USEFUL AS INHIBITORS OF DPP-1
FIELD OF THE INVENTION
The present invention is directed to novel substituted benzothiazole and
benzoxazole derivatives, pharmaceutical compositions containing them and
their use in the treatment of disorders and conditions modulated by DPP-1 .
BACKGROUND OF THE INVENTION
Chronic Obstructive Pulmonary Disease (COPD) is characterized by the
progressive development of irreversible airflow limitation. COPD consists of
chronic obstructive bronchitis, with obstruction of small airways, and
emphysema, with enlargement of air spaces and destruction of lung
parenchyma, loss of lung elasticity, and closure of small airways. In COPD
patients, there were increased numbers of neutrophils, cytotoxic T lymphocytes
and macrophages in bronchoalveolar lavage (BAL) airways and lung
parenchyma. The presence of these inflammatory cells is correlated well with
severity of airway obstruction and alveolar wall destruction. It has been shown
that neutrophil elastase; cathepsin G and proteinase 3 can produce
emphysema and mucus hypersecretion in lab animals. Granzymes A & B are
the neutral serine proteases that are expressed exclusively in the granules of
activated cytotoxic T lymphocytes. In COPD the protease-anti protease balance
appears to be tipped in favor of increased proteolysis due to increase in
polymorphonuclear neutrophil (PMN) -derived proteases, cathepsins and matrix
metalloproteases (MMPs). Therefore, a drug that inhibits all or most of the
relevant proteases mentioned above is expected to be effective in the
treatment of COPD.
Dipeptidyl Peptidase-1 (DPP-1 , cathepsin C) is a member of the
lysosomal papain-type cysteine protease family that also includes cathepsin B,
K, H, L, O, and S. DPP-1 (MW 200kd) is composed of a dimer of disulfidelinked
heavy and light chains, both from a single protein precursor. DPP-1
mRNA is highly expressed in tissues such as lung, spleen, kidney and liver; in
inflammatory cells such as PMN, cytotoxic T lymphocytes, alveolar
macrophages and mast cells. The biological function of DPP-1 is to convert
inactive proenzymes into active enzyme by removing a dipeptide from Nterminal.
The proenzymes that are activated by DPP-1 are PMN-derived
proteases, granzymes A & B, chymase and tryptase. Since these enzymes
play an important pathological role in COPD, inhibition of DDP-1 by small
molecules would be a rational therapeutic intervention for COPD. Additional
therapeutic indications for a DPP-1 inhibitor are asthma, rhinitis, and
rheumatoid arthritis.
There remains a need for inhibitors of DPP-1 for the treatment of DPP-1
mediated disorders and conditions, including but not limited to rheumatoid
arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel
disease, cystic fibrosis, and abdominal aortic aneurism.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of formula (I)
wherein
a is an integer from 0 to 1;
R is selected from the group consisting of halogen, C -4alkyl, -CH2-OH,
C - alkoxy, phenyl, 5 to 6 membered heteroaryl, benzo[d][1 ,3]dioxolyl, -C0 2H,
-C(0)-NR RB, -C(0)-NH-(Ci -4alkyl)-0-(Ci -4alkyl), -C(0)-NH-phenyl, -C(0)-NHCH
2-phenyl, -C(0)-NH-C 3-6cycloalkyl and -CH2-NH-C3-6cycloalkyl;
wherein R and RB are each independently selected from the group
consisting of hydrogen and C -4alkyl;
and wherein the phenyl, whether alone or as part of a substituent group
is optionally substituted with one or more substituent independently selected
from halogen, hydroxy, C -4alkyl, fluorinated C -4alkyl, C -4alkoxy and
fluorinated C -4alkoxy;
X is selected from the group consisting of O and S;
d from the group consisting of-NH-CH2CH2-N(Rc)- and
wherein Rc is selected from the group consisting of
hydrogen, methyl and ethyl; (and wherein the L substituent group is
incorporated into the compound of formula (I) as drawn);
R2 is selected from the group consisting of C -4alkyl, C2-4alkenyl, C2-
alkynyl, -CH2-thienyl and -CH2-furyl;
and pharmaceutically acceptable salts thereof.
The present invention is further directed to processes for the preparation
of the compounds of formula (I). The present invention is further directed to a
product prepared according to the process described herein.
Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and the product prepared according to the
process described herein. An illustration of the invention is a pharmaceutical
composition made by mixing the product prepared according to the process
described herein and a pharmaceutically acceptable carrier. Illustrating the
invention is a process for making a pharmaceutical composition comprising
mixing the product prepared according to the process described herein and a
pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating a disorder mediated
by DPP-1 (cathepsin C) (selected from the group consisting of rheumatoid
arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel
disease, cystic fibrosis, and abdominal aortic aneurism) in a subject in need
thereof comprising administering to the subject a therapeutically effective
amount of any of the compounds or pharmaceutical compositions described
above.
Another example of the invention is the use of any of the compounds
described herein in the preparation of a medicament for treating: (a)
rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d)
sepsis, (e) irritable bowel disease, (f) cystic fibrosis, or (g) abdominal aortic
aneurism, in a subject in need thereof.
In another example, the present invention is directed to a compound as
described herein for use in a methods for treating a disorder selected from the
group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary
disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic
aneurism, in a subject in need thereof.
DETAI LED DESCRI PTION OF THE INVENTION
The present invention is directed to a process for the preparation of
compound of formula I)
wherein a, R ,X, L and R2 are as defined herein, and pharmaceutically
acceptable salts thereof. The compounds of formula (I) of the present invention
are inhibitors of DPP- 1 , useful in the treatment of disorders, diseases and
conditions mediated by DPP- 1 (cathepsin C), including, but not limited to,
rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis,
irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
In an embodiment of the present invention a is 0. In another
embodiment of the present invention a is 1.
In an embodiment of the present invention, R is selected from the group
consisting of halogen , Ci-2alkyl , -CH 2-OH , C -4alkoxy, phenyl , 5 to 6 membered
heteroaryl, benzo[d ][1 ,3]dioxolyl, -C02H, -C(0)-NR RB, -C(0)-N H-(Ci -4alkyl )-0-
(C -4alkyl), -C(0)-N H-phenyl, -C(0)-N H-CH 2-phenyl, -C(0)-NH-C3-6cycloalkyl
and -CH 2-NH-C3-6cycloalkyl ; wherein R and RB are each independently
selected from the group consisting of hydrogen and C -4alkyl; and wherein the
phenyl, whether alone or as part of a substituent group is optionally substituted
with one or more substituent independently selected from halogen, hydroxy, -
4alkyl , fluorinated C -2alkyl , C -4alkoxy and fluorinated C -2alkoxy.
In another embodiment of the present invention, R is selected from the
group consisting of halogen, -CH 2-OH , C -2alkoxy, phenyl , 6 membered
heteroaryl, benzo[d ][1 ,3]dioxolyl, -C02H, -C(0)-NR RB, -C(0)-N H-(Ci -4alkyl )-0-
(Ci 2alkyl), -C(0 )-NH-phenyl, -C(0 )-NH-CH2-phenyl, -C(0 )-NH-C5-6cycloalkyl
and -CH2-NH-C5 -6cycloalkyl; wherein R and RB are each independently
selected from the group consisting of hydrogen and C -4alkyl; and wherein the
phenyl, whether alone or as part of a substituent group is optionally substituted
with one to two substituent independently selected from halogen, hydroxy, -
2alkyl, CF3 and C -2alkoxy.
In an embodiment of the present invention, a is 1 and the R group is
bound at the -6-position of the bicyclic core (i.e. the 6-position of the
benzothiazole or benzoxazole core structure).
In another embodiment of the present invention, R is selected from the
group consisting of 6-(bromo), 6-(carboxy), 6-(hydroxymethyl), 6-(methoxy), 6-
(benzo[d][1 ,3]dioxol-5-yl), 6-(pyrid-3-yl), 6-(4-methylphenyl), 6-(3,4-
dimethoxyphenyl), 6-(3,4-difluorophenyl), 6-(4-trifluoromethyl-phenyl), 6-(4-
hydroxyphenyl), 6-(2-fluorophenyl), 6-(3,5-dichlorophenyl), 6-(3,4-
dimethoxyphenyl-amino-carbonyl), 6-(cyclopentyl-amino-carbonyl), 6-(4-
fluorophenyl-amino-carbonyl), 6-(n-butyl-amino-carbonyl), 6-(methoxy-n-propylamino-
carbonyl), 6-(dimethylamino-carbonyl), 6-(4-ethoxyphenyl-aminocarbonyl),
6-(n-propylamino-carbonyl), 6-(cyclohexyl-amino-carbonyl), 6-(3-
methoxy-benzyl-amino-carbonyl) and 6-(cyclopentyl-amino-methyl).
In another embodiment of the present invention, R is selected from the
group consisting of 6-(bromo), 6-(hydroxymethyl), 6-(benzo[d][1 ,3]dioxol-5-yl),
6-(pyrid-3-yl), 6-(4-methylphenyl), 6-(3,4-dimethoxyphenyl), 6-(3,4-
difluorophenyl), 6-(4-trifluoromethyl-phenyl), 6-(4-hydroxyphenyl), 6-(2-
fluorophenyl), 6-(3,5-dichlorophenyl), 6-(3,4-dimethoxyphenyl-amino-carbonyl),
6-(cyclopentyl-amino-carbonyl), 6-(4-fluorophenyl-amino-carbonyl), 6-(n-butylamino-
carbonyl), 6-(methoxy-n-propyl-amino-carbonyl), 6-(dimethylaminocarbonyl),
6-(4-ethoxyphenyl-amino-carbonyl), 6-(n-propylamino-carbonyl), 6-
(cyclohexyl-amino-carbonyl), 6-(3-methoxy-benzyl-amino-carbonyl) and 6-
(cyclopentyl-amino-methyl). In another embodiment of the present invention, R
is selected from the group consisting of 6-(hydroxymethyl), 6-
(benzo[d][1 ,3]dioxol-5-yl), 6-(pyrid-3-yl), 6-(3,4-dimethoxyphenyl), 6-(3,4-
difluorophenyl), 6-(4-hydroxyphenyl), 6-(2-fluorophenyl), 6-(3,4-
dimethoxyphenyl-amino-carbonyl), 6-(cyclopentyl-amino-carbonyl), 6-(4-
fluorophenyl-amino-carbonyl), 6-(n-butyl-amino-carbonyl), and 6-(cyclopentylamino-
methyl). In another embodiment of the present invention, R is selected
from the group consisting of 6-(benzo[d][1 ,3]dioxol-5-yl), 6-(pyrid-3-yl), 6-(4-
hydroxyphenyl) and 6-(3,4-dimethoxyphenyl-amino-carbonyl);
In an embodiment of the present invention, X is O. In another
embodiment of the present invention, X is S.
In an embodiment of the presen lected from the group
consisting of -NH-CH 2CH2-N(RC)- and wherein Rc is
selected from the group consisting of hydrogen and methyl. In another
embodiment of the present invention, L is selected from the group consisting of
-NH-CH 2CH2-NH-, -NH-CH 2CH2-N(CH3)- and
embodiment of the present lected from the group consisting of
-NH-CH 2CH2-N(CH3)- and
In an embodiment of the present invention, L is
another embodiment of the present invention, L is selected from the group
consisting of-NH-CH 2CH2-N(Rc )- and; wherein Rc is selected from the group
consisting of hydrogen, methyl and ethyl. In another embodiment of the
present invention, L is selected from the group consisting of-NH-CH 2CH2-NHand
-NH-CH 2CH2-N(CH3)-. In another embodiment of the present invention, L
is -NH-CH 2CH2-NH-. In another embodiment of the present invention, L is -
NH-CH2CH2-N(CH3)-.
In an embodiment of the present invention, R2 is selected from the group
consisting of C -4alkyl, C2-4alkynyl, -CH2-thienyl and -CH 2-furyl. In another
embodiment of the present invention, R2 is selected from the group consisting
of C -2alkyl, C2-4alkynyl, -CH2-thienyl and -CH 2-furyl. In another embodiment of
the present invention, R2 is selected from the group consisting of ethyl, npropyn-
2-yl, -CH2-(thien-2-yl), -CH2-(thien-3-yl) and -CH 2-(fur-2-yl). In another
embodiment of the present invention, R2 is selected from the group consisting
of -CH2-(thien-2-yl) and -CH 2-(fur-2-yl). In another embodiment of the present
invention, R2 is -CH2-(thien-2-yl).
In an embodiment, the present invention is directed to compounds of
formula (I) wherein the compound of formula (I) is present in the (S)
configuration in an enantiomeric excess of greater than or equal to about 80%,
more preferably, in an enantiomeric excess of greater than or equal to about
90%, more preferably still, in an enantiomeric excess of greater than or equal to
about 95%, more preferably still, in an enantiomeric excess of greater than or
equal to about 98%, most preferably, in an enantiomeric excess of greater than
or equal to about 99%.
Additional embodiments of the present invention, include those wherein
the substituents selected for one or more of the variables defined herein (i.e. a,
R , X, L, R2) are independently selected to be any individual substituent or any
subset of substituents selected from the complete list as defined herein. In
another embodiment of the present invention is any single compound or subset
of compounds selected from the representative compounds listed in Tables 1
and 2, below.
Representative compounds of the present invention are as listed in
Tables 1 to 2, below. One skilled in the art will recognize that in the recitation
of the bonding position of the (R )a substituent group(s) to the
core of the compounds of formula (I) (including in Tables 1 and 2, below), the
position of (R )a substituent group(s)shall be denoted according to the following
numbering scheme:
One skilled in the art will further recognize that in Tables 1 and 2 which
follow herein, in the column headed "(R )a" , the recitation of #-(substituted
group) shall denote the position at which the R group is bound to the
followed by the identification of the substituent group within the
parentheses. For example, the notation 6-(3,4-dimethoxy-phenyl-aminocarbonyl)
shall denoted a 3,4-dimethoxy-phenyl-amino-carbonyl substituent,
bound through the carbonyl portion, and bound at the 6-position of the
core.
Table 1: Representative Compounds of Formula (I)
6-(4-hydroxyphenyl) S -CH2-(thien-2-yl)
6-(2-fluorophenyl) S -CH2-(thien-2-yl)
6-(3,5-dichlorophenyl) S -CH2-(thien-2-yl)
6-(hydroxymethyl) S -CH2-(thien-2-yl)
6-(cyclopentyl-aminocarbonyl)
S -CH2-(thien-2-yl)
6-(4-fluorophenyl-aminocarbonyl)
S -CH2-(thien-2-yl)
6-(cyclopentyl-aminomethyl)
S -CH2-(thien-2-yl)
6-(n-butyl-amino-carbonyl) S -CH2-(thien-2-yl)
6-(methoxy-n-propylamino-
carbonyl) S -CH2-(thien-2-yl)
6-(carboxy) S -CH2-(thien-2-yl)
6-(dimethylamino-carbonyl) S -CH2-(thien-2-yl)
6-(4-ethoxyphenyl-aminocarbonyl)
S -CH2-(thien-2-yl)
6-(n-propyl-aminocarbonyl)
S -CH2-(thien-2-yl)
6-(cyclohexyl-aminocarbonyl)
S -CH2-(thien-2-yl)
6-(3-methoxybenzylamino-
carbonyl) S -CH2-(thien-2-yl)
Table 2 : Representative Compounds of Formula (I)
43 6-(methoxy) S H ethyl
44 a = 0 0 H n-propyn-2-yl
45 a = 0 0 H ethyl
46 a = 0 S H -CH2-(thien-2-yl)
47 a = 0 0 H -CH2-(thien-2-yl)
6-(3,4-dimethoxy-
48 phenyl-amino-carbonyl) S methyl -CH2-(thien-2-yl)
In another embodiment, the present invention is directed to compounds
of formula (I) whose IC5o, measured according to the procedure described in
Biological Example 1, is less than or equal to about 10 mM, preferably less than
or equal to about 5.0 mM, more preferably less than or equal to about 3.0 mM,
more preferably less than or equal to about 1.0 mM, more preferably less than
or equal to about 0.5 mM.
As used herein, "halogen" shall mean chlorine, bromine, fluorine and
iodine.
As used herein, the term "C -4alkyl" whether used alone or as part of a
substituent group, shall include any straight and branched carbon chain
compositions of one to four carbon atoms. For example, alkyl radicals include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. One
skilled in the art will recognize that the term "-(Ci -4alkyl)-" shall denote any C-i-
4alkyl carbon chain as herein defined, wherein said C -4alkyl chain is divalent
and is further bound through two points of attachment, preferably through two
terminal carbon atoms.
As used herein, unless otherwise noted, the term "fluorinated d^alkyl"
shall mean any Ci -4alkyl group, as herein defined, substituted with at least one
fluoro atom. Suitable examples include but are not limited to -CF 3, -CH2-CF3, -
CF2-CF2-CF2-CF3, and the like. Preferably, the halogenated or fluorinated alkyl
is -CF 3.
As used herein, the term "C2-4alkenyl" whether used alone or as part of
a substituent group, shall include straight and branched carbon chain
compositions of two to four carbon atoms, further containing one or more,
preferably one, unsaturated double bond. For example, C2-4alkenyl radicals
include ethenyl, n-propen-2-yl, n-buten-2-yl, and the like.
As used herein, the term "C2-4alkynyl" whether used alone or as part of
a substituent group, shall include straight and branched carbon chain
compositions of two to four carbon atoms, further containing one or more,
preferably one, unsaturated triple bond. For example, C2-4alkynyl radicals
include ethynyl, n-propyn-2-yl, n-butyn-2-yl, and the like.
As used herein, the term "alkoxy" whether used alone or as part of a
substituent group, shall denote an oxygen ether radical of any of the above
described straight and branched carbon chain compositions of one to six
carbon atoms. For example, alkoxy radicals include methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, and the like.
The prefix C c.g "wherein X and Y are integers, when used with alkoxy shall
mean an oxygen radical of any of the above described carbon chain
composition of between X and Y carbon atoms. For example, the term "C-ialkoxy"
shall mean an oxygen ether radical of any straight or branched carbon
chain composition of 1 to 4 carbon atoms. Suitably examples include methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy.
As used herein, unless otherwise noted, the term "fluorinated d .
4alkoxy" shall mean any C -4alkoxy group, as herein defined, substituted with
at least one fluoro atom. Suitable examples include but are not limited to -
OCF3, -OCH2-CF3, -OCF2-CF2-CF2-CF3, and the like. Preferably, the
halogenated or fluorinated alkoxy is -OCF 3.
As used herein, unless otherwise noted, the term "C 3-6cycloalkyl" shall
mean any stable 3-6 membered monocyclic, saturated ring system, for
example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, unless otherwise noted, " 5 to 6 membered heteroaryl"
shall denote any five or six membered, monocyclic aromatic ring structure
containing at least one heteroatom selected from the group consisting of O, N
and S, optionally containing one to three additional heteroatoms independently
selected from the group consisting of O, N and S. The 5 to 6 membered
heteroaryl group may be attached at any heteroatom or carbon atom of the ring
such that the result is a stable structure. Examples of suitable heteroaryl groups
include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,
imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, and the like. Preferred heteroaryl
groups include, but are not limited to, furyl, thienyl, imidazolyl, thiazolyl, pyridyl
and pyrimidinyl.
When a particular group is "substituted" (e.g., alkyl, cycloalkyl, phenyl,
heteroaryl, etc.), that group may have one or more substituents, preferably from
one to five substituents, more preferably from one to three substituents, most
preferably from one to two substituents, independently selected from the list of
substituents.
With reference to substituents, the term "independently" means that
when more than one of such substituents is possible, such substituents may be
the same or different from each other.
As used herein, the notation "*" shall denote the presence of a
stereogenic center. Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers. Where the
compounds possess two or more chiral centers, they may additionally exist as
diastereomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention. Preferably,
wherein the compound is present as an enantiomer, the enantiomer is present
at an enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to about 90%,
more preferably still, at an enantiomeric excess of greater than or equal to
about 95%, more preferably still, at an enantiomeric excess of greater than or
equal to about 98%, most preferably, at an enantiomeric excess of greater than
or equal to about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric excess of
greater than or equal to about 80%, more preferably, at an diastereomeric
excess of greater than or equal to about 90%, more preferably still, at an
diastereomeric excess of greater than or equal to about 95%, more preferably
still, at an diastereomeric excess of greater than or equal to about 98%, most
preferably, at an diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the
present invention may exist as polymorphs and as such are intended to be
included in the present invention. In addition, some of the compounds of the
present invention may form solvates with water (i.e., hydrates) or common
organic solvents, and such solvates are also intended to be encompassed
within the scope of this invention.
Under standard nomenclature used throughout this disclosure, the terminal
portion of the designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a "phenylCr
C6alkylaminocarbonylCi-C6alkyl" substituent refers to a group of the formula
Abbreviations used in the specification, particularly the Schemes and
Examples, are as follows:
Boc or BOC ferf-Butoxycarbonyl
Cbz Benzyloxy-carbonyl
DCM Dichloromethane
Dess-Martin Reagent [ 1 , 1 ,1-Triacetoxy-1 .1-dihydro-1 ,2-benziodoxol-
3-(1 H)-one]
DIPEA or DIEA Diisopropylethylamine
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
DTT Dithiothreitol
EDC or EDCI 1-Ethyl-3-(3-dimethylaminopropyl)
carbodiimide
EtOAc Ethyl Acetate
GR-AMC Glycine-Arginine-amino-4-methyl-coumain
GSH Glutathione
HATU 0-(7-Azabenzotriazol-1-yl)-N,N,N",N"-
Tetramethyl Uronium Hexafluorophosphate
HBTU 0-(1 H-Benzotriazol-1-yl)-N,N,N',N'-
tetramethyluronium hexafluorophosphate
HEPES 4-(2-Hydroxyethyl)-1 -Piperizine Ethane
Sulfonic Acid
HOBT or HOBt 1-Hydroxybenzotriazole
HPLC High Pressure Liquid Chromatography
MeOH Methanol
MOM Methoxymethyl
MTBE Methyl ierf-Butyl Ether
Na(OAc)3BH Sodium triacetoxyborohydride
NMP N-methyl-2-pyrrolidinone
Pd2(OAc)2 Palladium(ll)acetate
Pd(dppf)CI2 Dichloro[1 ,1'-bis(diphenylphosphine)
ferrocene]palladium(l I)
Pd(PPh3)4 Tetrakistriphenylphosphine palladium (0)
PyBOP Benzo-triazol-l-yloxytris(pyrrolidino)-
phosphonium hexafluorophosphate
TEA Triethylamine
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
THP Tetrahydropyranyl
TMS Trimethylsilyl
As used herein, unless otherwise noted, the term "isolated form" shall
mean that the compound is present in a form which is separate from any solid
mixture with another compound(s), solvent system or biological environment.
In an embodiment, the compound of formula (I) is prepared as an isolated form.
As used herein, unless otherwise noted, the term "substantially pure
compound" shall mean that the mole percent of impurities in the isolated
compound is less than about 5 mole percent, preferably less than about 2 mole
percent, more preferably, less than about 0.5 mole percent, most preferably,
less than about 0.1 mole percent. In an embodiment, the compound of formula
(I) is present as a substantially pure compound.
As used herein, unless otherwise noted, the term "substantially free of
a corresponding salt form(s)" when used to described the compound of
formula (I) shall mean that mole percent of the corresponding salt form(s) in the
isolated base of formula (I) is less than about 5 mole percent, preferably less
than about 2 mole percent, more preferably, less than about 0.5 mole percent,
most preferably less than about 0.1 mole percent. In an embodiment, the
compound of formula (I) is present in a form which is substantially free of
corresponding salt form(s).
As used herein, unless otherwise noted, the terms "treating",
"treatment" and the like, shall include the management and care of a subject or
patient (preferably mammal, more preferably human) for the purpose of
combating a disease, condition, or disorder and includes the administration of a
compound of the present invention to prevent the onset of the symptoms or
complications, alleviate the symptoms or complications, or eliminate the
disease, condition, or disorder.
As used herein, unless otherwise noted, the term "prevention" shall
include (a) reduction in the frequency of one or more symptoms; (b) reduction
in the severity of one or more symptoms; (c) the delay or avoidance of the
development of additional symptoms; and / or (d) delay or avoidance of the
development of the disorder or condition.
One skilled in the art will recognize that wherein the present invention is
directed to methods of prevention, a subject in need of thereof (i.e. a subject in
need of prevention) shall include any subject or patient (preferably a mammal,
more preferably a human) who has experienced or exhibited at least one
symptom of the disorder, disease or condition to be prevented. Further, a
subject in need thereof may additionally be a subject (preferably a mammal,
more preferably a human) who has not exhibited any symptoms of the disorder,
disease or condition to be prevented, but who has been deemed by a
physician, clinician or other medical profession to be at risk of developing said
disorder, disease or condition. For example, the subject may be deemed at
risk of developing a disorder, disease or condition (and therefore in need of
prevention or preventive treatment) as a consequence of the subject's medical
history, including, but not limited to, family history, pre-disposition, co-existing
(comorbid) disorders or conditions, genetic testing, and the like.
The term "subject" as used herein, refers to an animal, preferably a
mammal, most preferably a human, who has been the object of treatment,
observation or experiment. Preferably, the subject has experienced and / or
exhibited at least one symptom of the disease or disorder to be treated and / or
prevented.
The term "therapeutically effective amount" as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological or
medicinal response in a tissue system, animal or human that is being sought by a
researcher, veterinarian, medical doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified ingredients in the specified amounts.
As used herein, the term "DPP-1 mediated disorder" shall include any
condition, disease or disorder which may be mediated through inhibition of
DPP-1 activity. One skilled in the art will recognize that disorders mediated by
DPP-1 include, but are not limited to
(a) disorders of the respiratory tract: including obstructive diseases of
the airways including asthma, including bronchial, allergic, intrinsic, extrinsic,
exercise-induced, drug induce (including aspirin and NSAID-induced) and dust
induced asthma, both intermittent and persistent and of all severities, and other
causes of airway hyper-responsiveness; chronic obstructive pulmonary disease
(COPD); bronchitis, including infectious and eosinophilic bronchitis;
emphysema; bronchiectasis; cystic fibrosis; sacroidosis; farmer's lung and
related diseases; hypersensitive pnemonitis; lung fibrosis, including cryptogenic
fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating antineoplastic
therapy and chronic infection, including tuberculosis and
aspergillosis and other fungal infections; complications of lung transplantation;
vascullitic and thrombotic disorders of the lung vasculature, and pulmonary
hypertension; antitussive activity including treatment of chronic cough
associated with inflammatory and secretory conditions of the airways, and
iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa,
and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis
nervosa (hay fever); nasal polyposis; acute viral infection including the common
cold, and infection due to respiratory syncytial virus, influenza, coronavirus
(including SARS) and adenovirus;
(b) skin disorders: psoriasis, atopic dermatitis, contact dermatatis or
other eczematous deramtoses, and delayed-type hypersensitivity reactions;
phyto- and photodermatitis; seborrhoeic dermatistis, dermatitis herptiformis,
lichen planus, lichen slerosus et atrophica, pyoderma gangrenosum, skin
sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis
bullosa, urticaria, angioderma, vasculitides, toxid erythmas, cutaceous
eosinopiliass, alopecia areata, male-pattern baldness, Sweet's syndrome,
Weber-Christian syndrome, erythema multiforma; cellulitis, both infective and
non-infective; panniculitis; cutaceous lymphomas, non-melanoma skin cancer
and other dysplastic lesions; drug-induced disorders including fixed-drug
eruptions;
(c) eye disorders: blepharitis, conjunctivitis, including perennial and
vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis;
autoimmune, degenerative or inflammatory disorders affecting the retina;
opthalmitis including sympathetic opthalmitis; sarcoidosis; infections including
viral, fugal and bacterial;
(d) genitourinary disorders: nephritis including interstitial and
glomerulnephritis; nephritic syndrome; cystitis including acute and chronic
(interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis,
epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease;
erectile dysfunction;
(e) allograft rejection disorders: acute and chronic following, for example,
transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or
following blood transfusion; or chronic graft versus host disease;
(f) auto-immune and allergic disorders including rheumatoid arthritis,
irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis,
Hashimoto's thyroiditis, Grave's disease, Addison's disease, diabetes mellitus,
idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-lgE
syndrome, antiphospholipid syndrome and Sazary syndrome;
(g) cancers: including treatment of common cancers including prostate,
breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain
tumors and malignancies affecting the bone marrow (including leukaemias) and
lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma;
including the prevention and treatment of metastatic disease and tumor
recurrences, and paraneoplstic syndrome; and
(h) infectious diseases: viral diseases such as genital warts, common
warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum
contagiosum, variola, human immunodeficiency virus (HIV), human papilloma
virus (HPV), cytomegalovirus (CMV), varicella zoser virus (VZV), rhinovirus,
adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as
tubercuavium, leprosy; other infectious diseases such as fungal diseases,
Chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii,
cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and
leishmaniasis.
In another embodiment, the present invention is directed to methods for
the treatment and / or prevention of a DDP-1 mediated disorder; wherein the
DPP-1 mediated disorder is selected from the group consisting of chronic
obstructive pulmonary disease (COPD), asthma, acute lung injury, adult
respiratory distress syndrome, abdominal or thoracic aneurism, rheumatoid
arthritis, osteoarthritis, multiple sclerosis, sepsis and taxoplasmosis.
In another embodiment, the present invention is directed to methods for
the treatment and / or prevention of a DDP-1 mediated disorder; wherein the
DPP-1 mediated disorder is selected from the group consisting of rheumatoid
arthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis,
irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
As more extensively provided in this written description, terms such as
"reacting" and "reacted" are used herein in reference to a chemical entity that
is any one of: (a) the actually recited form of such chemical entity, and (b) any
of the forms of such chemical entity in the medium in which the compound is
being considered when named.
One skilled in the art will recognize that, where not otherwise specified,
the reaction step(s) is performed under suitable conditions, according to known
methods, to provide the desired product. One skilled in the art will further
recognize that, in the specification and claims as presented herein, wherein a
reagent or reagent class/type (e.g. base, solvent, etc.) is recited in more than
one step of a process, the individual reagents are independently selected for
each reaction step and may be the same of different from each other. For
example wherein two steps of a process recite an organic or inorganic base as
a reagent, the organic or inorganic base selected for the first step may be the
same or different than the organic or inorganic base of the second step.
Further, one skilled in the art will recognize that wherein a reaction step of the
present invention may be carried out in a variety of solvents or solvent systems,
said reaction step may also be carried out in a mixture of the suitable solvents
or solvent systems.
To provide a more concise description, some of the quantitative
expressions given herein are not qualified with the term "about". It is
understood that whether the term "about" is used explicitly or not, every
quantity given herein is meant to refer to the actual given value, and it is also
meant to refer to the approximation to such given value that would reasonably
be inferred based on the ordinary skill in the art, including approximations due
to the experimental and/or measurement conditions for such given value.
To provide a more concise description, some of the quantitative
expressions herein are recited as a range from about amount X to about
amount Y. It is understood that wherein a range is recited, the range is not
limited to the recited upper and lower bounds, but rather includes the full range
from about amount X through about amount Y, or any range therein.
Examples of suitable solvents, bases, reaction temperatures, and other
reaction parameters and components are provided in the detailed descriptions
which follows herein. One skilled in the art will recognize that the listing of said
examples is not intended, and should not be construed, as limiting in any way
the invention set forth in the claims which follow thereafter.
As used herein, unless otherwise noted, the term "aprotic solvent" shall
mean any solvent that does not yield a proton. Suitable examples include, but
are not limited to DMF, 1,4-dioxane, THF, acetonitrile, pyridine, 1,2-
dichloroethane, dichloromethane, MTBE, toluene, acetone, and the like.
As used herein, unless otherwise noted, the term "leaving group" shall
mean a charged or uncharged atom or group which departs during a
substitution or displacement reaction. Suitable examples include, but are not
limited to, Br, CI, I, mesylate, tosylate, and the like.
As used herein, unless otherwise noted, the term "nitrogen protecting
group" shall mean a group which may be attached to a nitrogen atom to
protect said nitrogen atom from participating in a reaction and which may be
readily removed following the reaction. Suitable nitrogen protecting groups
include, but are not limited to carbamates - groups of the formula -C(0)0-R
wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CHCH
2- , and the like; amides - groups of the formula -C(0)-R' wherein R' is for
example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives -
groups of the formula -S0 2-R" wherein R" is for example tolyl, phenyl,
trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-
methoxybenzene, and the like. Other suitable nitrogen protecting groups may
be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in
Organic Synthesis , John Wiley & Sons, 1991 .
As used herein, unless otherwise noted, the term "oxygen protecting
group" shall mean a group which may be attached to a oxygen atom to protect
said oxygen atom from participating in a reaction and which may be readily
removed following the reaction. Suitable oxygen protecting groups include, but
are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS),
MOM, THP, and the like. Other suitable oxygen protecting groups may be
found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in
Organic Synthesis , John Wiley & Sons, 1991 .
One skilled in the art will recognize that wherein a reaction step of the
present invention may be carried out in a variety of solvents or solvent systems,
said reaction step may also be carried out in a mixture of the suitable solvents
or solvent systems.
Where the processes for the preparation of the compounds according to
the invention give rise to mixture of stereoisomers, these isomers may be
separated by conventional techniques such as preparative chromatography.
The compounds may be prepared in racemic form, or individual enantiomers
may be prepared either by enantiospecific synthesis or by resolution. The
compounds may, for example, be resolved into their component enantiomers
by standard techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid
and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and
regeneration of the free base. The compounds may also be resolved by
formation of diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the compounds
may be resolved using a chiral HPLC column.
Additionally, chiral HPLC against a standard may be used to determine
percent enantiomeric excess (%ee). The enantiomeric excess may be
calculated as follows
[ (Rmoles-Smoles)/(Rmoles+Smoles) ] X 100%
where Rmoles and Smoles are the R and S mole fractions in the mixture
such that Rmoles+Smoles = 1. The enantiomeric excess may alternatively be
calculated from the specific rotations of the desired enantiomer and the
prepared mixture as follows:
ee = ([a-obs] / [a-max]) X 100.
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect sensitive or
reactive groups on any of the molecules concerned. This may be achieved by
means of conventional protecting groups, such as those described in Protective
Groups in Organic Chemistry , ed. J.F.W. McOmie, Plenum Press, 1973; and
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis , John
Wiley & Sons, 1991 . The protecting groups may be removed at a convenient
subsequent stage using methods known from the art.
For use in medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts." Other salts may, however, be
useful in the preparation of compounds according to this invention or of their
pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts
of the compounds include acid addition salts which may, for example, be
formed by mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid,
fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid,
tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the
compounds of the invention carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may include alkali metal salts, e.g., sodium or
potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts;
and salts formed with suitable organic ligands, e.g., quaternary ammonium
salts. Thus, representative pharmaceutically acceptable salts include, but are
not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate,
bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,
esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate,
pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,
polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to, the following:
acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic
acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-
(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid,
ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic
acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hipuric acid,
hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid,
lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-
disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotine acid, nitric acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, Lpyroglutamic
acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,
p-toluenesulfonic acid and undecylenic acid.
Representative bases which may be used in the preparation of
pharmaceutically acceptable salts include, but are not limited to, the following:
bases including ammonia, L-arginine, benethamine, benzathine, calcium
hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-
ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary
amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
The present invention includes within its scope prodrugs of the
compounds of this invention. In general, such prodrugs will be functional
derivatives of the compounds which are readily convertible in vivo into the
required compound. Thus, in the methods of treatment of the present
invention, the term "administering" shall encompass the treatment of the
various disorders described with the compound specifically disclosed or with a
compound which may not be specifically disclosed, but which converts to the
specified compound in vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs" , ed. H. Bundgaard, Elsevier,
1985.
Compounds of formula (I) wherein X is S and L is -NH-CH 2CH2-NRCmay
be prepared according to the process outlined in Scheme 1, below.
Scheme 1
Accordingly, a suitably substituted compound of formula (V), wherein
PG1 is a suitably selected nitrogen protecting group such as -C(0)CF 3, Boc,
CBz, and the like, a known compound or compound prepared by known
methods, is reacted with a suitably substituted compound of formula (IV),
wherein PG° is a suitably selected nitrogen protecting group such as Boc, CBz,
and the like, a known compound or compound prepared by known methods; in
the presence of a suitably selected coupling system such as HOBt in
combination with EDC, and the like; in the presence of a suitably selected
organic base such as TEA, DIPEA, pyridine, and the like; in a suitably selected
organic solvent such as DCM, DMF, and the like; to yield the corresponding
compound of formula (VII).
The compound of formula (VII) is selectively de-protected according to
known methods; to yield the corresponding compound of formula (VIII). For
example, wherein PG° is CBz, the compound of formula (VII) is de-protected by
reacting with 1,4-cyclohexadiene or 10% palladium on carbon, in a solvent
such as ethanol.
The compound of formula (VIII) is reacted with a suitably substituted
compound of formula (IX), a known compound or compound prepared by
known methods; in a suitably selected organic solvent such as DCM, THF,
chloroform, and the like, to yield the corresponding compound of formula (X).
The compound of formula (X) is reacted with benzyl-trimethylammonium
tribromide, a known compound; in a suitably selected organic
solvent such as DCM, 1,2-dimethoxyethane, acetonitrile, and the like, to yield
the corresponding compound of formula (XI).
The compound of formula (XI) is de-protected according to known
methods; to yield the corresponding compound of formula (la). For example,
wherein PG1 is -C(0)CF 3, the compound of formula (XI) is de-protected by
reacting with a suitably selected base such as NaOH, LiOH, and the like, in a
suitably selected solvent such as THF, water, and the like.
Compounds of formula (I) wherein L is -NH-CH 2CH2-N(RC)- may
alternatively be prepared according to the process outlined in Scheme 2,
below.
(XIV) (V)
(
Scheme 2
Accordingly, a suitably substituted compound of formula (XII), wherein
LG is a suitably selected leaving group such as bromo, chloro, and the like, a
known compound or compound prepared by known methods, is reacted with a
suitably substituted compound of formula (VI), wherein PG2 s a suitably
selected nitrogen protecting group such as Boc, CBz, and the like, a known
compound or compound prepared by known methods; in the presence of an
organic base such as DIPEA, TEA, pyridine, and the like; in a suitably selected
organic solvent such as NMP, DMF, and the like; preferably at an elevated
temperature in the range of from about 80°C to about 125°C, for example, at
about 120°C; to yield the corresponding compound of formula (XIII).
The compound of formula (XIII) is de-protected according to known
methods, to yield the corresponding compound of formula (XIV). For example,
wherein PG2 is Boc, the compound of formula (XIII) is de-protected by reacting
with a suitably selected acid such as HCI, TFA, and the like, in a suitably
selected organic solvent such as 1,4-dioxane, DCM, and the like.
The compound of formula (XIV) is reacted with a suitably substituted
compound of formula (V), wherein PG1 is a suitably selected nitrogen
protecting group such as Boc, CBz, and the like, a known compound or
compound prepared by known methods; in the presence of a suitably selected
coupling system such as HOBt in combination with EDCI, and the like; in the
presence of a suitably selected organic base such as TEA, DIPEA, pyridine,
and the like; in a suitably selected organic solvent such as DCM, DMF, and the
like; to yield the corresponding compound of formula (XV).
The compound of formula (XV) is de-protected according to known
methods to yield the corresponding compound of formula (lb). For example,
wherein PG3 is Boc, the compound of formula (XV) is de-protected by reacting
with a suitably selected acid such as HCI, TFA, and the like, in a suitably
selected organic solvent such as 1,4-dioxane, DCM, and the like.
One skilled in the art will recognize that compounds of formula (XII)
wherein a is 1 and wherein R is selected from the group consisting of -C(O)-
NR RB, -C(0)-NH-(Ci -4alkyl)-0-(Ci -4alkyl), -C(0)-NH-phenyl, -C(0)-NH-CH 2-
phenyl and -C(0)-NH-C 3-6cycloalkyl may be prepared as described in Scheme
3, below.
(Xlla)
Scheme 3
Accordingly, a suitably substituted compound of formula (II), wherein
LG is a suitably selected leaving group such as bromo, chloro, and the like, a
known compound or compound prepared by known methods, is reacted with a
suitably selected source of chlorine such as oxalyl chloride, thionyl chloride,
and the like; in the presence of a catalytic amount of DMF; in a suitably
selected solvent such as DCM, THF, and the like; to yield the corresponding
compound of formula (III).
The compound of formula (III) is reacted with a suitably substituted
amine, a compound of formula (IV), wherein R is -NR RB, -NH-(Ci - alkyl)-0-
(Ci -4alkyl), -NH-phenyl, -NH-CH 2-phenyl and -NH-C3-6cycloalkyl, a known
compound or compound prepared by known methods; in the presence of an
organic base such as DIPEA, TEA, pyridine, and the like; in an aprotic organic
solvent such as DCM, THF, chloroform, and the like; to yield the corresponding
compound of formula (XIlia).
Compounds of formula (I) wherein L is may be
prepared according to the process outlined in Scheme 4, below.
( )a-r
(XII)
Scheme 4
Accordingly, a suitably substituted compound of formula (XII), wherein
is a suitably selected leaving group such as bromo, chloro, and the like, a
known compound or compound prepared by known methods, is reacted with a
suitably substituted compound of formula (XVI), wherein PG3 is a suitably
selected nitrogen protecting group such as BOC, CBz, and the like, a known
compound or compound prepared by known methods; in the presence of a
suitably selected organic base such as DIPEA, TEA, pyridine, and the like; in a
suitably selected organic solvent such as NMP, DMF, and the like; preferably at
an elevated temperature in the range of from about 80°C to about 125°C, for
example, at about 120°C; to yield the corresponding compound of formula
(XVI I).
The compound of formula (XVI I) is de-protected according to known
methods, to yield the corresponding compound of formula (XVI II). For
example, wherein PG3 is Boc, the compound of formula (XVI I) is de-protected
by reacting with a suitably selected acid such as HCI , TFA, and the like, in a
suitably selected organic solvent such as 1,4-dioxane, DCM, and the like.
The compound of formula (XVI II) is reacted with a suitably substituted
compound of formula (V), wherein PG1 is a suitably selected nitrogen
protecting group such as -C(0)CF 3, Boc, CBz, and the like, a known
compound or compound prepared by known methods, in the presence of a
suitably selected coupling system such as HOBt in combination with EDCI , and
the like; in the presence of a suitably selected organic base such as TEA,
DIPEA, pyridine, and the like; in a suitably selected organic solvent such as
DCM, DMF, and the like; to yield the corresponding compound of formula (XIX).
The compound of formula (XIX) is de-protected according to known
methods to yield the corresponding compound of formula (lc). For example,
wherein PG1 is Boc, the compound of formula (XIX) is de-protected by reacting
with a suitably selected acid such as HCI , TFA, and the like, in a suitably
selected organic solvent such as 1,4-dioxane, DCM, and the like.
One skilled in the art will recognize that compounds of formula (lc)
wherein R is selected from the group consisting of C -4alkyl, optionally
substituted phenyl, 5 to 6 membered heteroaryl and benzo[d][1 ,3]dioxolyl , may
alternatively be prepared by reacting as described in Scheme 5, below.
H2N
(Id)
Scheme 5
Accordingly, a suitably substituted compound of formula (XlXa), a
compound of formula (XIX) wherein a is 1 and R is bromo, prepared for
example as described in Scheme 4 above, is reacted with a suitably substituted
boronic acid compound of formula (XXX), wherein R 2 is selected from the
group consisting of C -4alkyl, optionally substituted phenyl, 5 to 6 membered
heteroaryl and benzo[d][1 ,3]dioxolyl , a known compound or compound
prepared by known methods; in the presence of a suitably selected coupling
agent such as Pd(PPh 3) , Pd(OAc) 2, Pd(dppf)CI 2, and the like; in the presence
of a suitably selected inorganic base such as K2CC>3, and the like; in a suitably
selected solvent or mixture thereof such as 1,4-dioxane, water, a mixture of
THF and water, and the like; to yield the corresponding compound of formula
(XlXb).
The compound of formula (XlXb) is de-protected according to known
methods, for example, as described in Scheme 4 above, to yield the
corresponding compound of formula (Id).
Compounds of formula (I) wherein L is or -NHCH
2CH2-N(Rc )-and wherein R is selected from the group consisting of -C(O)-
NR RB, -C(0)-NH -(Ci - alkyl)-0 -(Ci - alkyl), -C(0)-NH-phenyl, -C(0)-NH-CH 2-
phenyl and -C(0)-NH-C 3-6cycloalkyl may alternatively be prepared according to
the rocess outlined in Scheme 6, below.
Scheme 6
Accordingly, a suitably substituted compound of formula (XX), wherein
A1 is C -4alkyl, preferably methyl or ethyl, and wherein LG2 is a suitably
selected leaving group such as bromo, chloro, and the like, a known compound
or compound prepared by known methods, is reacted as herein described, to
yield the corresponding compound of formula (XXI), wherein PG1 is a suitably
selected nitrogen protecting group such as Boc, CBz, and the like. For
example, the compound of formula (XX) may be reacted with a suitably
substituted compound of formula (VI), de-protected and then reacted with a
suitably substituted compound of formula (V), according to the process outlined
in Scheme 2 above. Alternatively, the compound of formula (XX) may be
reacted with a suitably substituted compound of formula (XVI), de-protected
and then reacted with a suitably substituted compound of formula (V),
according to the process outlined in Scheme 4 above.
The compound of formula (XXI) is reacted with a suitably selected base
such as NaOH, LiOH, and the like; in a suitably selected organic solvent such
as methanol, ethanol, and the like; to yield the corresponding compound of
formula (XXII).
The compound of formula (XXII) is reacted with a suitably substituted
compound of formula (IV), wherein R is -NR RB, -NH-(Ci -4alkyl)-0 -(Ci -4alkyl),
-NH-phenyl, -NH-CH 2-phenyl and -NH-C3 -6cycloalkyl, a known compound or
compound prepared by known methods; in the presence of a suitably selected
coupling agent such as HBTU, HATU, PyBOP, and the like; in the presence of
a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; in
a suitably selected organic solvent such as DMF, and the like; to yield the
desired, corresponding compound of formula (XXIII).
The compound of formula (XXIII) is de-protected according to known
methods, to yield the corresponding compound of formula (le). For example,
wherein PG1 is Boc, the compound of formula (XIX) is de-protected by reacting
with a suitably selected acid such as HCI, TFA, and the like, in a suitably
selected organic solvent such as 1,4-dioxane, DCM, and the like.
Compounds of formula (I) wherein L is and wherein R
is -CH 2-OH or-CH 2-NH-C3-6cycloalkyl, may be prepared according the process
(XXIX)
PG3
Scheme 7
Accordingly, a suitably substituted compound of formula (XX), wherein
A1 is C -4alkyl, preferably methyl or ethyl, and wherein LG2 is a suitably
selected leaving group such as bromo, chloro, and the like, a known compound
or compound prepared by known methods, is reacted with a compound of
formula (XVI), wherein PG3 is a suitably selected nitrogen protecting group
such as Boc, CBz, and the like, a known compound or compound prepared by
known methods; in the presence of a suitably selected inorganic base such as
K2C0 3, Cs2C0 3, and the like; in a suitably selected organic solvent such as
acetonitrile, DMF, and the like; to yield the corresponding compound of formula
(XXIV).
The compound of formula (XXIV) is reacted with a suitably selected
reducing agent such LiBH , LiAIH , NaBH , and the like; in a suitably selected
organic solvent such as THF, diethyl ether, and the like; to yield the
corresponding compound of formula (XXV).
The compound of formula (XXV) is then de-protected according to
known methods, reacted with a suitably substituted compound of formula (V),
as described in Scheme 4 above, to yield the corresponding compound of
formula (XXVI).
The compound of formula (XXVI) is then de-protected according to
known methods, to yield the corresponding compound of formula (If), a
compound of formula (I) wherein R is hydroxym ethyl.
Alternatively, the compound of formula (XXVI) is reacted with a suitably
selected oxidizing agent such as Dess-Martin reagent, Pyridinium
chlorochromate (PCC), a mixture of DMS/oxalyl chloride, and the like; in a
suitably selected organic solvent such as DCM, acetonitrile, and the like; to
yield the corresponding compound of formula (XXVII).
The compound of formula (XXVII) is reacted with a suitably substituted
compound of formula (XXVIII), wherein Q is C 3-6cycloalkyl, a known compound
or compound prepared by known methods; in the presence of a suitably
selected reducing agent such as Na(OAc)3BH, NaCNBH3, and the like; in a
suitably selected organic solvent such as DCM, dichloroethane, methanol, and
the like; to yield the corresponding compound of formula (XXIX).
The compound of formula (XXIX) is de-protected according to known
methods, to yield the corresponding compound of formula (Ig). For example,
wherein PG is BOC, the compound of formula (XXIX) is de-protected by
reacting with a suitably selected acid such as HCI, TFA, and the like, in a
suitably selected organic solvent such as 1,4-dioxane, DCM, and the like.
One skilled in the art will recognize that compounds of formula (I)
wherein L is -NH-CH 2CH2-N(RC)- may similarly be prepared according to the
process outlined in Scheme 7 above, by selecting and substituting a suitably
substituted compound of formula (VI) for the compound of formula (XVI).
The present invention further comprises pharmaceutical compositions
containing one or more compounds of formula (I) with a pharmaceutically
acceptable carrier. Pharmaceutical compositions containing one or more of the
compounds of the invention described herein as the active ingredient can be
prepared by intimately mixing the compound or compounds with a
pharmaceutical carrier according to conventional pharmaceutical compounding
techniques. The carrier may take a wide variety of forms depending upon the
desired route of administration (e.g., oral, parenteral). Thus for liquid oral
preparations such as suspensions, elixirs and solutions, suitable carriers and
additives include water, glycols, oils, alcohols, flavoring agents, preservatives,
stabilizers, coloring agents and the like; for solid oral preparations, such as
powders, capsules and tablets, suitable carriers and additives include starches,
sugars, diluents, granulating agents, lubricants, binders, disintegrating agents
and the like. Solid oral preparations may also be coated with substances such
as sugars or be enteric-coated so as to modulate major site of absorption. For
parenteral administration, the carrier will usually consist of sterile water and
other ingredients may be added to increase solubility or preservation.
Injectable suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or
more compounds of the present invention as the active ingredient is intimately
admixed with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques, which carrier may take a wide
variety of forms depending of the form of preparation desired for administration,
e.g., oral or parenteral such as intramuscular. In preparing the compositions in
oral dosage form, any of the usual pharmaceutical media may be employed.
Thus, for liquid oral preparations, such as for example, suspensions, elixirs and
solutions, suitable carriers and additives include water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets, gelcaps and
tablets, suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and the like.
Because of their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are obviously employed. If desired, tablets may be sugar coated or
enteric coated by standard techniques. For parenterals, the carrier will usually
comprise sterile water, through other ingredients, for example, for purposes
such as aiding solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid carriers,
suspending agents and the like may be employed. The pharmaceutical
compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder,
injection, teaspoonful and the like, an amount of the active ingredient
necessary to deliver an effective dose as described above. The
pharmaceutical compositions herein will contain, per unit dosage unit, e.g.,
tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from
about 0.01 to about 1,000 mg or any amount or range therein, and may be
given at a dosage of from about 0.01 mg/kg/day to about 100 mg/kg/day, or
any amount or range therein. The dosages, however, may be varied
depending upon the requirement of the patients, the severity of the condition
being treated and the compound being employed. The use of either daily
administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms such as tablets,
pills, capsules, powders, granules, sterile parenteral solutions or suspensions,
metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or
suppositories; for oral parenteral, intranasal, sublingual or rectal administration,
or for administration by inhalation or insufflation. Alternatively, the composition
may be presented in a form suitable for once-weekly or once-monthly
administration; for example, an insoluble salt of the active compound, such as
the decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose, sucrose,
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums,
and other pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a compound of the present
invention, or a pharmaceutically acceptable salt thereof. When referring to
these preformulation compositions as homogeneous, it is meant that the active
ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective dosage forms
such as tablets, pills and capsules. This solid preformulation composition is
then subdivided into unit dosage forms of the type described above containing
from 0.01 to about 1,000 mg of the active ingredient of the present invention.
The tablets or pills of the novel composition can be coated or otherwise
compounded to provide a dosage form affording the advantage of prolonged
action. For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope over the
former. The two components can be separated by an enteric layer which
serves to resist disintegration in the stomach and permits the inner component
to pass intact into the duodenum or to be delayed in release. A variety of
material can be used for such enteric layers or coatings, such materials
including a number of polymeric acids with such materials as shellac, cetyl
alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention
may be incorporated for administration orally or by injection include, aqueous
solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored
emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include synthetic
and natural gums such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The methods of treating described in the present invention may also be
carried out using a pharmaceutical composition comprising any of the compounds
as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical
composition may contain between about 0.01 mg and about 1,000 mg of the
compound, or any amount or range therein; preferably about 1.0 to about 500 mg
of the compound, or any amount or range therein, and may be constituted into
any form suitable for the mode of administration selected. Carriers include
necessary and inert pharmaceutical excipients, including, but not limited to,
binders, suspending agents, lubricants, flavorants, sweeteners, preservatives,
dyes, and coatings. Compositions suitable for oral administration include solid
forms, such as pills, tablets, caplets, capsules (each including immediate release,
timed release and sustained release formulations), granules, and powders, and
liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
Forms useful for parenteral administration include sterile solutions, emulsions and
suspensions.
Advantageously, compounds of the present invention may be administered
in a single daily dose, or the total daily dosage may be administered in divided
doses of two, three or four times daily. Furthermore, compounds for the present
invention can be administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to those of
ordinary skill in that art. To be administered in the form of a transdermal delivery
system, the dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover,
when desired or necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable binders
include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose,
corn sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,
sodium acetate, sodium chloride and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such
as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose
and the like. For parenteral administration, sterile suspensions and
solutions are desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is desired.
To prepare a pharmaceutical composition of the present invention, a
compound of formula (I) as the active ingredient is intimately admixed with a
pharmaceutical carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms depending of the
form of preparation desired for administration (e.g. oral or parenteral). Suitable
pharmaceutically acceptable carriers are well known in the art. Descriptions of
some of these pharmaceutically acceptable carriers may be found in The
Handbook of Pharmaceutical Excipients , published by the American
Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage Forms:
Tablets, Second Edition, Revised and Expanded , Volumes 1-3, edited by
Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications ,
Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms:
Disperse Systems , Volumes 1-2, edited by Lieberman et al; published by
Marcel Dekker, Inc.
Compounds of this invention may be administered in any of the foregoing
compositions and according to dosage regimens established in the art whenever
treatment of disorders mediated by DPP-1 is required.
The daily dosage of the products may be varied over a wide range from
0.1 to about 10,000 mg per adult human per day, or any amount or range therein.
For oral administration, the compositions are preferably provided in the form of
tablets containing about 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0,
100, 150, 200, 250, 500 and 1,000 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated. An effective
amount of the drug is ordinarily supplied at a dosage level of from about 0.01
mg/kg to about 100 mg/kg of body weight per day, or any amount or range
therein. Preferably, the range is from about 0.1 mg/kg to about 50.0 mg/kg of
body weight per day, or any amount or range therein. More preferably, from
about 0.1 mg/kg to about 25.0 mg/kg of body weight per day, or any amount or
range therein. More preferably, from about 0.1 mg/kg to about 15.0 mg/kg of
body weight per day, or any amount or range therein. More preferably, from
about 0.1 mg/kg to about 10.0 mg/kg of body weight per day, or any amount or
range therein. More preferably, from about 0.1 mg/kg to about 5.0 mg/kg of body
weight per day, or any amount or range therein. The compounds may be
administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode of
administration, the strength of the preparation, the mode of administration, and
the advancement of the disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight, diet and time of
administration, will result in the need to adjust dosages.
One skilled in the art will recognize that, both in vivo and in vitro trials
using suitable, known and generally accepted cell and / or animal models are
predictive of the ability of a test compound to treat or prevent a given disorder.
For example, Methot, N., et al., "In Vivo Inhibition of Serine Protease
Processing Requires a High Fractional Inhibition of Cathepsin C", Molecular
Pharmacology , (2008), Vol. 73, No. 6, pp1 857-1 865 disclose an in vivo assay
in rats for measuring inhibition of Cathepsin C (DPP-1 ) .
One skilled in the art will further recognize that human clinical trails
including first-in-human, dose ranging and efficacy trials, in healthy patients
and / or those suffering from a given disorder, may be completed according to
methods well known in the clinical and medical arts.
The following Examples are set forth to aid in the understanding of the
invention, and are not intended and should not be construed to limit in any way
the invention set forth in the claims which follow thereafter.
In the Examples which follow, some synthesis products are listed as
having been isolated as a residue. It will be understood by one of ordinary skill
in the art that the term "residue" does not limit the physical state in which the
product was isolated and may include, for example, a solid, an oil, a foam, a
gum, a syrup, and the like.
Example 1: Compound #41
(S)-2-amino-N-(2-(benzo[dlthiazol-2-ylamino)ethyl)butanamide hydrochloride
STEP A: To an ice cold mixture of W-2-trifluoroacetamido-L-butanoic
acid ( 1 .0079 g, 5.00 mmol) and N-hydroxybenzotriazole (886 mg, 6.60 mmol) in
dichloromethane (30 mL) was added N-carbobenzoxy-1 ,2-diaminoethane
hydrochloride ( 1 .5058 g, 6.50 mmol), triethylamine (2.3 mL, 16.5 mmol) and 1-
[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride ( 1 .2616 g, 6.60
mmol). The resulting mixture was stirred at 0°C for 2hours ("h") and then at
room temperature for 18h. The resulting mixture was diluted with DCM (50
mL), then washed with aqueous sodium chloride (2x25 mL). The organic layer
was dried over sodium sulfate, filtered and concentrated. The resulting residue
was purified by flash chromatography, eluting with 70% ethyl acetate in
heptane to yield (S)-benzyl 2-(2-(2,2,2-
trifluoroacetamido)butanamido)ethylcarbamate as a white solid.
HNMR (DMSO-d 6) 9.49 (d, J = 7.88 Hz, 1H), 8.19-8.17 (m, 1H), 7.39
(m + s, 6H), 5.00 (s, 2H), 4.20-3.99 (m, 1H), 3.31-3.03 (m, 4H), 1.81-1 .58 (m,
2H), 0.83 (t, J = 7.34, 7.34 Hz, 3H). MS MH+ = 376.
STEP B: To a heterogenous mixture of (S)-benzyl 2-(2-(2,2,2-
trifluoroacetamido)butanamido)ethylcarbamate ( . 9 3g, 3.20 mmol) and 10%
Pd on carbon ( 1 .2236 g) in ethanol (75 mL) was added 1,4-cyclohexadiene (3.0
mL, 32.0 mmol). The resulting mixture was stirred overnight at room
temperature. The resulting mixture was then filtered through a bed of CELITE ®
and concentrated. The residue was dissolved in chloroform and filtered again
through CELITE ® to yield (S)-N-(2-aminoethyl)-2-(2,2,2-
trifluoroacetamido)butanamide as an unstable oil which was stored in the
freezer.
HNMR (CDC ) d 6.91 (m, 1H), 6.77 (m, 1H), 4.20-3.99 (m, 1H), 3.60
(m, 2H), 3.40-2.83 (m, 2H), 2.89-284 (m, 2H), 1.98-1 .68 (m, 2H), 0.97-0.92 (m,
3H). MS MH+ = 242
STEP C: To a solution of the compound prepared in STEP B above
(263 mgs, ca 1.0 mmol) in methylene chloride ( 10 mL) was added phenyl
isothiocyanate (120 m I_, 1.00 mmol). The resulting mixture was stirred at room
temperature for 1h, then treated with benzyltrimethylammonium tribromide
(389.4 mgs 1.00 mmol). The resulting mixture was then stirred overnight. The
reaction was quenched with aqueous sodium bicarbonate and the mixture
extracted into methylene chloride. The organic layer was dried over sodium
sulfate, then filtered and concentrated to yield a residue which was purified by
normal phase column chromatography, eluting with 90:1 0:1
chloroform:methanol: concentrated ammonium hydroxide to yield (S)-N-(2-
(benzo[d]thiazol-2-ylamino)ethyl)-2-(2,2,2-trifluoroacetamido)butanamide as a
yellow solid.
HNMR (DMSO-d 6) d 9.49 (d, J = 7.88 Hz, 1H), 8.44- 8.30 (m, 1H), 8.06-
8.03 (m, 1H), 7.66 (d, J = 7.66 Hz, 1H), 7.51-7.30 (m, 1H), 7.24-7.19 (m, 1H),
7.04-6.99 (m, 1H), 4.22-4.15 (m, 1H), 3.43-3.21 (m, 4H), 1.81-1 .58 (m, 2H),
0.83 (t, J = 7.34, 7.34 Hz, 3H).
STEP D: To an ice cold solution of the compound prepared in STEP C
above (220.0 mgs, 0.545 mmol) in a 1:4 tetrahydrofuran:methanol mixture was
added 3N aqueous sodium hydroxide solution (0.6 mL). The resulting mixture
was stirred overnight at room temperature. After 1day ("d"), additional 3N
aqueous sodium hydroxide solution ( 1 mL) was added and the mixture stirred
for 4 h. The resulting mixture was extracted into chloroform. The organic layer
was dried over sodium sulfate, filtered and concentrated to yield a residue. The
residue was purified by preparative thin layer chromatography, eluting with a
90:1 0:1 chloroform:methanol: concentrated ammonium hydroxide mixture to
yield the title compound, as its corresponding free base. Acidification of the
free base in chloroform, with 1 N hydrogen chloride in diethyl ether yielded the
corresponding di-hydrochloride salt as a moisture-sensitive solid.
HNMR (DMSO-d 6) 10.41 -9.73 (br s, 1H), 8.83 (m, 1H), 8.32 br s,
3H), 7.82 (d, J = 7.86 Hz, 1H), 7.55 (d, J = 8.06 Hz,1 H), 7.38 (t, J= 7.40 Hz,
7.40Hz, 1H), 7.21 (t, J = 7.61 Hz, 7,61 Hz, 1H), 3.69-3.43 (m, 5H), 1.78-1 .68
(m, 2H), 0.84 (t, J = 7.34, 7.34 Hz, 3H).
Example 2: Compound #43
(S)-2-amino-N-(2-(6-methoxybenzo[dlthiazol-2-ylamino)ethyl)butanamide
h drochloride
STEP A: To a solution of (S)-N-(2-aminoethyl)-2-(2,2,2-
trifluoroacetamido)butanamide (276.6 mg, ca, 1. 10 mmol) in dichloromethane
(10 mL) was added 4-methoxyphenyl isothiocyanate (120 m I_, 0.868 mmol) .and
the resulting mixture was stirred for 72 h at room temperature. The resulting
mixture was then concentrated to an oil, which was purified by column
chromatography, eluting with 6% methanol in chloroform to yield (R)-N-(2-(3-(4-
methoxyphenyl)thioureido)ethyl)-2-(2,2,2-trifluoroacetamido)butanamide as a
solid.
HNMR (DMSO-d 6) d 9.63 - 9.42 (m, 2H), 8.24 - 8.22 (m 1H), 7.50 -
7.40 (m, 1H), 7.32 - 7.14 (m, 2H), 6.91 - 6.85 (m, 2H), 4.18 - 4.14 (m, 1H),
3.53 - 3.51 (m, 2H), 3.35 -3.22 (m, 2H), 3.73 (s, 3H), 1.81-1 .58 (m, 2H), 0.83
(t, J = 7.34, 7.34 Hz, 3H). MS MH+ = 407.
STEP B: A solution of (R)-N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-
(2,2,2-trifluoroacetamido)butanamide (412.5 mgs, 1.0 mmol) in methylene
chloride (10 mL) was treated with benzyltrimethylammonium tribromide (389.4
mgs 1.00 mmol) and the resulting mixture stirred overnight. The reaction was
then quenched with aqueous sodium bicarbonate and extracted into methylene
chloride. The organic layer was dried over sodium sulfate, then filtered and
concentrated to yield a residue which was purified by normal phase column
chromatography, eluting with 5% methanol in chloroform to yield (S)-N-(2-(6-
methoxybenzo[d]thiazol-2-ylamino)ethyl)-2-(2,2,2-trifluoroacetamido)-
butanamide as a yellow solid.
HNMR (DMSO-d 6) d 9.49 (d, J = 7.88 Hz, 1H), 8.36 - 8.14 (m, 1H), 7.84
- 7.81 (m, 1H), 7.37 - 7.28 (m, 2H ) , 6.88 - 6.80 (m, 1H), 4.46 - 4.12 (m, 1H),
3.73 (s, 3H), 3.55 - 3.27 (m, 4H), 1.81-1 .58 (m, 2H), 0.83 (t, J = 7.34, 7.34 Hz,
3H).MS MH+ = 405.
STEP C: To an ice cold solution of (S)-N-(2-(6-methoxybenzo[d]thiazol-
2-ylamino)ethyl)-2-(2,2,2-trifluoroacetamido)butanamide (229 mg, 0.567 mmol)
in a 1:4 tetrahydrofuran:methanol mixture was added 3N aqueous sodium
hydroxide solution ( 1 .2 ml_). The resulting mixture was stirred overnight at
room temperature. After 1d, additional 3N aqueous sodium hydroxide solution
(0.6 mL) was added and the mixture stirred for 4 h. The resulting mixture was
extracted into chloroform. The organic layer was dried over sodium sulfate,
filtered and concentrated to a residue. The residue was purified by preparative
thin layer chromatography, eluting with a 90:10:1 chloroform:methanol:
concentrated ammonium hydroxide mixture to yield the title compound as its
corresponding free base. Acidification of the free base in chloroform, with 1 N
hydrogen chloride in diethyl ether yielded the corresponding di-hydrochloride
salt as an off-white solid.
HNMR (DMSO-d 6) d 9.97 -9.65 (br s, 1H), 8.81 -8.78 (m, 1H), 8.28 ( br
s, 3H), 7.48-7.43 (m, 2H), 6.99 - 6.95 (m, 1H), 3.76 (s, 3H), 3.68 - 3.42 (m,
5H), 1.77-1 .68 (m, 2H), 0.84 (t, J = 7.34, 7.34 Hz, 3H). MS MH+ = 309.
Example 3: Compound #46
(S)-2-amino-N-(2-(benzordlthiazol-2-ylamino)ethyl)-3-(thiophen-2-
vDpropanamide hydrochloride
STEP A: 2-Bromo-1 .3-benzothiazole (505.5 mg , 2.36 mmol) and N-{2
aminoethyl) carbamic acid tert-butyl ester ( 1 . 1 356 g, 7.10 mmol) were stirred
a preheated oil bath (125°C) for 5h. The solid mass was dissolved in
chloroform, and the resulting solution was washed with aqueous sodium
bicarbonate then dried, filtered and concentrated to a yield a residue. The
residue was purified by flash chromatography, eluting with 60% ethyl acetate in
hexane to yield tert-butyl 2-(benzo[d]thiazol-2-ylamino)ethylcarbamate as a
white amorphous solid.
HNMR (DMSO-d 6) 8.05 -8.01 (m, 1H), 7.65 ( d, J = 7.75 Hz, 1H),
7.37 (d, J = 7.92 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.03 - 6.98 (m, 1H), 6.96 - 6.92
(m , 1H), 3.41- 3.36 (m, 2H), 3.28 - 3.12 (m, 2H), 1.37 (s, 9H). MS(MH+) = 294.
STEP B: tert-Butyl 2-(benzo[d]thiazol-2-ylamino)ethylcarbamate (597.7
mgs, 2.04 mmol) was dissolved in 1,4-dioxane (6 mL) then treated with 4N HCL
in 1,4-dioxane (6 mL) and stirred for 3h. A white separated solid was collected
by filtration, washed with diethyl ether and dried in vacuum oven overnight at
room temperature to yield the hydrochloride salt of N1-(benzo[d]thiazol-2-
yl)ethane-1 ,2-diamine as an off-white amorphous solid.
HNMR (DMSO-d 6) d 9.80-9.48 (br s , 1H), 8.27 (s, 4H), 7.83 (d, J =
7.85 Hz, 1H), 7.55 ( d, J = 7.96 Hz, 1H), 7.40 -7.35 (m, 1H), 7.23 - 7.19 (m,
1H), 3.78-3.76 (m, 2H) (m, 2H), 3.17 - 3.1 1 (m, 2H); MS(MH+) = 194.
STEP C: Boc-( )-(2-thienyl)-L-alanine ( 218.5 mg, 0.805 mmol), Nhydroxybenzotriazole
hydrate (109.8 mg, 0.813 mmol) and N1-(benzo[d]thiazol-
2-yl)ethane-1 ,2-diamine (212.1 mgs, 0.800 mmol) in dichloromethane ( 10 mL)
was cooled in an ice bath, then treated with triethylamine (0.45 mL, 3.23 mmol)
and 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (163.3 mg,
0.852 mmol). The resulting mixture was stirred overnight at room temperature,
then was diluted with dichloromethane, washed with water, dried over sodium
sulfate, filtered and concentrated to yield a flaky solid. The solid was purified
by flash column chromatography, eluting with 8% methanol in chloroform to
yield (S)-tert-butyl 1-(2-(benzo[d]thiazol-2-ylamino)ethylamino)-1 -oxo-3-
(thiophen-2-yl)propan-2-ylcarbamate as a white amorphous solid.
HNMR (DMSO-d 6) 8.32 - 8.15 (m , 1H), 8.01 -7.95 (m, 1H), 7.66 (d ,
J = 7.32 Hz, 1H), 7.39 (d, J = 7.86 Hz, 1H), 7.30 (d, J = 4.74 Hz, 1H), 7.24-7.19
(m, , 1H), 7.04 -7.00 (m, 1H), 6.96-6.85 (m, 3H), 4.1 5 - 4.03 (m, 1H), 3.41 -
3.19 (m, 4H), 3.16 - 2.95 (m, 2H), 1.33 (s, 9H); MS(MH+) = 447.
STEP D: (S)-tert-butyl 1-(2-(benzo[d]thiazol-2-ylamino)ethylamino)-1-
oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (195.9 mg, 0.439 mmol) was
suspended in 1,4-dioxane (4 mL) and treated with 4N HCI in 1,4-dioxane (4 mL,
16.0 mmol). The resulting mixture became homogenous, then a solid
separated as the stirring continued for 4 h. The solid was collected by filtration,
washed with 1,4-dioxane, then dried in a vacuum oven overnight at room
temperature, to yield the title compound as its corresponding hydrochloride salt,
as a white solid.
HNMR (DMSO-d 6) d 9.44 - 9.14 (br s , 1H), 8.85 - 8.81 (m, 1H), 8.39 (
br s, 3H), 7.77 (d, J = 7.67 Hz, 1H), 7.48 (d, J = 7.97 Hz, 1H), 7.41- 7.39 (m,
1H), 7.35 - 7.30 (m, 1H), 7.16 -7.1 3 (m, 1H), 6.98-6.95 (m, 2H), 3.96 - 3.94
(m, 1H), 3.55-3.21 (m, 6H).
Compound #42 MS (M+H) 289, was similarly prepared according to the
process described in Example 3 above, by selecting and substituting a suitably
substituted reagent for the Boc-( )-(2-thienyl)-L-alanine in STEP C above.
Example 4: Compound #44
(S)-2-amino-N-(2-(benzo[dloxazol-2-ylamino)ethyl)pent-4-vnamide
hydrochloride
STEP A: A mixture of 2-chlorobenzoxazole (0.6mL, 5.1 6 mmol) and N-
(2-aminoethyl) carbamic acid tert-butyl ester (2.4328g, 15.18 mmol)) was
stirred in a preheated oil bath at 125°C for 5h, then held at room temperature
overnight. The solidified mixture was dissolved in chloroform (125 mL),
washed with aqueous sodium bicarbonate (2x150mL), then brine (1x150). The
organic layer was dried over sodium sulfate, then filtered and concentrated in
vacuo. The resulting residue was purified by flash column chromatography,
eluting with 60% ethyl acetate in heptane to yield tert-butyl 2-(benzo[d]oxazol-
2-ylamino)ethylcarbamate as a beige powder.
HNMR (DMSO-d 6) d 7.94 -7.90 (m, 1H), 7.32 ( d, J = 7.83 Hz, 1H), 7.23
(d, J = 7.60 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.99 - 6.92 (m, 2H), 3.34-3.29 (m,
2H), 3.18 - 3.12 (m, 2H), 1.37 (s, 9H). MS(MH+) = 278.
STEP B: tert-Butyl 2-(benzo[d]oxazol-2-ylamino)ethylcarbamate (515.7
mg, 1.86 mmol) was dissolved in warm p-dioxane (6 mL) and was treated with
4N HCI in 1,4-dioxane (6 mL, 24.0 mmol). The resulting mixture was stirred for
3h as a solid separated from the acidic solution. Then, additional 4N HCI (2
mL, 8.0 mmol) was added and the resulting mixture stirred for 1 h, then stored
in the freezer overnight. The resulting solid was collected by filtration, washed
with 1,4-dioxane, then dried in vacuum oven overnight at room temperature to
yield the corresponding hydrochloride salt of N -(benzo[d]oxazol-2-yl)ethane-
1,2-diamine as a white powder.
HNMR (DMSO-d 6) d 8.70 (br s , 1H), 8.16 (s, 3H), 7.43 (d, J = 7.85 Hz,
1H), 7.31 ( d, J = 7.81 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.10 - 7.04 (m, 1H), 3.61
-3.57 (m, 2H) 3.17 - 3.06 (m, 2H); MS(MH+) = 178.
STEP C: A cold mixture of Boc-L-propargyl-glycine (128.2 mg, 0.602
mmol), N-hydroxybenzotriazole hydrate (84.5 mg, 0.625 mmol) and the
hydrochloride salt of N -(benzo[d]oxazol-2-yl)ethane-1 ,2-diamine (152.3 mg,
0.609 mmol) in dichloromethane (6 mL) was cooled in an ice bath, then treated
with triethylamine (0.34 mL, 2.44 mmol) and 1-[3-dimethylaminopropyl]-3-ethyl
carbodiimide hydrochloride ( 1 19.6 mg, 0.624 mmol). The resulting mixture was
stirred for 40h at room temperature, then diluted with dichloromethane, washed
with water, dried over sodium sulfate, filtered and concentrated to yield a
residue The residue was purified by flash column chromatography, eluting with
8% methanol in chloroform to yield (S)-tert-butyl 1-(2-(benzo[d]oxazol-2-
ylamino)ethylamino)-1-oxopent-4-yn-2-ylcarbamate as a solid.
HNMR (DMSO-d 6) 8.32 - 8.15 (m, 1H), 7.88 (br s, 1H), 7.32 (d, J =
7.83 Hz, 1H), 7.24 (d, J = 7.63 Hz, 1H), 7.13 - 7.08 (m, 1H), 6.99 - 6.92 (m,
2H), 4.08 - 4.01 (m, 1H), 3.46 - 3.33 (m, 4H), 2.81 (s, 1H), 2.58 - 2.35 (m,
2H), 1.37 (s, 9H). MS(MH+) = 373.
STEP D: (S)-tert-Butyl 1-(2-(benzo[d]oxazol-2-ylamino)ethylamino)-1-
oxopent-4-yn-2-ylcarbamate (99.5 mg, 0.267 mmol) was dissolved in 1,4-
dioxane (3.5 mL) and treated with 4N HCI in 1,4-dioxane (3.5 mL). The
reuslitng mixture was stirred for 2.5 h and a solid separated from the solution.
HCI in 1,4-dioxane ( 1 mL) was added and the resulting mixture was stirred for 3
h. The solid product was collected by filtration, washed with 1,4-dioxane, then
dried in vacuum oven for 1day at room temperature to yield the title compound
as its corresponding hydrochloride salt, as a white solid.
HNMR (DMSO-d 6) d 9.75 - 9.40 (br s, 1H), 9.30 - 9.05 (br s , 1H), 8.91
- 8.72 (br s, 1H), 8.49 (br s, 3H), 7.45 (d , J = 7.94 Hz, 1H), 7.32 (d, J = 7.66
Hz, 1H), 7.23 - 7.19 (m, 1H), 7.1 1 - 7.08 (m, 1H), 3.88 - 3.77 (m, 1H), 3.55-
3.21 (m, 4H), 2.76 - 2.67 (m , 2H), 2.60 (s, 1H).
The following compounds were similarly prepared according to the
process described in Example 4 above, , by selecting and substituting suitably
substituted reagents for the Boc-( )-(2-thienyl)-L-alanine in STEP C above.
Compound #45 MS (M+H) 263
Compound #47 MS (M+H) 331
Example 5: Compound #48
(S)-2-(2-(2-amino-N-methyl-3-(thiophen-2-yl)propanamido)ethylamino)-N-(3,4-
dimethoxyphenyl)benzo[dlthiazole-6-carboxamide
STEP A: 2-Bromo-6-benzothiazolecarboxylic acid (496.0 mg, 192 mmol)
was suspended in dichloromethane (15 mL), cooled in ice bath, then treated
with 2M oxalyl chloride in dichloromethane (2 mL, 4 mmol) and 1 drop of
dimethylformamide. The resulting homogenous mixture was stirred for 3h, then
concentrated to a solid. The solid was dissolved in dichloromethane (20 mL),
the resulting solution was cooled in an ice bath, then treated with
diisopropylethylamine (0.45 mL, 2.58 mmol) and 4-aminoveratole (323.9 mg,
2.1 1 mmol). The resulting mixture was stirred overnight at room temperature,
then diluted with dichloromethane, washed with water, washed with brine, dried
over sodium sulfate, filtered and concentrated to yield 2-bromo-N-(3,4-
dimethoxyphenyl)benzo[d]thiazole-6-carboxamide as a brown solid.
HNMR (DMSO-d 6) 10.3 (s, 1H), 8.69 (s, 1H), 8.10 (s, 2H), 7.47 (d , J
= 2.23 Hz, 1H), 7.37 - 7.33 (m, 1H), 6.94 (d, J = 8.73 Hz, 1H), 3.76 (s, 3H),
3.75 (s, 3H). MS MH+ = 393.
STEP B: A mixture of 2-bromo-N-(3,4-
dimethoxyphenyl)benzo[d]thiazole-6-carboxamide (392.4 mg, 0.998 mmol), N-
(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (193.4 mg, 1. 1 1 mmol)
and N-N-diisopropylethylamine (148.6 mg, 1.15 mmol) in 1-methyl-2-
pyrrolidinone (3 mL) was stirred in a preheated oil bath at 120°C for 4h, then
allowed to cool to room temperature, poured into water and extracted into ethyl
acetate. The organic layer was washed with water, dried (sodium sulfate),
filtered and concentrated in vacuo. The resulting residue was purified by
gradient flash column chromatography, eluting with 70% to 80% ethyl acetate
in heptane to yield tert-butyl 2-(6-(3,4-
dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-ylamino)ethyl(methyl)carbamate
as a beige powder.
HNMR (DMSO-d 6) d 9.99 (s, 1H), 8.44 - 8.28 (m, 1H), 8.27 (s, 1H),
7.85 (d, J = 8.48 Hz, 1H), 7.61 - 7. 44 (m, 2H), 7.36 - 7.32 (m, 1H), 6.92 (d, J =
8.79 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.61 - 3.50 (m, 4H), 2.85 - 2.81 (m,
3H), 1.36 - 1.26 (m , 9H). MS MH+ = 487.
STEP C: tert-Butyl 2-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-
2-ylamino)ethyl(methyl)carbamate (327.1 mg, 0.672 mmol) was dissolved in
1,4-dioxane (4 mL) and then treated with 4N HCI in 1,4-dioxane (4 mL, 16.0
mmol). The resulting mixture was stirred for 2h and a solid separated from the
solution. The solid was collected by filtration, washed with 1,4-dioxane, then
dried in vacuum oven for 2d at room temperature to yield the hydrochloride salt
of N-(3,4-dimethoxyphenyl)-2-(2-(methylamino)ethylamino)benzo[d]thiazole-6-
carboxamide as a yellow solid.
HNMR (methanol d4) d 8.36 (d, J = 1.53 Hz, 1H), 8.05 - 8.02 (m, 1H),
7.66 ( d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.22 - 7.19 ( m, 1H), 6.94 (d,
J = 8.7 Hz, 1H), 3.96 -3.92 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.45 - 3.39 ( m,
2H), 2.80 (s, 3H). MS MH+ = 387.
STEP D: N-(3,4-dimethoxyphenyl)-2-(2-
(methylamino)ethylamino)benzo[d]thiazole-6-carboxamide ( 278.3 mgs, 0.606
mmol), N-hydroxybenzotriazole hydrate ( 1 16.6 mg, 0.761 mmol) and Boo-(b)-
(2-thienyl)-L-alanine (206.5 mgs, 0.761 mmol) in N-N-dimethylformamide (2
mL) was cooled in an ice bath, then treated with triethylamine (245.2 mL, 2.42
mmol) and 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (145.9
mg, 0.761 mmol). The resulting mixture was stirred overnight at room
temperature. After 18h, water was added and a solid separated, which solid
was collected by filtration. The solid was then washed with additional water
and dried under house vacuum. The resulting solid was purified by flash
column chromatography, eluting with 4% methanol in chloroform to yield (S)-
tert-butyl 1-((2-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-
ylamino)ethyl)(methyl)amino)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate as
a solid.
HNMR (DMSO-d 6) 9.99 (s, 1H), 8.69 (s, 1H), 8.41 - 8.32 (m, 1H),
8.28 (m, 1H), 7.95 - 7.85 (m, 2H), 7.61 - 7. 44 (m, 1H), 7.36 - 7.32 (m, 1H),
6.98-6.95 (m, 3H), 4.65 - 4.45 (m, 1H), 4.00 (br s, 1H) 3.75 (s, 3H), 3.74 (s,
3H), 3.43 (m, 2H), 3.32 (m, 2H), 3.16 - 2.95 (m, 2H), 2.90 (s, 3H), 1.40 (s , 9H).
MS MH+ = 640.
STEP E: (S)-tert-Butyl 1-((2-(6-(3,4-
dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-ylamino)ethyl)(methyl)amino)-1-
oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (286.6 mg, 0.448 mmol) was
dissolved in 1,4-dioxane (3 mL) and then treated with 4N HCI in 1,4-dioxane (3
mL, 12.0 mmol). The resulting mixture was stirred for 2.5 h and a yellow solid
separated from the solution. The solid was collected by filtration, then washed
with 1,4-dioxane (3x 10 mL). The resulting hydrochloride salt was converted to
its corresponding free base by partitioning between chloroform and aqueous
sodium bicarbonate, then purified by preparative thin-layer chromatography,
eluting with 90/10/1 chloroform : methanol : concentrated ammonium
hydroxide. The free base was dissolved in chloroform (3 mL) and treated with
1N hydrogen chloride in diethyl ether (0.8 mL). The separated solid was
covered with diethyl ether, collected by filtration and dried in vacuum oven to
yield the title compound as an off-white solid.
HNMR (DMSO-d 6) d 9.99 (s, 1H), 9.00 (br s, 3H), 8.69 (s, 1H), 8.28 (m,
1H), 7.85 (m, 2H), 7.61 - 7. 44 (m, 1H), 7.36 - 7.32 (m, 1H), 6.98-6.95 (m, 3H),
4.65 - 4.45 (m, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.43 (m, 2H), 3.32 (m, 2H), 3.26
- 3.16 (m, 2H), 2.90 (s, 3H).
Example 6: Compound #2
(S)-2-amino-1-(4-(benzo[dloxazol-2-yl)piperazin-1-yl)-3-(thiophen-2-yl)propan-
1-one h drochloride
STEP A: 2-Piperidino-1 ,3-benzoxazole ( 203.6 mgs, 1.00 mmol), Nhydroxybenzotriazole
hydrate (138.2 mg, 1.02 mmol) and Boc- -(2-thienyl)-Lalanine
(272.6 mgs, 1.00 mmol) in dichloromethane (10 ml_) was cooled in an
ice bath, then treated with triethylamine (0.30 ml_, 2.1 5 mmol) and 1-[3-
dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (199.5 mg, 1.04
mmol). The resulting mixture was stirred overnight at room temperature. After
18h, the resulting mixture was diluted with chloroform and washed with water.
The organic layer was dried over sodium sulfate, filtered and concentrated to a
residue. The residue was purified by flash column chromatography, eluting
with 3% methanol in chloroform to yield (S)-tert-butyl 1-(4-(benzo[d]oxazol-2-
yl)piperazin-1 -yl)-1 -oxo-3-(thiophen-2-yl)propan-2-ylcarbamate as a colorless
glass.
HNMR (DMSO-d 6) d 8.31 (s , 1H), 7.36 ( d, J = 7.83Hz, 1H), 7.33 -
7.29 (m, 2H), 7.19 - 7.14 (m, 1H), 7.06 -7.01 (m, 1H), 6.94 - 6.92 (m, 2H), 4.66
- 4.53 (m, 1H), 3.80 - 3.54 (m, 8H), 3.25 - .00 (m, 2H), 1.36 (s, 9H);
MS(MH+) = 457.
STEP B: (S)-tert-butyl 1-(4-(benzo[d]oxazol-2-yl)piperazin-1 -yl)-1 -oxo-3-
(thiophen-2-yl)propan-2-ylcarbamate (367.5 mg, 0.805 mmol) was dissolved in
1,4-dioxane (5 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (5
mL, 12.0 mmol). The resulting mixture was stirred at room temperature for 3h,
then additional 4N HCI in 1,4-dioxane ( 1 mL) was added and the resulting
mixture stirred for 18 h. The resulting solid was collected by decantation,
washed with 1,4-dioxane, and purified by recrystallization from an isopropanoldiethyl
ether mixture to yield the title compound as an off-white solid.
HNMR (DMSO-d 6) d 8.43 (s , 3H), 7.46 - 7.42 (m, 2H), 7.33 - 7.30 (m,
1H), 7.20 - 7.15 (m, 1H), 7.08 - 7.00 (m, 2), 3.73 - 3.1 1 (m, 10H); MS(MH+) =
357.
Compound # 1 MS (M+H) 373 was similarly prepared according to the
process described in Example 6 above, by substituting 2-(piperazin-1-
yl)benzo[d]thiazole for 2-piperidino-1 ,3-benzoxazole in STEP A above.
Example 7: Compound #4
(S)-2-(4-(2-aminobutanoyl)piperazin-1-yl)-N-(3,4-
dimethoxyphenyl)benzo[dlthiazole-6-carboxamide hvdrochlordie
STEP A: 2-Bromo-N-(3,4-dimethoxyphenvl)benzordlthiazole-6-
carboxamide (612.2 mg, 1.56 mmol), N-Boc piperazine (300.8 mg, 1.61 mmol)
and diisopropylethylamine (0.3 mL, 1.72 mmol) in N-methyl-2-pyrrolidinone (5.5
mL) was stirred at 120°C (oil bath) for 4h, then at room temperature for 18h.
The resulting mixture was diluted with water and the solid separated from the
solution. The solid was collected by filtration, dissolved in ethyl acetate,
washed with water (2X), then dried, filtered and concentrated. The resulting
residue was purified by flash chromatography, eluting with 5% methanol in
chloroform to yield tert-butyl 4-(6-(3,4-
dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1 -carboxylate as a
brown glassy solid.
HNMR (DMSO-d 6) 10.0 (s, 1H), 8.39 (s, 1H), 7.92 - 7.89 (m, 1H),
7.53 (d, J = 8.49 Hz, , 1 H), 7.47 (d , J = 2.1 Hz, 1H), 7.36 - 7.32 (m, 1H), 6.94
(d, J = 8.73 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.64 - 3.61 (m, 4H), 3.52 -3.50
(m, 4H), 1.43 (s, 9H); MS MH+ = 499.
STEP B: tert-Butvl 4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-
2-yl)piperazine-1 -carboxylate (507.1 mg, 1. 15 mmol) was treated with
trifluoroacetic acid (24 mL). The resulting homogenous mixture was stirred for
30 min, then diluted with diethyl ether and cooled in ice bath. The resulting
solid was collected by filtration and dried in vacuum oven at room temperature
to yield N-(3,4-dimethoxyphenyl)-2-(piperazin-1 -yl)benzo[d]thiazole-6-
carboxamide as a khaki colored amorphous solid.
HNMR (DMSO-d 6) 10.0 (s, 1H), 9.25 (br s, 2H), 8.45 (s, 1H), 7.93 (d,
J = 8.43 Hz, 1H), 7.58 (d, J = 8.42 Hz, 1H), 7.48 (d, J = 2.1 Hz, , 1 H), 7.36 -
7.33 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.88 - 3.84 (m, 4H), 3.75 (s, 3H), 3.74
(s, 3H), 3.28 (m, 4H); MS MH+ = 399.
STEP C: N-(3,4-dimethoxyphenyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-
carboxamide ( 2 11.0 mg, 0.412 mmol), N-hydroxybenzotriazole hydrate (70.3
mg, 0.52 mmol) and Boc-L-a-aminobutyric acid ( 104.8 mg, 0.515 mmol) in
LJV-dimethylformamide (2 mL) was cooled in an ice bath, then treated with
triethylamine (0.2 mL, 1.43 mmol) and 1-[3-dimethylaminopropyl]-3-ethyl
carbodiimide hydrochloride (104.5 mg, 0.545 mmol). The resulting mixture was
stirred overnight at room temperature. After 18h, water was added and a solid
separated, which was collected by filtration. The solid was washed with
additional water and dried under house vacuum, then purified by preparative
TLC, eluting with 5% methanol in chloroform to yield (S)-tert-butyl 1-(4-(6-(3,4-
dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxobutan-2-
ylcarbamate as a beige solid.
HNMR (CDCI3) d 8.24 (d, J = 1.65 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.58
(d, J = 8.4Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.03 - 6.99 (m 1H), 6.85 (d, J = 8.7
Hz, 1H), 5.34 (d, J = 8.8 Hz, 1H), 4.63 - 4.55 (m, 1H), , 3.92 (s, 3H), 3.89 (s,
3H), 3.77 - 3.62 (m, 8H), 1.83 - 1.66 (m, 1H), 1.60 - 1.51 (m, 1H), 1.45 (s, 9H),
0.96 (t, J = 7.4,7.4Hz, 3H); MS MH+ = 584.
STEP D: The (S)-tert-butyl 1-(4-(6-(3,4-
dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxobutan-2-
ylcarbamate (142.8 mg, 0.245 mmol) was dissolved in p-dioxane (3 mL),
treated with 4N hydrogen chloride in 1,4-dioxane (3 mL, 12.0 mmol) and the
resulting mixture was stirred at room temperature for 5.5 h. The resulting
heterogenous mixture was concentrated under high vacuum, then covered with
diethyl ether and placed under high vacuum for 2d to yield the title compound
as a pale yellow powder.
HNMR (CDCIs) d 10.0 (s, 1H),8.50 - 8.42 (m, 1H), 8.24 (br s, 3H), 7.93
(d, J= 8.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.35 (d, J
= 8.3 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 4.62 - 4.42 (m, 2H), , 3.75 (s, 3H), 3.74
(s, 3H), 3.70 - 3.59 (m, 8H), 1.82 - 1.68 (m, 2H), 0.96 (t, J = 7.4,7.4Hz, 3H);
MS MH+ = 484.
The following compounds were similarly prepared according to the
process described in Example 7 above, by selecting and substituting a suitabl
substituted reagent for the Boc-L-(a)-aminobutyric acid in STEP C.
Compound #6 MS (M+H) 536
Compound #12 MS (M+H) 552
Example 8: Compound #3
(S)-2-(4-(2-amino-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)-N-(3,4-
dimethoxyphenyl)benzo[dlthiazole-6-carboxamide hydrochloride
STEP A: N-(3,4-dimethoxyphenyl)-2-(piperazin-1-yl)benzo[d]thiazole-6-
carboxamide ( 1 .00 g, 2.51 mmol), Boc-L-2-thienylalanine (0.68 g, 2.551 mmol),
diisopropylethylamine ( 1 .75 ml, 10.04 mmol) and HBTU ( 1 .24 g, 3.26 mmol)
were dissolved in DMF (71 ml) and stirred overnight. The reuslting mixture was
diluted with ethyl acetate (154 ml), washed with 1N HCI (3 X 77 ml), washed
with brine (77 ml), dried (MgS0 4) and concentrated in vacuo. The resulting
residue was chromatographed, eluting with dichloromethane/methanol (97:3) to
yield (S)-tert-butyl 1-(4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-
yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate.
HNMR (CDCI3) d 8.22 (s, 1H), 7.78-7.76 (m, 2H), 7.57 (d, J= 8.4 Hz,
1H), 7.47 (d, J= 2.2 Hz, 1H), 7.1 7 (d, J= 5.1 Hz, 1H), 7.01-6.84 (m, 4H), 5.40-
5.38 (m, 1H), 4.90-4.85 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.80-3.1 1 (m, 10H),
1.44 (s, 9H).
STEP B: (S)-tert-butvl 1-(4-(6-(3,4-
dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-
(thiophen-2-yl)propan-2-ylcarbamate (0.95 g, 1.45 mmol) was dissolved in 1,4-
dioxane (2 ml) and treated with 4M HCI in 1,4-dioxane (2 ml). The resulting
mixture was stirred at room temperature overnight. The resulting solid was
filtered and treated with 4M HCI in 1,4-dioxane (2 ml), again stirring overnight.
The solid was filtered, dissolved in dichloromethane and washed with saturated
NaHC03 to yield the title compound as its corresponding free base. The free
base was chromatographed eluting with dichloromethane/methanol/ammonium
hydroxide to yield the free base as a residue. The free base residue (0.50 g,
0.91 mmol) was dissolved in dichloromethane (2 ml) and treated with 1M HCI
in diethyl ether (0.91 ml, 0.91 mmol) and the resulting mixture stirred at room
temperature for 2 h. The resulting solid was filtered, washed with diethyl ether
(2X) and dried to yield (S)-2-(4-(2-amino-3-(thiophen-2-yl)propanoyl)piperazin-
1-yl)-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide, as its
corresponding hydrochloride salt.
HNMR (CD3OD) d 8.29 (s, 1H), 7.93-7.90 (m, 1H), 7.56-7.52 (m, 1H),
7.42-7.38 (m, 2H), 7.21-7.1 1 (m, 1H), 7.09-7.02 (m, 2H), 6.95-6.93 (m, 1H),
4.75-4.72 (m, 1H), 3.85 (s, 3H), 3,93 (s, 3H), 3.80-3.58 (m, 5H), 3.49-3.39 (m,
3H), 3.31-3.22 (m, 2H). ES-MS m/z 552 (MH+) ;
Calculated for C27H29N5O4S2 HCI 0.03 H20 : C, 54.64; H, 5.220; N,
11.80; CI, 5.97; H20 , 0.91 . Measured: C, 54.93' H, 5.1 7; N, 11.67; CI, 6.1 1;
H20 , 1.18.
Example 9: Compound #19
(S)-2-(4-(2-amino-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)-Ncvclopentylbenzo[
dlthiazole-6-carboxamide
STEP A: 2-Bromo-6-benzothiazolecarboxvlic acid (0.500 g, 1.94 mmol)
was suspended in dichloromethane/methanol (12 ml, 6:1 ) and cooled to 0°C
with an ice-water bath. Then, 2M (trimethylsilyl)diazomethane (2.91 ml, 5.81
mmol) was added dropwise over 5 min. The resulting mixture was warmed to
room temperature and stirred at room temperature for 2 hrs. The resulting
mixture was concentrated in vacuo to yield methyl 2-bromobenzo[d]thiazole-6-
carboxylate.
HNMR (CDCI3) d 8.55 (s, 1H), 8.15 (d, J= 8.6 Hz, 1H), 8.02 (d, J= 8.6
Hz, 1H), 3.07 (s, 3H).
STEP B: Methyl 2-bromobenzo[d]thiazole-6-carboxylate (0.52 g, 1.90
mmol), Boc-piperazine (0.44 g. 2.38 mmol) and potassium carbonate (0.53 g,
3.80 mmol) were suspended in acetonitrile (21 ml) and refluxed overnight. The
resulting mixture was then cooled to room temperature, concentrated in vacuo
to approximately 2 ml, diluted with water and extracted with ethyl acetate. The
organic layer was dried (MgS0 4) and concentrated in vacuo to yield a residue
which was treated with trifluoroacetic acid/dichloromethane (6 ml, 1: 1 ) for 1.5
hrs. The resulting mixture was concentrated in vacuo, the resulting residue
was dissolved in dichloromethane and washed with saturated sodium
bicarbonate to yield methyl 2-(piperazin-1-yl)benzo[d]thiazole-6-carboxylate.
HNMR (CDCI3) d 8.30 (s, 1H), 7.98 (d, J= 8.5 Hz, 1H), 7.52 (d, J= 8.5
Hz, 1H), 3.91 (s, 3H), 3.68-3.65 (m, 4H), 3.03-3.00 (m, 4H).
STEP C: Methyl 2-(piperazin-1-yl)benzo[d]thiazole-6-carboxylate (0.35
g, 1.26 mmol), Boc-L-2-thienylalanine (0.34 g, 1.26 mmol),
diisopropylethylamine (0.88 ml, 5.06 mmol) and HBTU (0.62 g, 1.64 mmol)
were dissolved in DMF (36 ml) and the resulting mixture stirred overnight. The
resulting mixture was then diluted with ethyl acetate (78 ml), washed with 1N
HCI (3 X 39 ml), washed with brine (39 ml), dried (MgS0 ) and concentrated in
vacuo. The resulting residue was chromatographed eluting with
dichloromethane/methanol (97:3) to yield (S)-methyl 2-(4-(2-(tertbutoxycarbonylamino)-
3-(thiophen-2-yl)propanoyl)piperazin-1-
yl)benzo[d]thiazole-6-carboxylate.
HNMR (CDCI3) d 8.31 (s, 1H), 8.00 (d, J= 8.5 Hz, 1H), 7.53 (d, J= 8.5
Hz, 1H), 7.15 (d, J=4.4 Hz, 1H), 6.93-6.91 (m, 1H)m 6.88-6.87(m, 1H), 5.39-
5.37 (m, 1H), 4.90-4.84 (m, 1H), 3.92 (s, 3H), 3.89-3.83 (m, 1H), 3.69-3.40 (m,
7H), 3.29-3.10 (m, 2H), 1.44 (s,9H).
STEP D: (S)-methyl 2-(4-(2-(tert-butoxycarbonylamino)-3-(thiophen-2-
yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylate (0.61 g, 1. 15 mmol)
was dissolved in methanol (6 ml) followed by the addition of 1N NaOH ( 1 .26 ml,
1.26 mmol) and the resulting mixture heated to 50°C overnight. The resulting
mixture was then cooled to room temperature, acidified with 10% citric acid and
extracted with ethyl acetate. The organic layer was dried (MgS0 4) and
concentrated in vacuo to yield (S)-2-(4-(2-(tert-butoxycarbonylamino)-3-
(thiophen-2-yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylic acid.
HNMR (DMSO) d 8.39 (s, 1H), 7.89-7.83 (m, 1H), 7.49 (d, J= 8.5 Hz,
1H), 7.34-7.32 (m, 2H), 6.94-6.93 (m, 2H), 4.64-4.61 (m, 1H), 3.67-3.48 (m,
8H), 3.20-3.03 (m, 2H), 1.36 (s, 9H).
STEP E: (S)-2-(4-(2-(tert-Butoxvcarbonvlamino)-3-(thiophen-2-
yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylic acid (0.084 g, 0.155
mmol), cyclopentylamine (0.015 ml, 0.155 mmol), diisopropylethylamine (0.1 1
ml, 0.62 mmol) and HBTU (0.076 g, 0.20 mmol) were dissolved in DMF (4 ml)
and the resulting mixture stirred overnight. The resulting mixture was then
diluted with ethyl acetate (9 ml), washed with 1N HCI (3 X 5ml), brine (5 ml),
dried (MgS0 4) and concentrated in vacuo. The resulting residue was
chromatographed eluting with dichloromethane/ methanol (97:2) to yield a
residue which was dissolved in 1,4-dioxane ( 1 ml) and treated with 4M HCI in
1,4-dioxane for three days. The resulting solid was filtered, washed with ether
(3X) and dried to yield (S)-2-(4-(2-amino-3-(thiophen-2-yl)propanoyl)piperazin-
1-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide (Compound #26).
HNMR (CD3OD) d 8.24 (s, 1H), 7.89-7.87 (m, 1H), 7.56 (d, J= 8.5 Hz,
1H), 7.39-7.37 (m, 1H), 7.06-7.02 (m, 2H), 4.77-4.73 (m, 1H), 4.35-4.28 (m,
1H), 3,84-3.67 (m, 6H), 3.45-3.35 (m, 4H), 2.06-2.01 (m, 2H), 1.80-1 .74 (m,
2H), 1.69-1 .55 (m, 4H). ES-MS m/z 484 (MH+) .
The following compounds were similarly prepared according to the
process described in Example 9 above, by selecting and substituting a suitably
substituted reagent for the cyclopentylamine in STEP E.
Compound #20 MS (M+H) 5 10
Compound #24 MS (M+H) 472
Compound #25 MS (M+H) 488
Compound #27 MS (M+H) 444
Compound #28 MS (M+H) 536
Compound #29 MS (M+H) 458
Compound #30 MS (M+H) 498
Compound #31 MS (M+H) 536
Example 10: Compound #18
(S)-2-amino-1-(4-(6-(hvdroxymethyl)benzo[dlthiazol-2-yl)piperazin-1-yl)-3-
(thiophen-2-yl)propan-1 -one
STEP A: Ethyl 2-aminobenzothiazole-6-carboxylate (8.91 g) and CuBr2
(13.43 g) were combined in acetonitrile (300 mL). To the resulting deep green
solution was added tert-butylnitrite (7.14 mL). The resulting mixture was
heated to ~ 65 C for two hours, then concentrated to -50 mL. The resulting
concentrate was diluted with water (250 mL) and extracted with EtOAc (2 x 250
mL). The resulting yellow solution was concentrated to yield ethyl 2-
bromobenzo[d]thiazole-6-carboxylate as a yellow solid.
H NMR d 8.55 (s, 1H), 8.16 (dd, 1H, J = 8.6, 1.7 Hz), 8.03 (d, 1H, J =
8.3 Hz), 4.43 (q, 2H, J = 7.1 Hz), 1.43 (t, 3H, J = 7.1 Hz). MS : 286.0 (M+H).
STEP B: The ethyl 2-bromobenzo[d]thiazole-6-carboxylate ( 1 1. 1 g),
BOC-piperazine (9.03 g), potassium carbonate ( 1 1.7 g) and acetonitrile (400
mL) were combined and heated to reflux overnight. The resulting mixture was
cooled to room temperature, diluted with water and extracted with EtOAc. The
organics were concentrated to a yellow solid, which was recrystallized from
EtOAc/heptane to yield a ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-
yl)benzo[d]thiazole-6-carboxylate as a white powder, which was collected by
filtration.
1H NMR d 8.32 (d, 1H, J = 1.7 Hz), 8.01 (dd, 1H, J = 8.4, 1.8 Hz), 7.54
(d, 1H, J = 8.3 Hz), 4.37 (q, 2H, J = 7.1 Hz), 3.57-3.69 (m, 8H), 1.49 (s, 9H),
1.40 (t, 3H, J = 7.1 Hz). MS: 392.3 (M+H).
STEP C: The ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-
yl)benzo[d]thiazole-6-carboxylate ( 1 . 1 g) was dissolved in dry THF (50 mL) and
lithium borohydride (67 mg) was added. The resulting mixture was stirred
overnight at room temperature, then heated to reflux for 24 hours. Saturated
aqueous sodium bicarbonate was added and the resulting mixture was
extracted with ethyl acetate. The resulting solution was concentrated to yield
tert-butyl 4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate as
a white solid ( 1 .0 g). MS: 350.3 (M+H).
STEP D: The tert-butyl 4-(6-(hydroxymethyl)benzo[d]thiazol-2-
yl)piperazine-1-carboxylate ( 1 .0 g) was dissolved in a mixture of TFA (2 mL)
and DCM (20 mL) and stirred at room temperature. After four hours, the
resulting mixture was concentrated to yield (2-(piperazin-1-yl)benzo[d]thiazol-6-
yl)methanol as a yellow oil (0.7 g). MS: 250.3 (M+H).
STEP E: Boc-3-Alanine-(2-thienvl)-OH (0.84 g) and N-ethylmorpholine
( 1 .78 mL) were combined in DMF (25 mL). PyBOP ( 1 .61 g) was added and the
resulting mixture stirred at room temperature for 15 min. (2-(Piperazin-1-
yl)benzo[d]thiazol-6-yl)methanol (0.7 g) was added and the resulting mixture
stirred at room temperature overnight, then diluted with ethyl acetate and
saturated aqueous sodium bicarbonate. The resulting mixture was extracted
with ethyl acetate, concentrated and chromatographed (0 to 5% MeOH in
DCM) to yield (S)-tert-butyl 1-(4-(6-(hydroxymethyl)benzo[d]thiazol-2-
yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate as a white solid.
H NMR d 7.36 (s, 1H), 7.51 (d, 1H, J = 8.3 Hz), 7.26-7.30 (m, 1H), 7.15
(d, 1H, J = 4.1 Hz), 6.89-6.93 (m, 1H), 6.83-6.87 (m, 1H), 4.80-4.90 ( 1H, m),
4.71 (2H, s), 2.7-3.9 (m, 10H), 1.44 (s, 9H). MS : 503.3 (M+H).
STEP F: The (S)-tert-butyl 1-(4-(6-(hydroxymethyl)benzo[d]thiazol-2-
yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (83 mg) was
dissolved in dry 1,4-dioxane (3 mL) and HCI (4N in 1,4-dioxane, 1 mL) was
added. The resulting solution was stirred overnight at room temperature, then
concentrated to a white solid. The solid was chromatographed ( 94.5:5:0.5
dichloromethane:methanol:ammonium hydroxide) to yield the title compound as
a colorless oil, which was added to HCI/ether to yield (S)-2-amino-1-(4-(6-
(hydroxymethyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-3-(thiophen-2-yl)propan-1-
one as a white precipitate, which was collected by filtration.
H NMR d 7.63 (s, 1H), 7.51 (d, 1H, J = 8.3 Hz), 7.26-7.30 (m, 1H), 7.17
( 1H, dd, J = 5.1 , 1.0 Hz), 6.94 (dd, 1H, J = 5.1 , 3.4 Hz), 6.85 (d, 1H, J = 2.7
Hz), 4.71 (2H, s), 3.0-4.0 (m, 11H). MS: 403.2 (M+H).
Example 11: Compound #21
(S)-2-amino-1-(4-(6-((cvclopentylamino)methyl)benzo[dlthiazol-2-yl)piperazin-1-
-3-(thiophen-2-yl)propan-1-one
STEP A: (S)-tert-butyl 1-(4-(6-(hydroxymethyl)benzo[d]thiazol-2-
yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (0.859 g) and
Dess-Martin reagent ( 1 .09 g) were combined in dry DCM (20 mL) and the
resulting mixture stirred at room temperature for 24 hours. The resulting
mixture was diluted with saturated aqueous sodium bicarbonate and then
extracted with DCM. The combined organic layers were washed with saturated
aqueous Na2S20 3, concentrated, and chromatographed (0 to 5% MeOH in
DCM) to yield (S)-tert-butyl 1-(4-(6-formylbenzo[d]thiazol-2-yl)piperazin-1-yl)-1-
oxo-3-(thiophen-2-yl)propan-2-yl carbamate.
H NMR 9.93 (s, 1H), 8.13 (s, 1H), 7.81 (d, 1H, J = 8.3 Hz), 7.60 (d,
1H, J = 8.3), 7.10-7.20 (m, 1H), 6.85-6.95 (m, 2H), 5.53-5.70 (m, 1H), 4.84-4.95
(m, 1H), 3.05-3.88 (m, 10H), 1.44 (s, 9H). MS : 501 .3 (M+H).
STEP B: (S)-tert-Butyl 1-(4-(6-formylbenzo[d]thiazol-2-yl)piperazin-1 -yl)-
1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (45 mg), cyclopentylamine (12
mg), and sodium triacetoxyborohydride (29 mg) were combined in DCM ( 1 mL),
and the resulting mixture stirred at room temperature overnight, then heated to
reflux for 24 hours. The resulting mixture was then cooled to room
temperature, quenched with saturated aqueous sodium bicarbonate, extracted
with DCM, and chromatographed (0 to 5 % MeOH in DCM) to yield (S)-tertbutyl
1-(4-(6-((cyclopentylamino)methyl)benzo[d]thiazol-2-yl)piperazin-1 -yl)-1 -
oxo-3-(thiophen-2-yl)propan-2-ylcarbamate as a colorless oil.
H NMR d 8.07 (s, 1H), 7.45-7.65 (m, 2H), 7.15 (s, 1H), 6.82-6.96 (m,
2H), 4.81-4.92 (m, 1H), 2.8-3.9 (m, 13H), 1.26-1 .96 (m, 8H), 1.44 (s, 9H). MS :
570.3 (M+H).
STEP C: (S)-tert-Butyl 1-(4-(6-
((cyclopentylamino)methyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-
(thiophen-2-yl)propan-2-ylcarbamate (20 mg) was dissolved in dry 1,4-dioxane
(2 ml) and HCI (4N in 1,4-dioxane, ).5 mL) was added. The resulting mixture
was stirred overnight at room temperature, then concentrated and
chromatographed (94.5:5:0.5 dichloromethane:methanol:ammonium hydroxide)
to yield a colorless oil, which was added to HCI/diethyl ether. The resulting
white precipitate was collected and dried to yield the title compound.
H NMR d 7.48-7.66 (m, 2H), 7.15-7.33 (m, 2H), 6.82-6.98 (m, 2H), 3.0-
4.0 (m, 14H), 13.-2.0 (m, 8H). MS : 470.2 (M+H).
Example 12: Compound #14
(S)-2-amino-3-(thiophen-2-yl)-1-(4-(6-(4-(trifluoromethyl)phenyl)benzordlthiazol-
2-yl)piperazin-1 -yl)propan-1 -one
STEP A: 2-Chloro-6-bromobenzothiazole (2.29 g), piperazine ( 1 .59 g)
and sodium bicarbonate (3.1 0 g) were combined in isopropanol (75 mL) and
the resulting orange solution was heated to reflux overnight, then concentrated
to -15 mL, diluted with water, and extracted with DCM. The extracts were
concentrated to yield an orange solid which was chromatographed (0 to 5%
MeOH in DCM) to yield 6-bromo-2-(piperazin-1-yl)benzo[d]thiazole as a slightly
pink solid. MS: 297.9 (M+H).
STEP B: Boc-3-Alanine-(2-thienyl)-OH ( 1 .32 g) and N-ethylmorpholine
( 1 .54 mL) were dissolved in anhydrous DMF (25 mL) and then PyBOP (2.78 g)
was added. The resulting mixture was stirred for 15 min at room temperature,
then 6-bromo-2-(piperazin-1 -yl)benzo[d]thiazole ( 1 .45 g) was added. The
resulting mixture was stirred at room temperature overnight, diluted with
saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The
combined organic extracts were washed twice with brine and concentrated to
yield a brown oil. The oil was chromatographed (0 to 5% MeOH in DCM) to
yield (S)-tert-butyl 1-(4-(6-bromobenzo[d]thiazol-2-yl)piperazin-1 -yl)-1 -oxo-3-
(thiophen-2-yl)propan-2-ylcarbamate as a slightly orange solid. MS: 551 .0
(M+H).
STEP C: (S)-tert-Butyl 1-(4-(6-bromobenzo[d]thiazol-2-yl)piperazin-1 -yl)-
1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (80 mg), 4-
(trifluoromethyl)phenylboronic acid (33 mg), palladium
tetrakistriphenylphosphine (8 mg), and potassium carbonate (54 mg) were
combined in 1,4-dioxane (5 mL) and water ( 1 mL). The resulting mixture was
heated to 95°C overnight, then diluted with brine, extracted with DCM,
concentrated, and chromatographed (100% DCM) to yield (S)-tert-butyl 1-oxo-
3-(thiophen-2-yl)-1-(4-(6-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-
yl)piperazin-1-yl)propan-2-ylcarbamate as a colorless oil (96 mg).
H NMR d 7.83 (d, 1H, J = 1.7 Hz), 7.42-7.74 (m, 6H), 7.1 6 (d, 1H, J =
4.4 Hz), 6.86-6.94 (m, 2H), 5.44-5.52 ( 1H, m), 4.82-4.93 (m, 1H), 3.0-3.8 (m,
10H), 1.45 (s, 9H); MS: 6 17.3 (M+H).
STEP D: The (S)-tert-butyl 1-oxo-3-(thiophen-2-yl)-1-(4-(6-(4-
(trifluoromethyl)phenyl)benzo[d]thiazol-2-yl)piperazin-1-yl)propan-2-
ylcarbamate (96 mg) was dissolved in dry 1,4-dioxane (3 mL) and then HCI (4N
in 1,4-dioxane, 1 mL) was added. The resulting mixture was stirred at room
temperature overnight, then concentrated and chromatographed (93.5:6:0.5
DCM : MeOH : NH4OH) to yield a clear oil, which was added to 1N HCI/diethyl
ether. The resulting white precipitate was collected by filtration to yield the title
compound.
H NMR d 7.84 (d, 1H, J = 1.7 Hz), 7.53-7.72 (m, 6H), 7.1 5-7.1 9 (m, 1H),
6.85-6.95 (m, 2H), 3.0-4.0 (m, H); MS: 517.3 (M+H).
Compound #5 MS (M+H) 451 , was similarly prepared as described in
Example 12 above, by de-protecting the compound prepared in STEP B and
reacting (S)-tert-butyl 1-(4-(6-bromobenzo[d]thiazol-2-yl)piperazin-1 -yl)-1 -oxo-
3-(thiophen-2-yl)propan-2-ylcarbamate with HCI.
The following compounds were similarly prepared according to the
process described in Example 12 above, by selecting and substituting a
suitably substituted reagent for the boronic acid in STEP C.
Compound #8 MS (M+H) 463
Compound #9 MS (M+H) 509
Compound #10 MS (M+H) 493
Compound # 11 MS (M+H) 485
Compound #13 MS (M+H) 450
Compound #15 MS (M+H) 465
Compound #16 MS (M+H) 467
Compound #17 MS (M+H) 518
Biological Example 1: DPP-1 Inhibiiton Assay (in vitro)
Test compounds were assessed for DPP-1 (Cathepsin C) inhibitory
activity using a fluorogenic substrate, GR-AMC (Glycine-Arginine- amino-4-
methylcoumarin, Bachem, 1-1215). The amount of amino-methylcoumarin
released is proportional to the DPP-1 activity, and the reaction is monitored
kinetically with a Molecular Devices plate reader using black 96-well plates.
All compounds were tested under room temperature conditions. The
assay buffer consisted of 50 mM HEPES, pH 7.0, 100 mM NaCI, 2 mM
glutathione (GSH), and 0.002% TWEEN 20. GSH and TWEEN 20 were added
to the buffer fresh daily. Just prior to use, an in-house preparation of
recombinant human DPP-1 (240 mM stock, MW 49.6 kD) was diluted 600-fold
in assay buffer containing fresh 2 mM dithiothreitol (DTT) to activate the
enzyme, then diluted into assay buffer (without DTT) 133-fold for a DPP-1
working solution of 3 nM. Test compounds were diluted in DMSO for 20x their
final assay concentrations.
Additions to a 96-well black Costar 391 5 plates were as follows: 90 m I_ of
11 mM GR-AMC, 5 m I_ test compound (followed by mixing), and 5 m I_ 3 nM
DPP1 to start the reaction. Fluorescent reactions were monitored kinetically at
360 nm excitation , 440 nm emission on a Molecular Devices Spectramax XPS
reader. The Softmax Pro software of the reader determined the initial velocity
of the selected data (the first 3-5 minutes of the reaction), and the best linear
regression fit of the initial kinetic data. Final assay conditions were 0.15 nM
DPP-1 , 10 uM GR-AMC, 50 mM HEPES, pH 7.0, 100 mM NaCI, 2 mM GSH,
0.002% TWEEN 20, 1 mM DTT, 5.0 % DMSO. Initial velocity rates were plotted
vs. test compound concentration by use of a four-parameter logistics equation
(nonlinear regression, sigmoidal dose-response (variable slope), with fixed Hill
( 1 .0) using GraphPad Prism ® software for determination of DPP-1 IC50. Withinrun
assay coefficient of variation (CV) was generally <10%; between-run CV
<20%.
Representative compounds of the present invention were tested
according to the procedure as described above, with results as listed in Table
3, below. Where a compound was tested according to the above procedure
multiple times, the average value is listed in Table 3, below.
Table 3 : DPP-1 Inhibition
Solid, Oral Dosage Formulation - Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the
Compound #3, prepared as in Example 8, is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard
gel capsule.
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses all of the usual
variations, adaptations and/or modifications as come within the scope of the
following claims and their equivalents.

What is claimed:
1. A compound of formula I)
wherein
a is an integer from 0 to 1;
R is selected from the group consisting of halogen, C -4alkyl, -CH2-OH,
C - alkoxy, phenyl, 5 to 6 membered heteroaryl, benzo[d][1 ,3]dioxolyl, -C0 2H,
-C(0)-NR RB, -C(0)-NH-(Ci -4alkyl)-0-(Ci -4alkyl), -C(0)-NH-phenyl, -C(0)-NHCH2
-phenyl, -C(0)-NH-C 3-6cycloalkyl and -CH2-NH-C3-6cycloalkyl;
wherein R and RB are each independently selected from the group
consisting of hydrogen and Ci -4alkyl;
and wherein the phenyl, whether alone or as part of a substituent group
is optionally substituted with one or more substituent independently selected
from halogen, hydroxy, C -4alkyl, fluorinated C -4alkyl, C -4alkoxy and
fluorinated C -4alkoxy;
X is selected from the group consisting of O and S;
d from the group consisting of-NH-CH 2CH2-N(Rc )- and
wherein R is selected from the group consisting of
hydrogen, methyl and ethyl;
R2 is selected from the group consisting of C -4alkyl, C2-4alkenyl, C2-
alkynyl, -CH2-thienyl and -CH 2-furyl;
or a pharmaceutically acceptable salt thereof.
A compound as in Claim 1, wherein
a is an integer from 0 to 1;
R is selected from the group consisting of halogen, C -2alkyl, -CH2-OH,
alkoxy, phenyl, 5 to 6 membered heteroaryl, benzo[d][1 ,3]dioxolyl, -C0 2H,
-C(0)-NR R , -C(0 )-NH-(Ci-4alkyl)-0 -(Ci-4alkyl), -C(0 )-NH-phenyl, -C(0)-NHCH
2-phenyl, -C(0 )-NH-C3-6cycloalkyl and -CH2-NH-C3-6cycloalkyl;
wherein R and RB are each independently selected from the group
consisting of hydrogen and Ci-4alkyl;
and wherein the phenyl, whether alone or as part of a substituent group
is optionally substituted with one or more substituent independently selected
from halogen, hydroxy, C -4alkyl, fluorinated C -2alkyl, C -4alkoxy and
fluorinated C -2alkoxy;
X is selected from the group consisting of O and S;
d from the group consisting of -NH-CH2CH2-N(Rc)- and
wherein Rc is selected from the group consisting of
hydrogen, methyl and ethyl;
R2 is selected from the group consisting of C -4alkyl, C2-4alkynyl, -CH2-
thienyl and -CH 2-furyl;
or a pharmaceutically acceptable salt thereof.
3. A compound as in Claim 2, wherein
a is an integer from 0 to 1;
R is selected from the group consisting of halogen, -CH2-OH, C-i-
2alkoxy, phenyl, 6 membered heteroaryl, benzo[d][1 ,3]dioxolyl, -C0 2H, -C(O)-
NR RB, -C(0)-NH -(Ci -4alkyl)-0 -(Ci -2alkyl), -C(0)-NH-phenyl, -C(0)-NH-CH 2-
phenyl, -C(0)-NH-C 5-6cycloalkyl and -CH2-NH-C5-6cycloalkyl;
wherein R and RB are each independently selected from the group
consisting of hydrogen and C -4alkyl;
and wherein the phenyl, whether alone or as part of a substituent group
is optionally substituted with one to two substituent independently selected from
halogen, hydroxy, C -2alkyl, CF3 and C -2alkoxy;
X is selected from the group consisting of O and S;
wherein Rc is selected from the group consisting of hydrogen
and methyl;
R2 is selected from the group consisting of C2-4alkynyl, -CH2-
thienyl and -CH 2-furyl ;
or a pharmaceutically acceptable salt thereof.
4 A compound as in Claim 3, wherein
a is an integer from 0 to 1;
R is selected from the group consisting of 6-(bromo), 6-(carboxy), 6-
(hydroxymethyl), 6-(methoxy), 6-(benzo[d][1 ,3]dioxol-5-yl), 6-(pyrid-3-yl), 6-(4-
methylphenyl), 6-(3,4-dimethoxyphenyl), 6-(3,4-difluorophenyl), 6-(4-
trifluoromethyl-phenyl), 6-(4-hydroxyphenyl), 6-(2-fluorophenyl), 6-(3,5-
dichlorophenyl), 6-(3,4-dimethoxyphenyl-amino-carbonyl), 6-(cyclopentylamino-
carbonyl), 6-(4-fluorophenyl-amino-carbonyl), 6-(n-butyl-aminocarbonyl),
6-(methoxy-n-propyl-amino-carbonyl), 6-(dimethylamino-carbonyl),
6-(4-ethoxyphenyl-amino-carbonyl), 6-(n-propylamino-carbonyl), 6-(cyclohexylamino-
carbonyl), 6-(3-methoxy-benzyl-amino-carbonyl) and 6-(cyclopentylamino-
methyl);
X is selected from the group consisting of O and S;
R2 is selected from the group consisting of ethyl , n-propyn-2-yl , -CH2-
(thien-2-yl), -CH2-(thien-3-yl) and -CH 2-(fur-2-yl);
or a pharmaceutically acceptable salt thereof.
5. A compound as in Claim 4, wherein
a is an integer from 0 to 1;
R is selected from the group consisting of 6-(bromo), 6-(hydroxymethyl),
6-(benzo[d][1 ,3]dioxol-5-yl), 6-(pyrid-3-yl), 6-(4-methylphenyl), 6-(3,4-
dimethoxyphenyl), 6-(3,4-difluorophenyl), 6-(4-thfluoromethyl-phenyl), 6-(4-
hydroxyphenyl), 6-(2-fluorophenyl), 6-(3,5-dichlorophenyl), 6-(3,4-
dimethoxyphenyl-amino-carbonyl), 6-(cyclopentyl-amino-carbonyl), 6-(4-
fluorophenyl-amino-carbonyl), 6-(n-butyl-amino-carbonyl), 6-(methoxy-n-propylamino-
carbonyl), 6-(dimethylamino-carbonyl), 6-(4-ethoxyphenyl-aminocarbonyl),
6-(n-propylamino-carbonyl), 6-(cyclohexyl-amino-carbonyl), 6-(3-
methoxy-benzyl-amino-carbonyl) and 6-(cyclopentyl-amino-methyl);
R2 is selected from the group consisting of -CH2-(thien-2-yl) and -CH 2-
(fur-2-yl);
or a pharmaceutically acceptable salt thereof.
6. A compound as in Claim 5, wherein
a is an integer from 0 to 1;
R is selected from the group consisting of 6-(hydroxymethyl), 6-
(benzo[d][1 ,3]dioxol-5-yl), 6-(pyrid-3-yl), 6-(3,4-dimethoxyphenyl), 6-(3,4-
difluorophenyl), 6-(4-hydroxyphenyl), 6-(2-fluorophenyl), 6-(3,4-
dimethoxyphenyl-amino-carbonyl), 6-(cyclopentyl-amino-carbonyl), 6-(4-
fluorophenyl-amino-carbonyl), 6-(n-butyl-amino-carbonyl), and 6-(cyclopentylamino-
methyl);
R2 is -CH2-(thien-2-yl);
or a pharmaceutically acceptable salt thereof.
7. A compound as in Claim 6, wherein
a is 1;
R is selected from the group consisting of 6-(benzo[d][1 ,3]dioxol-5-yl),
6-(pyrid-3-yl), 6-(4-hydroxyphenyl) and 6-(3,4-dimethoxyphenyl-aminocarbonyl);
X is S;
d from the group consisting of -NH-CH 2CH2-N(CH3)- and
R2 is -CH2-(thien-2-yl);
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Claim 1.
9. A pharmaceutical composition made by mixing a compound of Claim 1
and a pharmaceutically acceptable carrier.
10. A process for making a pharmaceutical composition comprising mixing a
compound of Claim 1 and a pharmaceutically acceptable carrier.
11. A method of treating a disorder mediated by DPP-1 comprising
administering to a subject in need thereof a therapeutically effective amount of
a compound as in Claim 1.
12. The method of Claim 11, wherein the disorder mediated by DPP-1 is
selected from the group consisting of rheumatoid arthritis, asthma, chronic
obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis,
and abdominal aortic aneurism.
13. A method of treating rheumatoid arthritis, asthma, chronic obstructive
pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, or abdominal
aortic aneurism in a subject in need thereof comprising administering to the
subject a therapeutically effective amount of the composition of Claim 8.
14. A method of treating a disorder selected from the group consisting of
rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis,
irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism
comprising administering to a subject in need thereof a therapeutically effective
amount of the compound of Claim 1.
15. The use of a compound as in Claim 1 for the preparation of a
medicament for treating: (a) rheumatoid arthritis, (b) asthma, (c) chronic
obstructive pulmonary disease, (d) sepsis, (e) irritable bowel disease, (f) cystic
fibrosis, or (g) abdominal aortic aneurism in a subject in need thereof.
16. The use of a compound as in Claim 1, for use in a method for treating a
disorder selected from the group consisting of rheumatoid arthritis, asthma,
chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic
fibrosis, and abdominal aortic aneurism, in a subject in need thereof.