyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 0.997 mL of 1M boron tribromide (0.9 mmol) in 2 mL
dichloromethane, 0.1 50 g (0.433 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-octyl-
[ 1 ,2,4]oxadiazole (compound of Example 48) dissolved in 1 mL of dichloromethane
was added over a period of 15 -20 min at - 45 °C to - 40 °C. The reaction mixture
was stirred at - 45 °C to - 40 °C for 30 - 45 min and allowed to attain 25 °C to 30 °C
slowly, over a period of 1h. The reaction mass was further stirred at 25 °C to 30 °C
for 4 - 5 h. After completion of the reaction, the reaction mixture was quenched in 10
mL of chilled 5 % sodium bicarbonate solution, below 20 °C (pH: 8 - 9). 10 mL of
ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for
10-15 min. The organic layer was separated and the aqueous layer was washed with
10 mL of 10 % sodium chloride solution. The organic layer was collected and distilled
to obtain a crude residue, which was purified by column chromatography (silica gel,
chloroform - methanol) to yield the title compound.
Yield: 0.050 g (36.6 %) 1H NMR (CDCI3-d6, 300 MHz): 7.67 (d, 1H), 7.1 7 (s, 1H),
7.03 (d, 1H), 6.89 (d, 1H), 6.78 (d, 1H), 2.74 (t, 2H), 1.28 (m, 12H), 0.86 (m, 3H); MS
(ES-): 3 15 (M-1 ) .
Example 50:
N-hydroxyoctanimidamide
To a solution of 1.66 g (23.9 mmol) of hydroxylamine hydrochloride in 11 mL of
isopropyl alcohol, 2.95 g (35.1 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 2.0 g ( 15.97 mmol) of
octanenitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After completion of
the reaction, the reaction mixture was cooled to 25 °C to 30 °C, filtered and washed
with 2 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a
crude residue. The residue was chased with 5 mL of toluene, to yield the title
compound.
Yield: 2.1 g (83 %)
Example 5 1 :
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-heptyl-[1,2,4]oxadiazole
To a solution of 1.35 gm (6.5 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 6 mL of toluene, 1.14 gm (7.0 mmol) of 1, 1 -
carbonyldiimidazole was added lot wise at 25 °C to 30 °C under inert atmosphere.
The mass becomes thick and 5 mL of toluene was added and the resulting mixture
was stirred at 25 °C to 30 °C for 60 to 90 min. A solution of Nhydroxyoctanimidamide
(compound of Example 50; 2.1 g, 13.2 mmol) in 5 mL of
toluene was added to the above reaction mixture as one lot at 25 °C to 30 °C. The
reaction mixture was stirred at 25 °C to 30 °C under nitrogen for 12 - 14 h, followed
by stirring at 100 °C to 105 °C for 6 - 8 h. After completion of the reaction, the
reaction mixture was cooled to 25 °C to 30 °C and quenched with 10 mL of chilled
water under stirring at 25 °C to 30 °C. The organic layer was separated, and the
aqueous layer was washed with 5 mL of toluene. The organic layers were combined
and washed with 10 mL of 1N HCI solution, 10 mL of 5 % sodium bicarbonate
solution and 10 mL of 10 % sodium chloride solution. The organic layer was distilled
to obtain a crude residue, which was purified by column chromatography (silica gel,
chloroform - methanol) to yield the title compound.
Yield: 0.34 g ( 15.9 %)
Example 52:
4-[2-(3-Heptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 2.09 mL of 1M boron tribromide (2.0 mmol) in 2 mL
dichloromethane, 0.300 g (0.9 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-heptyl-
[ 1 ,2,4]oxadiazole (compound of Example 5 1) dissolved in 1 mL of dichloromethane
was added over a period of 15 -20 min at - 45 °C to - 40 °C. The reaction mixture
was stirred at - 45 °C to - 40 °C for 30 - 45 min and allowed to attain a temperature of
25 °C to 30 °C slowly, over a period of 1h. The reaction mixture was further stirred at
25 °C to 30 °C for 4 - 5 h. After completion of the reaction, the reaction mixture was
quenched in 10 mL of chilled 5 % sodium bicarbonate solution, below 20 °C (pH: 8 -
9). 10 mL of ethyl acetate was added to the reaction mass to dissolve the solid and
stirred for 10-15 min. The organic layer was separated and the aqueous layer was
washed with 10 mL of 10 % sodium chloride solution. The organic layer was
collected and distilled to obtain a crude residue, which was purified by column
chromatography (silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.1 32 g (48 %); 1H NMR (DMSO-d 6, 300 MHz): 8.06 (s, 2H), 7.53 (d, 1H),
7.01 (d, 1H), 6.85 (m, 1H), 6.77 (d, 1H), 6.64 (d, 1H), 2.61 (t, 2H), 1.64 (m, 2H), 1.23
(m, 8H), 0.76 (m, 3H); MS (ES-): 301 (M-1 ) .
Example 53:
N-hydroxy-nicotinimidamide
To a solution of 5.012 g (72.1 mmol) of hydroxylamine hydrochloride in 55 mL of
isopropyl alcohol, 8.8 g (105.7 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 5.0 g (48 mmol) of 3-
cyanopyridine was added and stirred at 80 °C to 85 °C for 3 - 4 h. After completion of
the the reaction, the reaction mixture was cooled to 25 °C to 30 °C, filtered and
washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled to
obtain a crude residue, which was chased with 5 mL of toluene to yield the title
compound.
Yield: 6.0 g (91 %).
Example 54:
3-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-yl}-pyridine
To a solution of 4.35 g (20.95 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 35 mL of toluene, 3.703 g (22.8 mmol) of 1,1-
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 15 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of N-hydroxy-nicotinimidamide
(compound of Example 53; 6 g, 43.7 mmol) in 5 mL of toluene was added to the
above reaction mixture at 25 °C to 30 °C. The reaction mixture was stirred at 25 °C
to 30 °C under nitrogen for 12 - 14 h, followed by stirring at 100 °C to 105 °C for 6 - 8
h. After completion of the reaction, the reaction mixture was cooled to 25 °C to 30 °C
and quenched with 10 mL of chilled water under stirring at 25 °C to 30 °C. The
organic layer was separated, and the aqueous layer was washed with 5 mL of
toluene. The organic layers were combined and washed with 10 mL of 1N HCI
solution, 10 mL of 5 % sodium bicarbonate solution and 10 mL of 10 % sodium
chloride solution. The organic layer was distilled completely to obtain a crude
residue, which was purified by column chromatography (silica gel, chloroform -
methanol) to yield the title compound.
Yield: 1.2 g ( 13.5 %).
Example 55:
4-[2-(3-Pyridin-3-yl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 0.35 mL of 1M boron tribromide (3.7 mmol) in 2 mL
dichloromethane, 0.500 g ( 1 .6 mmol) of 3-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-
[ 1 ,2,4]oxadiazol-3-yl}-pyridine (compound of Example 54) dissolved in 5 mL of
dichloromethane was added over a period of 15 -20 min at - 45 °C to - 40 °C. The
reaction mixture was stirred at - 45 °C to - 40 °C for 30 - 45 min and allowed to attain
a temperature of 25 °C to 30 °C slowly, over a period of 1h. The reaction mixture was
further stirred at 25 °C to 30 °C for 4 - 5 h. After completion of the reaction, the
reaction mixture was quenched in 10 mL of chilled 5 % sodium bicarbonate solution,
below 20 °C ( pH: 8 - 9). 10 mL of ethyl acetate was added to the reaction mixture to
dissolve the solid and stirred for 10-1 5 min. The organic layer was separated and the
aqueous layer was washed with 10 mL of 10 % sodium chloride solution. The
organic layer was collected and distilled to obtain a crude residue, which was purified
by column chromatography (silica gel, chloroform - methanol) to yield the title
compound.
Yield: 0.20 g (44.4 %); 1H NMR (DMSO-d6, 300 MHz): 9.25 (s, 1H), 8.84 (d, 1H),
8.53 (d, 1H), 7.76 (m, 2H), 7.13 (m, 3H), 6.80 (d, 1H); MS (ES-): 280 (M-1).
Example 56:
N-cycloheptanecarboximidamide
To a solution of 1.69 g (24.3 mmol) of hydroxylamine hydrochloride in 22 mL of
isopropyl alcohol, 2.99 g (35.7 mmol) of sodium bicarbonate was added. The
resulting mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 2.0 g (16.2 mmol) of
cycloheptanecarbonitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After the
completion of the reaction, the reaction mixture was cooled to 25 °C to 30 °C, filtered
and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled to
obtain a crude residue, which was chased with 5 mL of toluene to yield the title
compound.
Yield: 2.0 g (79.3 %).
Example 57:
3-Cycloheptyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole
To a solution of 1.30 g (6.2 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 22 mL of toluene, 1.098 g (6.7 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 22 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of Ncycloheptanecarboximidamide
(compound of Example 56; 2 g, 12.8 mmol) in 5 mL of
toluene was added to the above reaction mixture at 25 °C to 30 °C. The reaction
mixture was stirred at 25 °C to 30 °C under nitrogen for 12 - 14 h, followed by stirring
at 100 °C to 105 °C for 6 - 8 h. After completion of the reaction, the reaction mixture
was cooled to 25 °C to 30 °C and quenched with 10 mL of chilled water under stirring
at 25 °C to 30 °C. The organic layer was separated, and the aqueous layer was
washed with 5 mL of toluene. The organic layers were combined and washed with
10 mL of 1N HCI solution, 10 mL of 5 % sodium bicarbonate solution and 10 mL of
10 % sodium chloride solution. The organic layer was distilled completely to obtain a
crude residue, which was purified by column chromatography (silica gel, chloroform
- methanol) to yield the title compound.
Yield: 1.5 g (72.6 %).
Example 58:
4-[2-(3-Cycloheptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol
To a cooled solution of 1 mL of 1M boron tribromide (10.5 mmol) in 2 mL
dichloromethane, 1.5 g (4.5 mmol) of 3-cycloheptyl-5-[2-(3,4-dimethoxy-phenyl)-
vinyl]-[1 ,2,4]oxadiazole (compound of Example 57) dissolved in 15 mL of
dichloromethane was added over a period of 15 -20 min at - 45 °C to - 40 °C. The
reaction mixture was stirred at - 45 °C to - 40 °C for 30 - 45 min and allowed to attain
a temperature of 25 °C to 30 °C slowly, over a period of 1h. The reaction mixture was
further stirred at 25 °C to 30 °C for 4 - 5 h. After completion of the reaction, the
reaction mixture was quenched with 10 mL of chilled 5 % sodium bicarbonate
solution, below 20 °C ( pH: 8 - 9). 10 mL of ethyl acetate was added to the reaction
mixture to dissolve the solid and stirred for 10-1 5 min. The organic layer was
separated and the aqueous layer was washed with 10 mL of 10 % sodium chloride
solution. The organic layer was collected and distilled to obtain a crude residue,
which was purified by column chromatography (silica gel, chloroform - methanol) to
yield the title compound.
Yield: 0.35 g (25.6 %); 1H NMR (CDCI3-d6, 300 MHz): 9.58 (s, 1H), 9.21 (s, 1H),
7.61 (d, 1H), 7.1 1 (d, 1H), 7.06 (m, 1H), 6.91 (d, 1H), 6.77 (d, 1H), 2.95 (m, 1H), 1.96
(m, 2H), 1.71 (m, 5H), 1.57 (m, 5H); MS (ES-): 299 (M-1).
Example 59:
N-hydroxycyclohexanecarboximidamide
To a solution of 1.9 g (27.4 mmol) of hydroxylamine hydrochloride in 22 mL of
isopropyl alcohol, 3.3 g (40.3 mmol) of sodium bicarbonate was added. The resulting
mixture was stirred at 25 °C to 30 °C for 10 - 15 min. 2.0 g ( 18.3 mmol) of
cyclohexanecarbonitrile was added and stirred at 80 °C to 85 °C for 3 - 4 h. After the
reaction period, the reaction mass was cooled to 25 °C to 30 °C, filtered and washed
with 10 mL of isopropyl alcohol. The filtrate was collected and distilled out completely
to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the
title compound.
Yield: 2.0 g (76.9 %)
Example 60:
3-Cyclohexyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole
To a solution of 1.43 g (6.9 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid
(compound of Example 2; Step 1) in 22 mL of toluene, 1.21 g (7.5 mmol) of 1, 1 -
carbonyldiimidazole was added in portions at 25 °C to 30 °C under inert atmosphere.
To the thickened mixture, 22 mL of toluene was added and the resulting mixture was
stirred at 25 °C to 30 °C for 60 to 90 min. A solution of Nhydroxycyclohexanecarboximidamide
(compound of Example 59; 2 g, 14 mmol) in 5
mL of toluene was added to the above reaction mixture at 25 °C to 30 °C. The
reaction mixture was stirred at 25 °C to 30 °C under nitrogen for 12 - 14 h, followed
by stirring at 100 °C to 105 °C for 6 - 8 h. After completion of the reaction, the
reaction mixture was cooled to 25 °C to 30 °C and quenched with 10 mL of chilled
water under stirring at 25 °C to 30 °C. The organic layer was separated, and the
aqueous layer was washed with 5 mL of toluene. The organic layers were combined
and washed with 10 mL of 1N HCI solution, 10 mL of 5 % sodium bicarbonate
solution and 10 mL of 10 % sodium chloride solution. The organic layer was distilled
completely to obtain a crude residue, which was purified by column chromatography
(silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.8 g (37.2 %)
Example 6 1 :
4-[2-(3-Cyclohexyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1,2-diol
To a cooled solution of 0.55 mL of 1M boron tribromide (5.8 mmol) in 2 mL
dichloromethane, 0.8 g (2.5 mmol) of 3-cyclohexyl-5-[2-(3,4-dimethoxy-phenyl)-
vinyl]-[1 ,2,4]oxadiazole (compound of Example 60) dissolved in 8 mL of
dichloromethane was added over a period of 15 - 20 min at - 45 °C to - 40 °C. The
reaction mixture was stirred at - 45 °C to - 40 °C for 30 - 45 min and allowed to attain
a temperature of 25 °C to 30 °C slowly, over a period of 1h. The reaction mixture was
further stirred at 25 °C to 30 °C for 4 - 5 h. After completion of the reaction, the
reaction mixture was quenched with 10 mL of chilled 5 % sodium bicarbonate
solution, below 20 °C ( pH: 8 - 9). 10 mL of ethyl acetate was added to the reaction
mixture to dissolve the solid and stirred for 10-1 5 min. The organic layer was
separated and washed with 10 mL of 10 % sodium chloride solution. The organic
layer was distilled to obtain a crude residue, which was purified by column
chromatography (silica gel, chloroform - methanol) to yield the title compound.
Yield: 0.28 g (38.8 %); 1H NMR (CDCI3-d6, 300 MHz): 9.38 (s, 2H), 7.61 (d, 1H),
7.1 1 (d, 1H), 7.06 (m, 1H), 6.91 (d, 1H), 6.77 (d, 1H), 2.75 (m, 1H), 1.92 (m, 2H), 1.7
(m, 3H), 1.49 (m, 2H), 1.33 (m, 3H); MS (ES-): 285 (M-1).
Biological evaluation:
The efficacy of the compounds of the present invention in inhibiting the
imatinib mesylate sensitive cell line K-562 and Ba/F3 Bcr-Abl/ WT and imatinib
mesylate resistant cell lines, Ba/F3 Bcr-Abl/ T31 5I, Ba/F3 Bcr-Abl/ E255K, Ba/F3
Bcr-Abl/ H396P, Ba/F3 Bcr-Abl/ M351T, Ba/F3 Bcr-Abl/ F359V, Ba/F3 Bcr-Abl/
E255V, Ba/F3 Bcr-Abl/ F317L, Ba/F3 Bcr-Abl/ H396R, Ba/F3 Bcr-Abl/ M244V, Ba/F3
Bcr-Abl/ Q252H, Ba/F3 Bcr-Abl/ Y253F and Ba/F3 Bcr-Abl/ Y253H can be
determined by number of pharmacological assays described below. The exemplified
pharmacological assays, which follow, have been carried out with imatinib mesylate,
and compounds of the present invention.
Several imatinib-resistant cell lines were procured from Dr. Brian Druker's
laboratory, Howard Hughes Medical Institute, Oregon Health and Science University
(OHSU) Cancer Institute, Portland, Oregon, USA, the details of which are provided in
the Table 1. K562 cell line was procured from ATCC, USA. These cell lines were
maintained under optimum conditions of growth as suggested by the respective
suppliers.
Table 1: Description of imatinib sensitive and imatinib resistant cell lines
The following abbreviations are used throughout the specification and/or the
appended claims :
ATCC : American Type Culture Collection
OHSU : Oregon Health and Science University, Oregon
RPMI : Roswell Park Memorial Institute
PBS : Phosphate buffered saline
PI : Propidium Iodide
+ve : Positive
TG : Transforming Growth Factor-
Example 62:
ln-vitro assay:
Cell proliferation and cytotoxicity CCK-8 assay:
The assay was carried out as in reference, Biological and Pharmaceutical Bulletin,
1996, 19, 1518.
Cell Counting Kit-8 (CCK-8) assay is a sensitive colorimetric assay for the
determination of number of viable cells in cell proliferation and cytotoxicity assays.
Cell Counting Kit-8 (CCK-8) utilizes Dojindo's highly water-soluble tetrazolium salt.
The amount of the formazan dye generated by dehydrogenases in cells is directly
proportional to the number of living cells.
Source of cell lines and compound preparation:
Imatinib mesylate was purchased from Natco Pharma, India. For the compounds of
the present invention and standard imatinib mesylate, 10 mM stock was prepared in
DMSO.
The cell lines described in Table 1 were used to test the antiproliferative activity of
the compounds of the present invention.
Method:
Cells were seeded at a density of ~ 5 x 103 per well (0.09 ml.) in a transparent 96-
well tissue culture plate (NUNC, USA) and allowed to incubate at 37 °C, 5 % C0 2
incubator for 2-6 h. Different concentrations of compounds of the present invention
were added to the wells of the culture plate in triplicate. Imatinib mesylate was used
as a standard. Plates were further incubated in an incubator at 37 °C in presence of
5 % C0 2 for 72 h. 10 of the CCK-8 solution was added to each well and plate
was incubated for 1-4 h in the incubator. The absorbance was measured at 450 nm
using a microplate reader. The percent inhibition and IC5o were calculated in
comparison with control values.
The results are provided in the following Tables 2 and 3. Anti-proliferative activity of
compounds, expressed as IC50 values in for different cell lines with imatinib
mesylate resistant mutations (Ba/F3 Bcr-Abl/ E255K, Ba/F3 Bcr-Abl/ E255V, Ba/F3
Bcr-Abl/ F31 7L, Ba/F3 Bcr-Abl/ F359V, Ba/F3 Bcr-Abl/ H396R, Ba/F3 Bcr-Abl/
H396P, Ba/F3 Bcr-Abl/ M244V, Ba/F3 Bcr-Abl/ M351T, Ba/F3 Bcr-Abl/ Q252H,
Ba/F3 Bcr-Abl/ Y253F, Ba/F3 Bcr-Abl/ Y253H and Ba/F3 Bcr-Abl/ T31 5I) are given in
Table 3.
Anti-proliferative activity of the compounds of the present invention, expressed as
IC5o values in , in imatinib mesylate sensitive (Ba/F3 Bcr-Abl/ Wild Type) and
resistant (Ba/F3 Bcr-Abl/ T315I) cell lines are represented graphically in Figure 1.
Anti-proliferative activity of compounds, expressed as IC5o values in for several
cell lines with imatinib mesylate resistant mutations (Ba/F3, T31 5 1 , E255K, E255V,
Y253F, Y253H, F31 7L and H396P) are represented graphically in Figure 2.
Table 2 : Inhibitory concentrations (IC50) for compounds of the present invention in
imatinib mesylate sensitive and resistant cell lines
+ 0-10 ;
++ 11-100 ;
+++ >100 .
Table 3 : Cytotoxic inhibitory activity of compounds of the present invention
imatinib mesylate resistant cell lines
Conclusion: It is evident from the results that compounds of the present invention
exhibited significant inhibitory activity against Bcr-AbI mutated imatinib mesylate
resistant cells.
Example 63:
Flow cytometric analysis:
Effect of the compounds of present invention in Bcr-AbI mutated imatinib
mesylate-resistant cell lines on cell cycle and apoptosis using Flow cytometry.
The assay was carried out as in reference, FEBS Letters, 2007, 581 , 7, 1329-1334.
Flow cytometry was used to study the effect of compounds of the present invention
to induce apoptosis in Bcr-abl mutated imatinib mesylate resistant cell lines. Cells
were seeded at a density of 10 X 104 cells/mL and incubated in an incubator with 3 x
IC5o concentration of compounds and vehicle control (untreated) for 48 h at 37 °C in
the presence of 5 % C0 2. The experiment was repeated with 5 x IC5o concentration
of compounds and vehicle control (untreated) for 48 h and 96 h at 37°C in the
presence of 5 % C0 2. At the end of incubation, cells were harvested by
centrifugation at 1000 rpm for 10 minutes, washed with phosphate buffered saline
(PBS) and gradually resuspended in 70 % ice-cold ethanol (to facilitate the
permeablisation of stains). Cell suspension was stored for a minimum period of 4 h
before staining with propidium iodide (PI). Fixed cells were stained with PI (80
g/mL) in presence of RNase A (50 g/mL), and read on Becton Dickinson FACS
Calibur (USA) for cell cycle analysis. The results of this study are presented in
Tables 4-6.
Table 4 : Screening of (5X IC5o; 48 h time point) in imatinib mesylate resistant
cell lines
Table 5 : Screening of (3 X IC5o; 96 h time point) in imatinib mesylate resistant
cell lines
Table 6 : Screening of (5X IC5o; 96 h time point) in imatinib mesylate resistant
cell lines
Conclusion: Induction of apoptosis by the compounds of the present invention in
imatinib mesylate-resistant cell lines is significant.
Example 64:
TGFp assay:
TGF is a prime candidate for maintaining the CML stem cells in a non-cycling state.
An upregulation or prolongation of TGF signaling by Bcr-AbI suggests that one of
the mechanisms by which Bcr-AbI promotes the transformation of haemopoietic
progenitor cells, is by influencing the level of TGF signaling activity (FEBS Letters,
2007, 581 , 7, 1329-1334). TGF plays a vital role in the preservation of the
malignant progenitor population, and is partially responsible for the resistance to
treatments targeting Bcr-AbI observed in a proportion of CML patients.
Inhibition of TGF by the compounds of the present invention was demonstrated
using Western Blot Analysis.
Western Blot Analysis
The Western Blot assay was carried out as in reference, Analytical Biochemistry,
1981 , 112, 2, 195-203.
Western blot analysis was performed to decipher the mechanism of action of
compounds of the present invention. Ba/F3 Bcr-AbI/ T315I (imatinib mesylate
resistant) cells were seeded in tissue culture grade 75 mm2 flasks at a density of 2 to
4 x 06 cells per flask. The cells were incubated in a humidified incubator for 2-4 h at
37 °C. Subsequently, cells were treated with 3 x IC5o concentrations of the
compounds or standard molecule (imatinib mesylate/dasatinib). Cells were then
incubated for 72 h. Following the incubation, cells were harvested, washed with icecold
phosphate buffered saline (PBS) and lysed with cold Cell Lytic buffer (Sigma
Aldrich) supplemented with complete protease inhibitor cocktail (Roche, Germany).
The protein extracts were obtained after centrifugation at 14,000 g at 4 °C (30 min).
Aliquots of the resulting extracts were analyzed for their protein content using
Bradford Reagent (Sigma) as per the manufacturer's instructions. In all the
experiments, equivalent amounts of protein (70 g) were loaded on 7.5 % -10 %
Tris-glycine gels and resolved at 100 V for 2 h in a buffered solution (24.9 mM Tris
base, 250 mM glycine, 0.1 % SDS (sodium dodecyl sulfate)). After electrophoresis,
the proteins were transferred from the gel to a polyvinylidene difluoride membrane
(Sigma-Aldrich) at 25 V for 45 min. in transfer buffer (47.9 mM Tris base, 38.6 mM
glycine, 0.037 % SDS, 20 % methanol; pH 9.2-9.4). Blots were blocked in Trisbuffered
saline (TBS) (20 mM Tris base, 0.9 % NaCI; pH 7.4) containing 5 % nonfat
dry milk (Santa Cruz Biotechnology, USA) for 2 h at room temperature, and
incubated with gentle rocking after addition of the primary antibody which was
prepared in TBS at 4 °C for a time ranging from 16-18 h. Primary antibodies included
antibodies against TG , Smad2/3, phospho-Smad2/3 (Cell Signaling) and -Actin
(Cell Signaling). Following the incubation, membranes were washed and then
probed with horse-radish peroxidase (HRP)-conjugated secondary antibody. Bands
were visualized using chemiluminescent peroxidase substrate (Pierce, IL) and a
Kodak Imaging station. Blots were stripped with stripping buffer (50 mM Tris-HCI pH
6.8, 1 % SDS and 100 mM -mercaptoethanol) for 30 min at 55 C, washed and reprobed
with a primary antibody to the housekeeping protein -actin was used as a
loading control.
The results are depicted in Figure 3.
Conclusion: Compound of Example 3 and Compound of Example 4 strongly
downregulated p-Smad2 and p-Smad3, effector target molecules of TG signaling,
indicating their role in inhibiting the TG pathway in imatinib mesylate/ dasatinib
resistant cell line, T31 5I.
Example 65:
Inhibition of autophosphorylation of Bcr-Abl protein:
Bcr-Abl protein autophosphorylation at Tyr-245 is involved in the activation
mechanism of the kinase (Leukemia Research, 2008, 32, 936-943). The assay was
carried out using Western blot analysis according to the reference, Analytical
Biochemistry, 1981 , 112, 2, 195-203, with certain modifications.
Western Blot Analysis
Western blot analysis was performed to decipher the mechanism of action of
compounds of the present invention. Ba/F3 Bcr-Abl/ T31 5 I (imatinib mesylate
resistant) cells were seeded in tissue culture grade 75 mm2 flasks at a density of 2 to
4 x 06 cells per flask. The cells were incubated in a humidified incubator for 2-4 h at
37 °C. Subsequently, cells were treated with respective concentrations of the
compounds. Cells were then incubated for 72 h. Following the incubation, cells
were harvested, washed with ice-cold phosphate buffered saline (PBS) and lysed
with cold Cell Lytic buffer (Sigma Aldrich) supplemented with complete protease
inhibitor cocktail (Roche, Germany). The protein extracts were obtained after
centrifugation at 14,000 rpm at 4 °C (30 min). Aliquots of the resulting extracts were
analyzed for their protein content using Bradford Reagent (Sigma) as per the
manufacturer's instructions. Aliquots containing 500 g protein were used for
immunoprecipitation using c-Abl antibody (Santacruz Biotechnology, USA) and
protein A-sepharose beads. The precipated protein were loaded on 7.5 % Trisglycine
gels and resolved at 100 V for 2 h in a buffered solution (24.9 mM Tris base,
250 mM glycine, 0.1 % SDS (sodium dodecyl sulfate)). After electrophoresis, the
proteins were transferred from the gel to a polyvinylidene difluoride membrane
(Sigma-Aldrich) at 70 V for 1.5 h in transfer buffer (47.9 mM Tris base, 38.6 mM
glycine, 0.037 % SDS, 20 % methanol; pH 9.2-9.4) using wet transfer method. Blots
were blocked in TBST (Tris-buffered saline (TBS) (20 mM Tris base, 0.9 % NaCI; pH
7.4) with 0.1 % Tween 20 (Sigma Aldrich, USA)) containing 5 % nonfat dry milk
(Santa Cruz Biotechnology, USA) for 2 h at room temperature, and incubated with
gentle rocking after addition of the primary antibody which was prepared in TBST at
4 °C for a time ranging from 16-18 h. Primary antibodies included antibodies
phospho-Bcr-abl-Tyr245 (Cell Signaling Technology) and c-Abl (Santacruz
Biotechnology, USA). Following the incubation, membranes were washed and then
probed with horse-radish peroxidase (HRP)-conjugated secondary antibody
(Santacruz Biotechnology). Bands were visualized using chemiluminescent
peroxidase substrate (Pierce, IL) and a Kodak Imaging station.
The results are depicted in Figure 4.
Conclusion: The compounds of the present invention downregulated
autophosphorylation of Bcr-abl protein in imatinib mesylate/ dasatinib resistant cell
line, T315I.
Example 66:
Inhibition of phosphorylation of CRKL protein:
Phospho-CRKL monitoring has been recognized as a prognostic marker in CML
patients treated with first and second generation Bcr-Abl inhibitors (Haematologica,
2008, 93, 5, 765-769). The assay was carried out using Western blot analysis
according to the reference, Analytical Biochemistry, 1981 , 112, 2, 195-203, with
certain modifications.
Western Blot Analysis
Western blot analysis was performed to decipher the mechanism of action of
compounds of the present invention. Ba/F3 Bcr-Abl/ T31 5 I (imatinib mesylate
resistant) cells were seeded in tissue culture grade 75 mm2 flasks at a density of 2 to
4 x 06 cells per flask. The cells were incubated in a humidified incubator for 2-4 h at
37 °C. Subsequently, cells were treated with respective concentrations of the
compounds. Cells were then incubated for 72 h. Following the incubation, cells
were harvested, washed with ice-cold phosphate buffered saline (PBS) and lysed
with cold Cell Lytic buffer (Sigma Aldrich) supplemented with complete protease
inhibitor cocktail (Roche, Germany). The protein extracts were obtained after
centrifugation at 14,000 rpm at 4 °C (30 min). Aliquots of the resulting extracts were
analyzed for their protein content using Bradford Reagent (Sigma) as per the
manufacturer's instructions. Equivalent protein samples (70 g) were loaded on 10
% Tris-glycine gels and resolved at 100 V for 2 h in a buffered solution (24.9 mM Tris
base, 250 mM glycine, 0.1 % SDS (sodium dodecyl sulfate)). After electrophoresis,
the proteins were transferred from the gel to a polyvinylidene difluoride membrane
(Sigma-Aldrich) at 70 V for 1.5 h in transfer buffer (47.9 mM Tris base, 38.6 mM
glycine, 0.037 % SDS, 20 % methanol; pH 9.2-9.4) using wet transfer method. Blots
were blocked in TBST (Tris-buffered saline (TBS) (20 mM Tris base, 0.9 % NaCI; pH
7.4) with 0.1 % Tween 20 (Sigma Aldrich, USA)) containing 5 % nonfat dry milk
(Santa Cruz Biotechnology, USA) for 2 h at room temperature, and incubated with
gentle rocking after addition of the primary antibody which was prepared in TBST at
4 °C for a time ranging from 16-18 h. Primary antibodies used were phospho-CRKLTyr-
207 (Cell Signaling Technology) and -actin (Sigma Aldrich, USA). Following the
incubation, membranes were washed and then probed with horse-radish peroxidase
(HRP)-conjugated secondary antibody (Santacruz Biotechnology, USA). Bands were
visualized using chemiluminescent peroxidase substrate (Pierce, IL) and a Kodak
Imaging station.
The results are depicted in Figure 5 and Figure 6B.
Conclusion: The compounds of the present invention downregulated
phosphorylation of CRKL protein in imatinib mesylate resistant P loop mutant cell
line, E255V in a dose-dependent manner.
The compound of Example 3 was found to inhibit phospho-CRKL in three other
mutant cell lines (E255V, M351T and Y253H).
Example 67:
ln-vivo efficacy testing of the compounds of the present invention in imati nibresistant
and imatinib-sensitive tumor models was studied by using cell lines
such as Ba/F3 transfectants expressing full-length wild type Bcr-Abl (Ba/F3
Bcr-Abl/WT) or mutated Bcr-Abl (Ba/F3 Bcr-Abl/T315l).
Objective:
In- vivo efficacy testing of compounds of the present invention in imatinib resistant
and imatinib sensitive tumor models was carried out according to the reference
Cancer Research, 2002, 62, 7 149-71 53.
Cell Lines:
Cell lines Ba/F3 transfectants expressing full-length wild type imatinib sensitive
(Ba/F3 Bcr-Abl/WT) or mutated imatinib resistant (Ba/F3 Bcr-Abl/T31 5l) were used in
this study. These recombinant cell lines were licensed from Dr. Brian Druker's
laboratory, Howard Hughes Medical Institute, Oregon Health and Science University
Cancer Institute, Portland, Oregon, USA.
Compound storage:
The compounds of the present invention including standard were stored at 4-8 °C in
an amber colored bottle. The compounds in solutions were also maintained at 4-8 °C
in a refrigerator. Sample for animal injection was made fresh everyday, residual
volume were pooled and discarded as per standard operating procedure (SOP) for
chemical disposals.
Dose preparation:
Required compound was weighed and admixed with 0.5 % (w/v)
carboxymethylcellulose (CMC) and triturated with Tween-20 (secundum artum) with
gradual addition of water to make up the final concentration. Imatinib mesylate was
used as a standard.
Efficacy study in SCID mice:
A group of 110 Severely Combined Immune-Deficient (SCID strain-CBySmn.CB17-
Prkdcscid/ , The Jackson Laboratory, Stock # 001803) male mice, 5-6 weeks old,
weighing -20 g, were used.
All animal experiments were carried out in accordance with the
guidelines of Committee for the Purpose of Control and Supervision of Experiments
on Animals (CPCSEA). All animal experiments were approved by Institutional
Animal Ethics Committee (IAEC) of Piramal Life Sciences Limited, Goregaon East,
Mumbai, India.
Ba/F3 Bcr-Abl/WT cells and Ba/F3 Bcr-Abl/T315l cells were grown in
RPMI1640 medium containing 10 % fetal calf serum in 5 % C0 2 incubator at 37 °C.
Cells were pelleted by centrifugation at 1000-rpm for 10 minutes. Cells were
resuspended in saline to get a count of 80-100 X 106 cells per mL, 0.2 mL of this cell
suspension was injected by subcutaneous (s.c.) route in SCID mice. Mice were
observed alternate days for palpable tumor mass. Once the tumor size reached a
size of 5-7 mm in diameter, animals were randomized into respective treatment
groups. Dose of control or test compound was administered every day. Tumor size
was recorded at 2-5 day intervals. Tumor weight (mg) was estimated according to
the formula for a prolate ellipsoid: {Length (mm) x [width (mm) ] x 0.5} assuming
specific gravity to be one and to be three. Tumor growth in compound treated
animals is calculated as T/C (Treated/Control) x 100% and Growth inhibition Percent
(Gl%) was [ 1 00-T/C%]. Respective treatment groups are presented in Table 7.
Results are presented in Table 8.
Table 7 : Treatment groups in the xenograft models (SET I and SET II)
(SET I) Designation: Ba/F3 Bcr-Abl/T315l
single administration for 12 days
Table 8 : Tumor growth inhibition percent (% Gl) for compounds of the present
invention in imatinib mesylate sensitive (Ba/F3 Bcr-Abl/WT) and resistant cell
lines (Ba/F3 Bcr-Abl/T31 5l ) .
Imatinib mesylate is inactive at 200 mpk b.i.d. in Ba/F3 Bcr-Abl/T315l (% Gl < 15)
Conclusion: The data presented in Figure 7 and Figure 8 demonstrates that the
compounds of the present invention exhibited significantly greater in-vivo efficacy
than imatinib mesylate in inhibiting the most predominant mutated form of Bcr-Abl
i.e. Ba/F3 Bcr-Abl/T315l when tested at the same doses as that of wild type Bcr-Abl
expressing xenograft i.e. Ba/F3 Bcr-Abl/WT.
It should be noted that, as used in this specification and the appended claims,
the singular forms "a", "an", and "the" include plural referents unless the content
clearly dictates otherwise. Thus, for example, reference to a composition containing
"a compound" includes a mixture of two or more compounds. It should also be noted
that the term "or" is generally employed in its sense including "and/or" unless the
content clearly dictates otherwise.
All publications and patent applications in this specification are indicative of
the level of ordinary skill in the art to which this invention pertains.
The invention has been described with reference to various specific and
preferred embodiments and techniques. However, it should be understood that many
variations and modifications may be made while remaining within the spirit and
scope of the invention.
A comp
Formula 1
wherein,
R is selected from hydroxy, (CrCi 2)-alkoxy or aryloxy;
R2 is selected from hydroxy, nitro, (CrCi 2)-alkoxy, aryloxy, NH-S02-(Ci-Ci 2)-alkyl,
NH-S0 2-aryl and NRaRb; wherein Ra and R are independently selected from
hydrogen, (Ci-Ci 2)-alkyl, aralkyl, aryl or heterocyclyl;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3;
wherein,
(Ci-Ci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, (Ci-Ci 2)-alkoxy, unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclyl, COORa, C(0)Ra, SRa, NRaRb and
C(0)NRaRb;
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclyl, COORa, C(0)Ra, SRa, NRaRb and
C(0)NRaR ;
(C3-Ci 2)-cycloalkyl is unsubstitued or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (C
C 2)-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)Ra,SRa, NRaRb and C(0)NRaR ;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, (CrCi 2)-alkyl, (C2-Ci 2)-alkenyl, (C2-Ci 2)-alkynyl, (C C 2)-
alkoxy, unsubstituted or substituted heterocyclyl, COORa, C(0)Ra, SRa, NRaRb and
C(0)NRaRb;
aryl of aryloxy is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (C2-Ci 2)-
alkenyl, (C2-Ci 2)-alkynyl, unsubstituted or substituted heterocyclyl, COORa, C(0)Ra,
SRa, NRaRb and C(0)NRaRb;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (C2-Ci 2)-
alkenyl, (C2-Ci 2)-alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (Ci-Ci 2)-
alkoxy, unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, SRa, NRaRb, (Ci-Ci 2)-alkyl-NR aRb and C(0)NRaR ; and
Ra and Rb are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
2. The compound of formula 1 according to claim 1,
wherein,
R is selected from hydroxy, (Ci-Ci 2)-alkoxy or aryloxy;
R2 is selected from hydroxy, (Ci-Ci 2)-alkoxy or aryloxy;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3;
wherein,
(Ci-Ci 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
(C3-Ci 2)-cycloalkyl is unsubstituted or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aryl and unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, unsubstituted or
substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-alkynyl and
unsubstituted or substituted heterocyclyl;
aryl of aryloxy is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (Ci-Ci 2)-
alkoxy, unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
3. The compound of formula 1 according to claim 1 or claim 2,
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is hydroxy or (Ci-Ci 2)-alkoxy;
R3 is hydrogen or (Ci-Ci 2)-alkyl; and
n is Oor l ;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl and unsubstituted or
substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb; and
Ra and Rb are independently selected from hydrogen, (Ci-Ci 2) alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
4. The compound of formula 1 according to any one of the claims 1 to 3,
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is hydrogen or unsubstituted (Ci-Ci 2)-alkyl; and
n is 0 or 1;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
5. The compound of formula 1 according to claim 1 or claim 2,
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is hydroxy or (Ci-Ci 2)-alkoxy;
R3 is (C3-Ci 2)-cycloalkyl; and
n is 0 or 1;
wherein,
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
(C3-Ci 2)-cycloalkyl is unsubstituted or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aryl and unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
6. The compound of formula 1 according to any one of the claims 1, 2 and 5,
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is unsubstituted (C3-Ci 2)-cycloalkyl; and
n is 0 or 1;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
7. The compound of formula 1 according to claim 1 or claim 2,
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is aryl; and
n is 0 or 1;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (Ci-Ci 2)-alkyl-NR aR ; and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
8. The compound of formula 1 according to any one of the claims 1, 2 and 7,
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is phenyl; and
n is 1;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
9. The compound of formula 1 according to claim 1 or claim 2,
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is heterocyclyl; and
n is 0 or 1;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (Ci-Ci 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb; and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
10. The compound of formula 1 according to any one of the claims 1, 2 and 9,
wherein,
R is hydroxy or unsubstituted (CrCi 2)-alkoxy;
R2 is hydroxy or unsubstituted (CrCi 2)-alkoxy;
R3 is heterocyclyl; and
n is 1;
wherein,
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, (CrCi 2)-alkyl, unsubstituted or substituted aralkyi, COORa, NRaRb and (C
C 2)-alkyl-NR aRb; and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyi, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
11. The compound of formula 1 according to any one of the claims 1, 2, 9 and 10,
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R3 is piperidine or pyridine; and
n is 0 or 1;
wherein,
piperidine is unsubstituted or substituted with one or more groups selected from
halogen, (CrCi 2)-alkyl, unsubstituted or substituted aralkyi, COORa, NRaRb and ( -
C 2)-alkyl-NR aRb; and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyi, aryl and
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
12. The compound of formula 1 according to claim 1,
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH-S02-(C C 2)-alkyl, NH-S0 2-aryl or NRaRb; wherein Ra
and R are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyi, aryl or
heterocyclyl;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3;
wherein,
(CrCi 2)-alkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and unsubstituted or
substituted heterocyclyl;
alkyl of (CrCi 2)-alkoxy is unsubstituted or substituted with one or more groups
selected from halogen, hydroxy, cyano, nitro, unsubstituted or substituted aryl and
unsubstituted or substituted heterocyclyl;
(C3-Ci 2)-cycloalkyl is unsubstitued or substituted with one or more groups selected
from halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl, (C
C 2)-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted
heterocyclyl, COORa, C(0)Ra,SRa, NRaR and C(0)NRaRb;
aryl is unsubstituted or substituted with one or more groups selected from halogen,
hydroxy, cyano, nitro, unsubstituted or substituted (Ci-Ci 2)-alkyl and unsubstituted or
substituted heterocyclyl;
aryl of aralkyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted (C2-Ci 2)-alkenyl, unsubstituted or substituted (C2-Ci 2)-
alkynyl and unsubstituted or substituted heterocyclyl;
heterocyclyl is unsubstituted or substituted with one or more groups selected from
halogen, hydroxy, cyano, nitro, unsubstituted or substituted (CrCi 2)-alkyl,
unsubstituted or substituted aralkyl, unsubstituted or substituted aryl, COORa,
C(0)Ra, NRaRb and (C C 2)-alkyl-NR aRb;and
Ra and R are independently selected from hydrogen, (C C 2) alkyl, aralkyl, aryl or
heterocyclyl;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
13. The compound of formula 1 according to claim 1 or claim 12,
wherein,
R is hydroxy or unsubstituted (Ci-Ci 2)-alkoxy;
R2 is selected from nitro, NH-S0 2-(Ci-Ci2)-alkyl, NH-S0 2-aryl or NRaRb; wherein Ra
and R are independently selected from hydrogen, (CrCi 2)-alkyl, aralkyi, aryl or
heterocyclyl;
R3 is hydrogen or unsubstituted (Ci-Ci 2)-alkyl; and
n is 0 or 1;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
14. The compound of formula 1 according to any one of the claims 1 to 13, selected
from:
4-[2-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-ethyl-[1 ,2,4]oxadiazole;
4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-propyl-[1 ,2,4]oxadiazole;
4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-Benzyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-3-propyl-[1 ,2,4]oxadiazole;
2-Methoxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenylamine;
N-{2-Methoxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide;
N-{2-Hydroxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide;
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
3-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-5-propyl-[1 ,2,4] oxadiazole;
2-Amino-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-
piperidine - 1-carboxylic acid tert-butyl ester;
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-
piperidine;
4-[2-(3-Piperidin-4-ylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-
diol;
4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-1 -
isopropyl-piperidine;
4-{2-[3-(1-lsopropyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-
benzene-1 ,2-diol;
[2-(4-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-ylmethyl}-
piperidin-1 -yl)-ethyl]-dimethyl-amine;
4-(2-{3-[1-(2-Dimethylamino-ethyl)-piperidin-4-ylmethyl]-
[ 1 ,2,4]oxadiazol-5-yl}-vinyl)-benzene-1 ,2-diol;
1-Benzyl-4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-
ylmethylj-piperidine;
4-{2-[3-(1-Benzyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-
benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-nonyl-[1 ,2,4]oxadiazole;
4-[2-(3-Nonyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2- diol;
3-Cyclopropyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Cyclopropyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-pentyl-[1 ,2,4]oxadiazole;
4-[2-(3-Pentyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-hexyl-[1 ,2,4]oxadiazole;
4-[2-(3-Hexyl-[1 ,2,4]oxadizol-vinyl]-benzyldiol;
3-Cyclohexylmethyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-
[ 1 ,2,4]oxadiazole;
4-[2-(3-Cyclohexylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-octyl-[1 ,2,4]oxadiazole;
4-[2-(3-Octyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-heptyl-[1 ,2,4]oxadiazole;
4-[2-(3-Heptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-{5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazol-3-yl}-pyridine;
4-[2-(3-Pyridin-3-yl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-Cycloheptyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Cycloheptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
3-Cyclohexyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1 ,2,4]oxadiazole;
4-[2-(3-Cyclohexyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
15. The compound of formula 1, according to any one of the claims 1 to 14,
selected from:
4-[2-(3-Methyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Ethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Benzyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
N-{2-Hydroxy-5-[2-(3-propyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-
methanesulfonamide;
2-Nitro-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
2-Amino-4-[2-(5-propyl-[1 ,2,4]oxadiazol-3-yl)-vinyl]-phenol;
4-[2-(3-Piperidin-4-ylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-
diol;
4-{2-[3-(1-lsopropyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-
benzene-1 ,2-diol;
4-(2-{3-[1-(2-Dimethylamino-ethyl)-piperidin-4-ylmethyl]-
[ 1 ,2,4]oxadiazol-5-yl}-vinyl)-benzene-1 ,2-diol;
4-{2-[3-(1 -Benzyl-piperidin-4-ylmethyl)-[1 ,2,4]oxadiazol-5-yl]-vinyl}-
benzene-1 ,2-diol;
4-[2-(3-Nonyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2- diol;
4-[2-(3-Cyclopropyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Pentyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Hexyl-[1 ,2,4]oxadizol-vinyl]-benzyldiol;
4-[2-(3-Cyclohexylmethyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Octyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Heptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Pyridin-3-yl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Cycloheptyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
4-[2-(3-Cyclohexyl-[1 ,2,4]oxadiazol-5-yl)-vinyl]-benzene-1 ,2-diol;
or a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
16. A process for the preparation of the compound of formula 1.
Formula 1
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is hydroxy or (CrCi 2)-alkoxy;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3; which process comprises:
Step 1) activating 3,4-(dialkoxy)cinnamic acid (compound of formula 3) with 1, 1 '-
carbonyldiimidazole (CDI) at room temperature (20 °C to 35 °C) in solvent selected
from toluene, DMF and THF to obtain the corresponding activated form of the
compound of formula 3;
3
wherein - and R2 are (Ci-Ci 2)alkoxy;
Step 2) reacting the activated compound of formula 3 (obtained in Step 1) with a
compound of formula 4;
4
wherein n and R3 are as defined in formula 1;
to obtain compound of formula 5;
wherein - and R2 are (CrCi 2)-lkoxy; n and R3 are as defined in formula 1;
Step 3) dehydrating the compound of formula 5 (obtained in Step 2) by treatment
with CDI in a solvent selected from toluene, DMF and THF at 50 °C to 120 °C for 6
to 12 h to obtain compound
wherein and R2 are (CrCi 2)-alkoxy; n and R3 are as defined in formula 1;
Step 4) treating the compound of formula 6 (obtained in Step 3) with a dealkylating
agent selected from boron tribromide, anhydrous AICI3/DMS or anhydrous
AICb/EtSH at a temperature ranging from -78 °C to 0 °C when the dealkylating agent
used is boron tribromide or at a temperature ranging from 0 °C to 30 °C when the
dealkylating agent used is anhydrous AICI3/DMS or anhydrous AICI3/EtSH, in
dichloromethane as solvent to obtain the compound of formula 1 (wherein R =
R2=OH); and
Step 5) optionally converting the compound of formula 1 to its corresponding salt.
17. A process for t ula 1,
Formula 1
wherein,
R is hydroxy;
R2 is hydroxy;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl and
heterocyclyl; and
n is an integer from 0-3; which process comprises:
Step 1) protecting 3,4-dihydroxycinnamic acid with imidazole and t-butyldimethylsilyl
chloride (TBDMSCI) in DMF over a period of 40-1 00 h at room temperature (20 °C to
35 °C) in a solvent selected from THF and methanol to obtain compound of formula
9;
wherein L is t-butyldimethylsilyloxy;
Step 2) treating the compound of formula 9 (obtained in Step 1) with oxalyl chloride
and catalytic amount of DMF at a temperature ranging from 20 °C to 35 °C to obtain
compound of formula 10;
wherein L is t-butyldimethylsilyloxy;
Step 3) treating the compound of formula 10 (obtained in Step 2) with compound 4;
HO (CH 2)NR3
NH2
4
wherein n and R3 are as defined in Formula 1;
in a solvent selected from xylene and toluene in the presence of pyridine as a base
at 120 °C to 140 °C to obtain compound of formula 11;
11
wherein L is t-butyldimethylsilyloxy; n and R3 are as defined in formula 1; and
Step 4) desilylation of compound of formula 11 (obtained in Step 3) using 1.0 M
TBAF solution in THF at a temperature ranging from 20 °C to 35 °C to obtain the
compound of formula 1; and
Step 5) optionally converting the compound of formula 1 to its corresponding salt.
18. A process for the preparation of the compound of formula 1,
Formula 1
wherein,
R is hydroxy;
R2 is hydroxy;
R3 is selected from hydrogen, (CrCi2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3; which process comprises:
Step 1) converting caffeic acid into its corresponding methyl ester as compound of
formula 12 by reacting with oxalyl chloride and methanol at a temperature ranging
from 20 °C to 35 °C;
12
wherein X is methyl;
Step 2) treating compound of formula 12 (obtained in Step 1) with imidazole and
TBDMSCI at room temperature (20 °C to 35 °C) in a solvent selected from THF and
methanol to obtain compound of formula 13;
13
wherein L is t-butyldimethylsilyloxy and X is methyl;
Step 3) treating compound of formula 13 (obtained in Step 2) with compound of
formula 4 in presence of sodium hydride in THF at 40 °C to 80 °C for 6-8 h;
wherein n and R3 are as defined in Formula 1;
to obtain compound of formula 1; and
Step 4) optionally converting the compound of formula 1 to its corresponding salt.
A process for the preparation of the compound of formula 1,
Formula 1
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is selected from nitro, amino, NHS0 2-alkyl or NHS0 2-aryl;
R3 is selected from hydrogen, (Ci-Ci 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3; which process comprises:
Step 1) nitration of 4-alkoxy benzaldehyde using suitable nitrating agent selected
from a mixture of ammonium nitrate and trifluoroacetic anhydride (TFAA), or a
mixture of HN0 3 and H2S0 4 at temperature ranging from 25 °C to 30 °C to obtain the
compound of formula 15;
wherein is (CrCi 2)-alkoxy, R2 is nitro;
Step 2) subjecting the compound of formula 15 (obtained in Step 1) to Knoevenagel
condensation with malonic acid to obtain compound of formula 16;
wherein is (CrCi 2)-alkoxy, R2 is nitro;
Step 3) activating compound of formula 16 with 1, 1 '-carbonyldiimidazole (CDI) or 1-
hydroxybenzotriazole (HOBt) at room temperature (20 °C to 35 °C) in a solvent
selected from DMF and THF for 40 minutes;
Step 4) reacting activated compound 16 (obtained in Step 3) with compound of
formula 4;
4
wherein n and R3 are as defined in Formula 1;
to obtain compound of formula 17;
wherein is (CrCi 2)-alkoxy, R2 is nitro, n and R3 are as defined in formula 1;
Step 5) dehydrating compound of formula 17 (obtained in Step 2) by treatment with
CDI in DMF at 50 °C to 120 °C for 6 - 12 h to obtain compound of formula 18;
wherein - is (CrCi 2)-alkoxy, R2 is nitro, n and R3 are as defined in formula 1;
Step 6) treating compound of formula 18 (obtained in Step 5) with a suitable
reducing agent selected from stannous chloride or Fe in HCI in a solvent selected
from ethyl acetate and methanol, to obtain compound of formula 19;
wherein is (CrCi 2)-alkoxy, R2 is NH2, n and R3 are as defined in formula 1;
Step 7) treating compound of formula 19 (obtained in Step 6) with alkyl sulfonyl
chloride at room temperature (25 °C to 30 °C) in dichloromethane in presence of a
base selected from pyridine and triethylamine, to obtain corresponding sulfonamide
as compound of formula 20
wherein - is (CrCi 2)-alkoxy, R2 is NHS0 2-alkyl or NHS0 2-aryl, n and R3 are as
defined in formula 1;
Step 8) treating compound of formula 20 (obtained in Step 7) with a dealkylating
agent selected from boron tribromide, anhydrous AICI3/DMS and anhydrous
AICI3/EtSH at a temperature ranging from -78 °C to 0 °C when boron tribromide is
used or at a temperature of 0 °C to 30 °C when anhydrous AICI3/DMS and
anhydrous AICI3/EtSH is used in dichloromethane as solvent to obtain compound of
formula 1(wherein R is OH, R2 is NHS0 2-alkyl or NHS0 2-aryl) ; and
Step 9) optionally converting the compound of formula 1 to its corresponding salt.
20. A process for the preparation of the compound of formula 1,
Formula 1
wherein,
R is hydroxy or (CrCi 2)-alkoxy;
R2 is nitro or amino;
R3 is selected from hydrogen, (CrCi 2)-alkyl, (C3-Ci 2)-cycloalkyl, aralkyl, aryl or
heterocyclyl; and
n is an integer from 0-3; which process comprises:
Step 1) nitration of 4-alkoxy benzaldehyde using suitable nitrating agent selected
from a mixture of ammonium nitrate and trifluoroacetic anhydride (TFAA) or a
mixture of HN0 3 and H2S0 4 at temperature ranging from 25 °C to 30 °C to obtain
compound of formula 15;
15
wherein R is (Ci-Ci 2)-alkoxy, R2 is nitro;
Step 2) subjecting compound of formula 15 (obtained in Step 1) to Knoevenagel
condensation with malonic acid to obtain compound of formula 16;
16
wherein is (Ci-Ci 2)-alkoxy, R2 is nitro;
Step 3) activating compound of formula 16 with 1, 1 '-carbonyldiimidazole (CDI) or a
combination of N, N'-dicyclohexyl carbodiimide (DCC) and 1-hydroxybenzotriazole
(HOBt) at room temperature (20 °C to 35 °C) in a solvent selected from DMF or THF
over a period of 40 minutes;
Step 4) reacting the activated compound of formula 16 (obtained in Step 3) with a
compound of formula 4;
4
wherein n and R3 are as defined in Formula 1;
at a temperature ranging from 120 °C - 160 °C for 3-5 h to obtain a compound of
formula 1 (major) wherein is (CrCi 2)-alkoxy and R2 is nitro; and a compound of
formula 1 (minor) wherein R is hydroxy and R2 is nitro;
Step 5) reducing the compound of formula 1 wherein R is hydroxy and R2 is nitro
using a reducing agent selected from stannous chloride in a solvent selected from
ethyl acetate and methanol, or Fe in HCI at a temperature ranging from 50 °C to 100
°C to obtain compound of formula 1; wherein R is hydroxy and R2 is NH2; and
Step 6) optionally converting the compound of formula 1 wherein is hydroxy and
R2 is nitro or the compound of formula 1 wherein R is hydroxy and R2 is NH2 to its
corresponding salt.
2 1. A process for t ula 1,
Formula 1
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is hydroxy or (Ci-Ci 2)-alkoxy;
R is
, wherein R4 is selected from hydrogen, (Ci-Ci 2)alkyl and benzyl; and
n is 1; which process comprises:
Step 1) converting compound of formula 3 (wherein to
compound of formula 24, which is the corresponding alkyl ester by conventional
method;
wherein
Step 2) treating the compound of formula 25A;
25A
with f-butoxycarbamate in presence aqueous sodium hydroxide as a base in a
suitable solvent selected from THF or dichloromethane at a temperature ranging
from 20 °C to 35 °C to obtain compound of formula 25B;
25B
Step 3) refluxing the compound of formula 25B with cyanomethyl phosphonic acid
diethylester as a cyanomethylating reagent in the presence of anhydrous potassium
carbonate as a base in THF as solvent at a temperature ranging from 20 °C to 50 °C
to obtain compound of formula 25C;
25C
Step 4) reducing the compound of formula 25C using a reducing agent such as
H2/Pd-C in methanol at a temperature ranging from 20 °C to 35 °C at a pressure
ranging from 40-60 psi to obtain compound of formula 25D;
25D
Step 5) treating compound of formula 25D with hydroxylamine hydrochloride in
presence of anhydrous potassium carbonate as a base in a solvent selected from
alcohol and aqueous alcohol at a temperature ranging from 20 °C to 35 °C to obtain
compound of formula 25;
25
Step 6) treating the compound of formula 24 (obtained in Step 1) with the compound
of formula 25 (obtained in Step 2C); in the presence of sodium hydride as a base in
THF as solvent at a temperature ranging from 20 °C to 60 °C to obtain compound of
formula 26;
wherein and R2 are (CrCi 2)-alkoxy;
Step 7) Deprotecting compound of formula 26 (obtained in Step 6) with trifluoroacetic
acid as a deprotecting agent in dichloromethane as solvent at a temperature ranging
from 20 °C to 35 °C to obtain compound of formula 1; wherein and R2 are (C
C -alkoxy; n=1 ; and
, wherein R4 is hydrogen;
Step 8) alkylating the compound of formula 27 (obtained in Step 7) by heating with
an alkyl halide or benzyl halide in presence of a suitable base selected from
anhydrous K2C0 3 and sodium hydride, in dry DMF as solvent, at a temperature
ranging from 25 °C to 100 °C to obtain compound of formula 1; wherein and R2
are Cr C 2)-alkoxy; n=1 ; and
, wherein R4 is selected from alkyl and benzyl;
Step 9) treating compound of formula 28 (obtained in Step 8) with a dealkylating
agent selected from boron tribromide, anhydrous AICI3/DMS and anhydrous
AICb/EtSH at a temperature ranging from -78 °C to 0 °C when boron tribromide is
used or at a temperature ranging from 0 °C to 30 °C when anhydrous AICI3/DMS and
anhydrous AICI3/EtSH is used in dichloromethane as solvent to obtain compound of
formula 1 wherein R and R2 are hydroxy; n=1 ; and
R3 is , wherein R4 is selected from alkyl and benzyl;
Step 10) optionally converting compound of formula 1 (obtained in Step 7) to the
corres onding compound of formula 1; wherein R and R2 are hydroxy; n=1 ; and
R3 is , wherein R4 is hydrogen; and
Step 11) optionally converting compounds of formula 1 as obtained in steps 7, 8, 9
and 10 to their corresponding salts.
A process for the preparation of the compound of formula 1,
Formula 1
wherein,
R is hydroxy or (Ci-Ci 2)-alkoxy;
R2 is hydroxy or (Ci-Ci 2)-alkoxy;
R3 is
N-R
; wherein * is the point of attachment and wherein R4 is selected from
hydrogen, (CrCi 2)alkyl and benzyl ; and n is 1; which process comprises:
Step 1) converting compound of formula 3;
3
wherein and R2 are (CrCi 2)-alkoxy; to the compound of formula 30, which is the
corresponding acid chloride of the compound of formula 3;
wherein R and R2 are alkoxy;
Step 2) treating the compound of formula 25A;
25A
with R4-X (wherein R4 is (Ci -Ci 2)alkyl or benzyl and X is halide) in presence of
anhydrous potassium carbonate as a base in dry DMF as a solvent at a temperature
ranging from 20 °C to 35 °C to obtain compound of formula 31A;
Step 3) refluxing the compound of formula 25A or the compound of formula 31A with
cyanomethyl phosphonic acid diethylester as a cyanomethylating reagent in
presence of anhydrous potassium carbonate as a base in THF as solvent at a
temperature ranging from 20 °C to 50 °C to obtain compound of formula 3 1B;
Step 4) treating compound of formula 3 1B in methanol as a solvent with magnesium
turnings as a reducing agent at a temperature ranging from 0 °C to 10 °C to obtain
compound of formula 3 1C;
Step 5) treating compound of formula 3 1C with hydroxylamine hydrochloride in
presence of anhydrous potassium carbonate as a base in a suitable solvent such as
alcohol or aqueous alcohol at a temperature ranging from 20 °C to 35 °C to obtain
compound of formula 3 1 ;
HO-N
- (CH RH
N ' n 3
3 1
wherein n=1 and R3 is
-
; wherein * is the point of attachment and R4 is
selected from hydrogen, (CrCi 2)alkyl or benzyl;
Step 6) treating compound of formula 30 (obtained in Step 1) with the compound of
formula 3 1 (obtained in Step 5), in a solvent selected from xylene and toluene in
presence of pyridine as a base at a temperature ranging from 120 °C to 140 °C, or in
presence of sodium acetate as a base in aqueous ethanol as a solvent to obtain
compound of formula 1 wherein and R2 are (CrCi 2)-alkoxy; n=1 and R3
is , wherein R4 is selected from hydrogen or a compound of formula 1 ;
wherein and R2 are (CrCi 2)-alkoxy; n=1 ;
, wherein R4 is alkyl or benzyl;
Step 7) treating any one of the compound of formula 1 (obtained in Step 6) with a
suitable dealkylating agent selected from boron tribromide, DMSO/KCN and
anhydrous ZnCI2, to obtain compound of formula 1 wherein R and R2 are hydroxy;
n=1 and
, wherein R4 is hydrogen; or a compound of formula 1 wherein R
and R2 are hydroxy; n=1 ; and
R 3 is , wherein R4 is alkyl or benzyl; and
Step 8) optionally converting any one of the compounds of formula 1 as obtained in
steps 6 and 7 to their corresponding salts.
23. A pharmaceutical composition, comprising a therapeutically effective
amount of compound of formula 1, according to any one of the claims 1 to 15, or a
stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof; as an active
ingredient, either alone or with at least one pharmaceutically acceptable excipient.
24. A method for the treatment of cancer, comprising administering to a
mammal in need thereof a therapeutically effective amount of compound of formula
1, according to any one of the claims 1 to 15, or a stereoisomer, tautomer,
pharmaceutically acceptable salt, pharmaceutically acceptable solvate or
pharmaceutically acceptable polymorph thereof.
25. The method according to claim 24, wherein the cancer is selected from
leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphocytic
leukemia, adult acute myeloid leukemia, chronic lymphocytic leukemia, chronic
myeloid leukemia, and hairy cell leukemia.
26. The method according to claim 24 or claim 25, wherein the cancer is
chronic myeloid leukemia.
27. The method according to any one of the claims 24 to 26, wherein the
cancer is chronic myeloid leukemia resistant to treatment with imatinib mesylate.
28. A method of reducing the proliferation of cells that are resistant to
treatment with imatinib mesylate, comprising administering to a mammal in need
thereof a therapeutically effective amount of a compound of formula 1, according to
any one of the claims 1 to 15; or a stereoisomer, tautomer, pharmaceutically
acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable
polymorph thereof.
29. The method according to claim 28, wherein the resistance of the cells
to treatment with imatinib mesylate is caused by Bcr-Abl mutation.
30. The method according to claim 29, wherein the cells resistant to
imatinib mesylate comprise: Ba/F3 Bcr-Abl/T31 5l, Ba/F3 Bcr-Abl/E255K, Ba/F3 Bcr-
Abl/H396P, Ba/F3 Bcr-Abl/M351T, Ba/F3 Bcr-Abl/F359V, Ba/F3 Bcr-Abl/E255V,
Ba/F3 Bcr-Abl/F317L, Ba/F3 Bcr-Abl/H396R, Ba/F3 Bcr-Abl/M244V, Ba/F3 Bcr-
Abl/Q252H, Ba/F3 Bcr-Abl/Y253F, and Ba/F3 Bcr-Abl/Y253H.
3 1. A method for inhibiting transforming growth factor-() ,
comprising administering to a mammal in need thereof a therapeutically effective
amount of the compound of formula 1 according to any one of the claims 1 to 15; or
a stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
32. A method for reducing proliferation of chronic myeloid leukemia (CML)
stem cells mediated by inhibition of transforming growth factor-() , comprising
administering to a mammal in need thereof a therapeutically effective amount of
compound of formula 1 according to any one of the claims 1 to 15; or a
stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically
acceptable solvate or pharmaceutically acceptable polymorph thereof.
33. Use of a compound of formula 1 according to any one of the claims 1
to 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt,
pharmaceutically acceptable solvate or pharmaceutically acceptable polymorph
thereof; for the treatment of cancer.
34. The use of a compound of formula 1 according to claim 33; wherein the
cancer is selected from leukemia, acute lymphoblastic leukemia, acute myeloid
leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.
35. The use of a compound of formula 1 according to claim 33 or claim 34;
wherein the cancer is chronic myeloid leukemia (CML).
36. The use of a compound of formula 1 according to any one of the claims
33 to 35; wherein the cancer is chronic myeloid leukemia (CML), that is resistant to
treatment with imatinib mesylate.
37. The use according to claim 36, wherein the resistance to imatinib
mesylate is caused by Bcr-Abl mutation.
38. The use according to claim 36 or claim 37, wherein the resistance to
imatinib mesylate arises from a mutation found in cells comprising: Ba/F3 Bcr-
Abl/T315l, Ba/F3 Bcr-Abl/E255K, Ba/F3 Bcr-Abl/H396P, Ba/F3 Bcr-Abl/M351T,
Ba/F3 Bcr-Abl/F359V, Ba/F3 Bcr-Abl/E255V, Ba/F3 Bcr-Abl/F317L, Ba/F3 Bcr-
Abl/H396R, Ba/F3 Bcr-Abl/M244V, Ba/F3 Bcr-Abl/Q252H, Ba/F3 Bcr-Abl/Y253F, and
Ba/F3 Bcr-Abl/Y253H.
39. Use of a compound of formula 1 according to any one of the claims 1
to 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt,
pharmaceutically acceptable solvate or pharmaceutically acceptable polymorph
thereof; for the inhibition of transforming growth factor-() .
40. Use of a compound of formula 1 according to any one of the claims 1
to 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt,
pharmaceutically acceptable solvate or pharmaceutically acceptable polymorph
thereof; for reduction in the proliferation of chronic myeloid leukemia (CML) stem
cells mediated by inhibition of transforming growth factor-() .
4 1. Use of a compound of formula 1 according to any one of the claims 1
to 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt,
pharmaceutically acceptable solvate or pharmaceutically acceptable polymorph
thereof; for the manufacture of a medicament for the treatment of cancer.
42. The use of a compound of formula 1 according to claim 4 1 ; wherein the
cancer is selected from from leukemia, acute lymphoblastic leukemia, acute myeloid
leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.
43. The use of a compound of formula 1 according to claim 4 1 or claim 42;
wherein the cancer is chronic myeloid leukemia (CML).
44. The use of a compound of formula 1 according to any one of the claims
4 1 to 43; wherein the cancer is chronic myeloid leukemia (CML), that is resistant to
treatment with imatinib mesylate.