Derivatives of dolastatin 10 and auristatins
The subject of the present invention concerns novel derivatives of dolastatin 10
and auristatins, their methods of production, pharmaceutical compositions containing
the same and the use thereof as medicinal product in particular in the treatment of
cancer.
Dolastatin 10 (D10) is a cytotoxic peptide derivative isolated from a marine
mollusc {Dolabella auricularia) whose absolute configuration was determined and later
confirmed after total synthesis of the product (Pettit G. R. J. Am. Chem. Soc. 1987, 109,
6883; Pettit G. R. J. Am. Chem. Soc. 1987, 109, 7581; Pettit, G. R Heterocycles 1989,
28, 553; Pettit, G. R. J. Am. Chem. Soc. 1989,1 11, 5015; Pettit G. R. J. Am. Chem. Soc.
1991, 113, 6692). D10 is formed of 5 units called dolavaline (Dov), valine (Val),
dolaiso leucine (Dil), dolaproine (Dap) and dolaphenine (Doe). A certain number of
analogues of this compound have been synthesised by modifying the nature of its
component amino acids (Pettit G. R. J. Med. Chem. 1990, 33, 3133; Miyazaki K.
Peptide Chemistry 1993, 31, 85; Miyazaki K. Chem. Pham. Bull. 1995, 43, 1706).
Modifications of the C-terminal part (right end) have also been performed and have led
to numerous derivatives which include auristatin E or F (Pettit G. R. Anticancer Drug
Design, 1998, 13, 243; Pettit G. R. Antimicrobial Agents And Chemotherapy, 1998,
2961).
Dolastatin 10
Auristatin F
The present invention has focused on modification of the N-terminal part (left
end) of derivatives of dolastatin 10 and auristatins E and F. The few examples published
in the literature on modifications made at this position have led to losses of activity
(Miyazaki K. Chem. Pham. Bull. 1995, 43, 1706). The compounds described in the
present invention differ from the prior art through their original chemical structures and
also through their remarkable biological property that is fully unexpected having regard
to the elements published in the literature. These remarkable activities result in making
these compounds suitable for use in the treatment of cancer.
In addition, these compounds have the advantage of being both active as
cytotoxic agents and more soluble than the parent compounds.
The subject of the present invention is thus a compound of following formula
(I):
Ri is H or OH,
R2 is a group: (Ci-C 6)alkyl (e.g. methyl), COOH, COO-((Ci-C 6)alkyl) (such as
COOMe) or thiazolyl (such as thiazol-2-yl),
R3 is H or a (Ci-C )alkyl group (such as methyl), in particular a (Ci-C6)alkyl
group, and
R 4 is:
a saturated or unsaturated, straight-chain or branched hydrocarbon chain having 1 to
8 carbon atoms e.g. a (Ci-C8)alkyl group, the said chain being substituted by one or
more groups (in particular one) chosen from among OH and R R with R and R
each independently of one another representing H or a (Ci-C )alkyl group (e.g.
methyl),
a -(CH 2CH2X1)(CH2CH2X2)a2(CH2CH2X3 )a3 (CH2CH2X4)a4 (CH2CH2X5)a5R group
with Xi, X2, X3, X4 and X each independently of one another representing O or NRs,
a2, a3, a4 and a each independently of one another representing 0 or 1 (in particular
with a2 + a3 + a4 + a = 1 or 2, in particular 1), and R7 and R each independently of
one another representing H or a (Ci-C )alkyl group (such as methyl),
an aryl-(Ci-C8)alkyl group optionally substituted (and preferably substituted) by one
or more groups (in particular one, preferably on the aryl part), chosen from among
the aryl, OH and NR9R10 groups with R and Rio each independently of one another
representing H or a (Ci-C )alkyl group (such as methyl),
a heterocycle-(Ci-C8)alkyl group optionally substituted by one or more groups (in
particular one, preferably on the heterocycle part) chosen from among the (CiC
)alkyl, OH and NR12R13 groups with Ri2 and R13 each independently of one
another representing H or a (Ci-C )alkyl group (such as methyl), or
■ a -CO-((Ci-Cs)alkyl) group substituted by one or more groups (in particular one)
chosen from among OH and NR14R15 with R14 and R15 each independently of one
another representing H or a (Ci-C6)alkyl group (such as methyl),
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
The radicals R2 to R4, and in particular R4, may be chiral groups and may be in
the form of their different stereoisomers and optionally in the form of a mixture of
stereoisomers.
By « stereoisomer », in the meaning of the present invention is meant a
geometric isomer or an optical isomer.
Geometrical isomers result from the different position of the substituents on a
double bond which may therefore have a Z or E configuration.
Optical isomers result in particular from the different position in space of the
substituents on a carbon atom comprising 4 different substituents. This carbon atom
then forms a chiral or asymmetric centre. Optical isomers comprise diastereoisomers
and enantiomers. Optical isomers which are images of one another in a mirror but which
cannot be superimposed are called « enantiomers ». Optical isomers which are not
superimposable images of one another in a mirror are called « diastereoisomers ».
A mixture containing equal quantities of two individual enantiomer forms of
opposite chirality is called a « racemic mixture ».
In the present invention by « pharmaceutically acceptable » is meant that which
can be used in the preparation of a pharmaceutical composition which is generally, safe
non-toxic and neither biologically nor otherwise undesirable, and which is acceptable
for veterinary use as well as for human pharmaceutical use.
By « pharmaceutically acceptable salt, hydrate or solvate » of a compound is
meant a salt, hydrate or solvate which is pharmaceutically acceptable as defined herein
and which has the desired pharmacological activity of the parent compound.
Pharmaceutically acceptable salts notably comprise:
(1) the addition salts of a pharmaceutically acceptable acid formed with
pharmaceutically acceptable inorganic acids such as hydrochloric, hydrobromic,
phosphoric, sulfuric and similar acids; or formed with pharmaceutically acceptable
organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic, tartaric,
citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic,
stearic, lactic and similar acids; and
(2) the addition salts of a pharmaceutically acceptable base formed when an acid
proton present in the parent compound is either replaced by a metallic ion e.g. an
alkaline metal ion, an alkaline-earth metal ion or an aluminium ion; or coordinated with
a pharmaceutically acceptable organic base such as lysine, arginine and similar; or with
a pharmaceutically acceptable inorganic base such as sodium hydroxide, potash,
calcium hydroxide and similar.
These salts can be prepared from the compounds of the invention containing a
base or acid function, and the corresponding acids or bases using conventional chemical
methods.
The formula (I) compounds of the invention are preferably in salt form, and in
particular a pharmaceutically acceptable acid addition salt.
Preferably, the compounds of formula (I) according to the present invention are
in the form of a pharmaceutically acceptable acid addition salt, the acid possibly being
trifluoroacetic acid, acetic acid or hydrochloric acid for example, and in particular
trifluoroacetic acid.
The solvates comprise the conventional solvates obtained at the last preparation
step of the compounds of the invention due to the presence of solvent, the solvent
possibly being ethanol for example.
By « alkyl » in the present invention is meant a straight-chain or branched,
saturated hydrocarbon chain. For example, mention can be made of methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups.
By « (Cx- Cy)alkyl » in the meaning of the present invention is meant an alkyl
chain such as defined above comprising x to y carbon atoms. Therefore, a (Ci-C6)alkyl
group is an alkyl chain having 1 to 6 carbon atoms.
By « aryl » in the meaning of present invention is meant an aromatic
hydrocarbon group preferably having 6 to 10 carbon atoms and able to comprise one or
two fused rings. For example a phenyl or a naphthyl can be cited. Advantageously it is a
phenyl.
By « heterocycle » in the meaning of present invention is meant a saturated,
unsaturated or aromatic hydrocarbon group having 1 or 2 fused rings and in which one
or more, advantageously 1 to 4, more advantageously 1 or 2 of the carbon atoms are
each replaced by a heteroatom chosen from among oxygen, nitrogen and sulfur.
Advantageously the heterocycle comprises 5 to 10 carbon atoms and heteroatoms. For
example, mention can be made of furan, pyrrole, thiophene, thiazole, isothiazole,
oxadiazole, imidazole, oxazole, isoxazole, pyridine, pyrimidine, piperazine, piperidine,
quinazoline, quinoline, quinoxaline, benzofuran, benzothiophene, indoline, indolizine,
benzothiazole, benzothiophene, benzopyran, benzoxazole, benzo[l,3]dioxole,
benzoisoxazole, benzimidazole, chromane, chromene, dihydrobenzofuran,
dihydrobenzothiophene, dihydroisoxazole, isoquinoline, dihydrobenzo[l,4]dioxin,
imidazo[l,2-a]pyridine, furo[2,3-c]pyridine, 2,3-dihydro-l H -indene, [l,3]dioxolo[4,5-c]
pyridine, pyrrolo[l,2-c]pyrimidine, pyrrolo[l,2-a]pyrimidine, tetrahydronaphthalene
and benzo[b][l,4]oxazin.
In the present invention, the heterocycle is more particularly a saturated,
unsaturated or aromatic ring with 5 to 6 members comprising 1 or 2 nitrogen atoms. For
example, mention can be made of pyrrole, imidazole, pyridine, pyrimidine, piperazine
and piperidine rings. Preferably it is a pyridine, a piperidine, or an imidazole.
By « aryl-(Ci-Cs)alkyl » in the meaning of the present invention is meant an
aryl group such as defined above linked to the remainder of the molecule via an alkyl
group such as defined above and comprising 1 to 8, in particular 1 to 6, advantageously
1 to 4, preferably 1 or 2 carbon atoms. The aryl moiety is preferably a phenyl moiety.
The (Ci-Cs)alkyl moiety is advantageously a (Ci-C4)alkyl, peferably a (Ci-C2)alkyl. In
particular, the aryl-(Ci-C8)alkyl group is a benzyl or phenethyl group.
By « heterocycle-(Ci-C 8)alkyl » in the meaning of the present invention is meant
a heterocycle group such as defined above linked to the remainder of the molecule via
an alkyl group such as defined above and having 1 to 8, in particular 1 to 6,
advantageously 1 to 4 and preferably 1 or 2 carbon atoms. The (Ci-Cs)alkyl moiety is
advantageously a (Ci-C4)alkyl, peferably a (Ci-C2)alkyl. The heterocycle is more
particularly a saturated, unsaturated or aromatic ring with 5 to 6 members comprising 1
or 2 nitrogen atoms, such as a pyrrole, an imidazole, a pyridine, a pyrimidine, a
piperazine or a piperidine, preferably a pyridine, a piperidine, or an imidazole.
By « unsaturated » it is meant to qualify a compound comprising an unsaturation
i.e. a double or triple bond.
Among the compounds of the invention, one particularly appreciated class of
compounds corresponds to the formula (I) compounds in which Ri is OH and R2
represents a (Ci-C )alkyl group, such as methyl.
Another particularly appreciated class of compounds corresponds to the formula
(I) compounds in which Ri is a hydrogen and R2 is a thiazole (in particular a thiazol-2-yl
group).
Another class of particularly appreciated compounds corresponds to the formula
(I) compounds in which Ri is a hydrogen and R2 is a COO(Ci-Ce)alkyl group such as
COOMe.
Another class of particularly appreciated compounds corresponds to the formula
(I) compounds in which Ri is a hydrogen and R2 is a COOH group.
Therefore the compounds of the invention are advantageously formula (I)
compounds in which:
- Ri=OH and R2=Me (methyl), or
- Ri=H and R2=COOH, COOMe or thiazol-2-yl.
Another class of particularly appreciated compounds corresponds to the formula
(I) compounds in which R4 is a heterocycle-(Ci-C 8)alkyl unsubstituted or substituted by
a group chosen from among NRi 2Ri3 and OH.
Similarly, the present invention particularly concerns the formula (I) compounds
in which R4 is an aryl-(Ci-C 8)alkyl substituted by one or more groups chosen from
among NR9R10 and OH.
According to one particular embodiment of the present invention, R2 is more
particularly a methyl, COOH, COOMe or thiazol-2-yl group.
Preferably, Ri is H and R2 is COOH or COO(Ci-C 6)alkyl, notably COOH or
COOMe.
According to a first preferred embodiment, Ri is H and R2 is COOH.
According to a second preferred embodiment, Ri is H and R2 is COOMe.
R3 particularly represents H or a methyl group, advantageously a methyl group.
According to a particular embodiment, R 4 represents:
a saturated or unsaturated, straight-chain or branched hydrocarbon chain having 1
to 8 carbon atoms e.g. a (Ci-Cs)alkyl group, the said chain being substituted by one
or more groups (in particular one) chosen from among OH and R R with R and
R each independently of one another representing H or a (Ci-C )alkyl group (e.g.
methyl),
a -(CH2CH2X1)(CH2CH2X2)a2(CH2CH2X3 )a3 (CH2CH2 X4)a4 (CH2CH2X5)a5R group
with Xi, X2, X3, X4 and X each independently of one another representing O or
NRs, a2, a3, a4 and a each independently of one another representing 0 or 1 (in
particular with a2 + a3 + a4 + a = 1 or 2, in particular 1), R7 representing H and R
representing H or a (Ci-C )alkyl group (such as methyl),
an aryl-(Ci-C8)alkyl group substituted (and preferably substituted) by one or more
groups (in particular one, preferably on the aryl part), chosen from among the aryl,
OH and NR9R10 groups with R and Rio each independently of one another
representing H or a (Ci-C )alkyl group (such as methyl),
a heterocycle-(Ci-C 8)alkyl group optionally substituted by one or more groups (in
particular one, preferably on the heterocycle part) chosen from among the (Ci-
C )alkyl, OH and NRi2Ri3 groups with Ri2 and Ri3 each independently of one
another representing H or a (Ci-C )alkyl group (such as methyl), or
a COCHR 16 R14R1 group with Ri4 and R1 each independently of one another
representing H or a (Ci-C )alkyl group (such as methyl) and Ri representing H or a
(Ci-C )alkyl group, preferably a (Ci-Ce)alkyl group.
According to another particular embodiment of the invention, R4 represents a
roup:
(Ci-Ce)alkyl, in particular (C2-C )alkyl substituted by a group chosen from among
(CH2CH2Xi)(CH2CH2X2)a2(CH2CH2X3)a3R with a2 + a3 advantageously
representing 1 or 2, in particular 1, and advantageously with R = H,
aryl-(Ci-C2)alkyl substituted by a group (preferably on the aryl moiety) chosen
from among OH and NR9R10 ,
heterocycle-(Ci-C2)alkyl optionally substituted by a group (in particular substituted
with one group, preferably on the heterocycle moiety) chosen from among
NR12R13, OH and (Ci-Ce)alkyl groups, preferably chosen from among OH and
COCHR16NR14R15 with Ri6 representing H or a (Ci-C )alkyl group, preferably a
(Ci-C )alkyl group.
According to another particular embodiment of the invention, R4 represents a
roup:
(Ci-Ce)alkyl, in particular (C2 -C )alkyl substituted by a group chosen from among
(CH2CH2Xi)(CH2CH2X2)a2(CH2CH 2X3)a3R7 with a2 + a3 advantageously
representing 1 or 2, in particular 1, and advantageously with R = H,
aryl-(Ci-C2)alkyl substituted by a group (preferably on the aryl moiety) chosen
from among OH and NR9R10, or
heterocycle-(Ci-C2)alkyl optionally substituted by a group (in particular substituted
with one group, preferably on the heterocycle moiety) chosen from among
NR12R13, OH and (Ci-C )alkyl groups, preferably chosen from among OH and
According to another particular embodiment, R4 represents:
an aryl-(Ci-C 8)alkyl group optionally substituted (and preferably substituted) by
one or more groups (in particular one, preferably on the aryl part), chosen from
among the aryl, OH and NR9R10 groups with R and Rio each independently of one
another representing H or a (Ci-C )alkyl group (such as methyl), or
a heterocycle-(Ci-C 8)alkyl group optionally substituted by one or more groups (in
particular one, preferably on the heterocycle part) chosen from among the (Ci-
C )alkyl, OH and NR12R13 groups with Ri2 and R13 each independently of one
another representing H or a (Ci-Ce)alkyl group (such as methyl).
According to still another particular embodiment, R4 represents:
an aryl-(Ci-C 8)alkyl group substituted by one or more groups (in particular one,
preferably on the aryl part) chosen from among OH and NR9R10 groups, or
a heterocycle-(Ci-C 8)alkyl group optionally substituted by one or more groups (in
particular substituted with one group, preferably on the heterocycle part) chosen
from among the (Ci-C )alkyl, OH and NR12R13 groups, preferably chosen from
among OH and NR12R13.
According to another particular embodiment, R 4 represents:
- an aryl-(Ci-C 4)alkyl group substituted by one or more groups (in particular one,
preferably on the aryl part) chosen from among OH and NR9R10 groups, or
- a heterocycle-(Ci-C 4)alkyl group optionally substituted by one or more groups (in
particular substituted with one group, preferably on the heterocycle part) chosen
from among the (Ci-C )alkyl, OH and NR12R13 groups, preferably chosen from
among OH and NR12R13.
According to yet another particular embodiment of the invention, R4 represents a
group:
- aryl-(Ci-C 2)alkyl substituted by a group (preferably on the aryl moiety) chosen
from among OH and NR9R10 , or
- heterocycle-(Ci-C 2)alkyl optionally substituted by a group (in particular
substituted with one group, preferably on the heterocycle moiety) chosen from
among NR12R13 , OH and (Ci-C )alkyl groups, preferably chosen from among OH
In the above particular embodiments for R4 , the aryl group is advantageously a
phenyl group.
In the above particular embodiments for R4 , the heterocycle is advantageously a
saturated, unsaturated or aromatic ring with 5 or 6 members having 1 or 2 nitrogen
atoms. For example, mention can be made of pyrrole, imidazole, pyridine, pyrimidine,
piperazine, or piperidine rings. Preferably it is a pyridine, piperidine or imidazole.
In the above particular embodiments for R4 , the aryl moiety and the heterocycle
moiety advantageously are each substituted with one group.
Advantageously, R4 represents a group:
- -(CH 2)m R R6 with m representing 1, 2, 3, 4, 5, 6, 7 or 8, in particular 2, 3 or 4,
- -(CH 2CH2Xi)(CH2CH2X2)(CH2CH2X 3)R7 or
preferably - H2¾ Ci) H2¾ C2 7, advantagesouly with R7 = H,
- phenyl-(Ci-C 2)alkyl substituted by a group (preferably on the phenyl moiety)
chosen from among OH and NR9R10 ,
- heterocycle-(Ci-C 2)alkyl optionally substituted by a group (preferably on the
heterocycle moiety) chosen from among OH and NR12R13 , the heterocycle being a
saturated, unsaturated or aromatic ring with 5 or 6 members comprising 1 or 2
nitrogen atoms, chosen in particular from among pyridine, piperidine and
imidazole, or
- -CO-CHR16-NR14R15 with Ri6 representing a (Ci-C6)alkyl group.
In particular, R4 represents a group:
- -(CH 2)m R R6 with m representing 1, 2, 3, 4, 5, 6, 7 or 8, in particular 2, 3 or 4,
- -(CH 2CH2X1)(CH2CH2X2)(CH2CH2X3)R7 or -(CH 2CH2X1)(CH2CH2X2)R ,
preferably -(CH 2CH2Xi)(CH 2CH2X2)R , advantagesouly with R = H,
- phenyl-(Ci-C 2)alkyl substituted by a group (preferably on the phenyl moiety)
chosen from among OH and NR9R10 , or
- heterocycle-(Ci-C 2)alkyl optionally substituted by a group (preferably on the
heterocycle moiety) chosen from among OH and NRi2Ri3, the heterocycle being a
saturated, unsaturated or aromatic ring with 5 or 6 members comprising 1 or 2
nitrogen atoms, chosen in particular from among pyridine, piperidine and
imidazole.
In particular, R4 can represent a group:
- phenyl-(Ci-C 2)alkyl substituted by a group (preferably on the phenyl moiety)
chosen from among OH and NR9R10 , or
- heterocycle-(Ci-C 2)alkyl optionally substituted by a group (preferably on the
heterocycle moiety) chosen from among OH and NRi2Ri3, the heterocycle being a
saturated, unsaturated or aromatic ring with 5 or 6 members comprising 1 or 2
nitrogen atoms, chosen in particular from among pyridine, piperidine and
imidazole.
In particular, R4 can represent a group:
- phenyl-(Ci-C 2)alkyl substituted by one group (preferably on the phenyl moiety)
chosen from among OH and NR9R10 , or
- heterocycle-(Ci-C 2)alkyl substituted by one group (preferably on the heterocycle
moiety) chosen from among OH and NRi 2Ri3, the heterocycle being a saturated,
unsaturated or aromatic ring with 5 or 6 members comprising 1 or 2 nitrogen atoms,
chosen in particular from among pyridine, piperidine and imidazole.
R4 may in particular be chosen from among:
- -(CH 2)2NH2, -(CH 2)2NHMe, -(CH 2)3NH2, -(CH 2)3NHMe, -(CH 2)4NH2,
-(CH 2)4NHMe,
-(CH 2)20(CH 2)2OH, -(CH 2)20(CH 2)2NH2, -(CH 2)20(CH 2)2NHMe,
O O
MeHN. A / MeHN O
MeHN
, and
R 4 may in particular be chosen from among:
-(CH 2)2NH2, -(CH 2)2NHMe, -(CH 2)3NH2, -(CH 2)3NHMe, -(CH2)4NH2
-(CH 2)4NHMe,
-(CH 2)20(CH 2)2OH, -(CH 2)20(CH 2)2NH2, -(CH 2)20(CH 2)2NHMe,
Advantageously,R 4 is chosen from among:
According to another particular embodiment of the invention R4 is an aryl-(Ci-
Cs)alkyl group substituted by one or more groups (particularly one, preferably on the
aryl moiety) chosen from among OH and NR9R10 , and particular from among OH and
NR9R10 . Advantageously, it is an aryl-(Ci-C 2)alkyl group substituted by one or more
groups (particularly one, preferably on the aryl moiety) chosen from among OH and
NR9R10 , and particularly from among OH and NR9R10 . The aryl group is preferably a
phenyl group.
According to this embodiment, R3 is advantageously a methyl group.
R4 represents advantageously an aryl-(Ci-Cs)alkyl group, notably an aryl-(Ci-
C 4)alkyl group, such as an aryl-(Ci-C 2)alkyl group, substituted by one group chosen
from among OH and NR9R10, and notably being NR9R10.
R4 represents advantageously an aryl-(Ci-Cs)alkyl group, notably an aryl-(Ci-
C4)alkyl group, such as an aryl-(Ci-C 2)alkyl group, substituted by one group on the
aryl moiety chosen from among OH and NR9R10 , and notably being NR9R10.
The aryl group is advantageously a phenyl group.
Thus R4 can represent in particular a phenyl-(Ci-C 2)alkyl substituted by one
group (preferably on the phenyl moiety) chosen from among OH and NR9R10 , and
notably being NR9R10.
s have the following formula:
wherein X0 represents OH or NR9R10, n particular NR9R10, and m represents an integer
comprised between 1 and 8, notably between 1 and 4, and advantageously is 1 or 2.
to a preferred embodiment, R4 has the following formula:
with Xo and m as defined previously, and in particular with and m=l or 2.
Advantageously, the formula (I) compound is chosen from among the
compounds 1 to 60 described in the examples below.
A further subject of the present invention is a formal (I) compound such as
defined above for use as medicinal product, in particular for the treatment or prevention
of cancer or benign proliferative disorders.
The present invention also concerns the use of a formula (I) compound such as
defined above for producing a medicinal product, particularly intended for the treatment
or prevention of cancer or benign proliferative disorders.
The present invention also concerns a method for treating or preventing cancer
or benign proliferative disorders comprising the administration to a person in need
thereof of an effective amount of a formula (I) compound such as defined above.
The cancer to be treated or prevented is more particularly cancer of the lung,
pancreas, skin, head, neck, uterus, ovaries, anus, stomach, colon, breast, oesophagus,
small intestine, thyroid gland, lymphatic system, prostate, kidney, or bladder, or an
acute or chronic leukaemia, or a combination of two or more of these cancers.
By benign proliferative disorders is meant proliferating disorders which cannot
give rise to metastases or which have not yet progressed towards a cancer (pre
cancerous tumours).
A further subject of the present invention is a pharmaceutical composition
comprising a formula (I) compound such as defined above and at least one
pharmaceutically acceptable excipient.
The active ingredient can be administered in unit forms of administration, in a
mixture with conventional pharmaceutical carriers, to animals or to human beings.
Suitable unit forms of administration comprise forms via oral route, forms for
sublingual or buccal administration, forms for administration via parenteral route
(subcutaneous, intradermal, intramuscular or intravenous), forms for topical
administration (on the skin and mucosa, including intranasal and intraocular
administration) and forms for rectal administration.
Such compositions may be in the form of a solid, liquid, emulsion, lotion or
cream.
As solid compositions, for oral administration, use can be made of tablets, pills,
powders (hard or soft gelatine capsules) or granules. In these compositions, the active
ingredient of the invention is mixed with one or more inert diluents such as starch,
cellulose, sucrose, lactose or silica, in a stream of argon. These compositions may also
comprise substances other than diluents, for example one or more lubricants such as
magnesium stearate or talc, a colouring agent, a coating (coated tablets) or a varnish.
As liquid compositions for oral administration, use can be made of solutions,
suspensions, emulsions, syrups and elixirs that are pharmaceutically acceptable and
contain inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.
These compositions may comprise substances other than diluents; for example wetting,
sweetening, thickening, flavouring or stabilising products.
The sterile compositions for parenteral administration may preferably be
aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, use
can be made of water, propyleneglycol, a polyethyleneglycol, vegetable oils, in
particular olive oil, injectable organic esters e.g. ethyl oleate or other suitable organic
solvents. These compositions may also contain adjuvants, in particular wetting, isotonic,
emulsifying, dispersing and stabilising agents. Sterilisation can be performed in several
manners, for example by sanitising filtration, by incorporating sterilising agents into the
composition, by radiation or by heating. They can also be prepared in the form of solid
sterile compositions which can be dissolved at the time of use in sterile water or any
other injectable sterile medium.
The compositions for rectal administration are suppositories or rectal capsules
which, in addition to the active ingredient, contain excipients such as cocoa butter,
semi-synthetic glycerides or polyethyleneglycols.
The compositions for topical administration may for example be creams, lotions,
eye drops, mouthwash, nasal drops or sprays.
The doses are dependent on the desired effect, on the length of treatment and the
route of administration used. In general the physician will determine the suitable dosage
in relation to the age, weight and all other factors particular to the subject to be treated.
Another active ingredient may be contained in the pharmaceutical compositions
according to the present invention. In particular, it may be an anticancer agent, and in
particular a cytotoxic anticancer agent such as navelbine, vinflunine, taxol, taxotere, 5-
fluorouracil, methotrexate, doxorabicin, camptothecin, gemcitabin, etoposide, cis-platin
or carmustine (also called BCNU); or a hormonal anticancer agent such as tamoxifen or
medroxyprogesterone.
Radiation treatment (X-ray or gamma ray) may also be associated with the
administering of a compound of the present invention. Such radiation can be given
using an external source or by implanting minute internal radioactive sources.
The present invention also concerns the preparation of the formula (I)
compounds according to the invention using the general methods described in the
following synthesis schemes, optionally supplemented by any standard operation when
needed that is described in the literature or well known to persons skilled in the art, or
described in the examples in the experimental part hereof.
Scheme 1
Scheme 1 illustrates the first general method which can be used to prepare
formula (I) compounds. In the above general formulas, Ri, R2, and R3 are such as
previously defined, R4a represents a R4 group such as previously defined optionally in
protected form and G is a protective group.
The first step consists of the condensing of compound (II), protected on its
amine function by a protective group G, with compound (III). X may represent a leaving
group such as a chlorine. In this case the first step consists of the reaction between an
acid chloride and an amine. This reaction can be conducted using methods and
techniques well known to those skilled in the art. In one particularly appreciated
method, the two entities are caused to react in the presence of an organic or inorganic
base e.g. Et3N, iPr2NEt, pyridine, NaH, Cs2C0 3, K2C0 3 in a solvent such as THF,
dichloromethane, DMF, DMSO, at a temperature notably between -20°C and 100°C. X
may also be a hydroxyl (OH). In this case, the first step is a condensation reaction
between the carboxylic acid (II) and the amine (III). This reaction can be performed
following methods and techniques well known to skilled persons. In one particularly
appreciated method, these two entities are caused to react in the presence of a coupling
agent such as l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), 3-hydroxyl,
2,3-benzotriazin-4(3H)-one, a tertiary amine such as diisopropylethylamine, in a
polar aprotic solvent such as dichloromethane or DMF, at a temperature notably
between -15°C and 40°C. In another particularly appreciated method, these two entities
are caused to react in the presence of diethyl phosphorocyanidate (DEPC), a tertiary
amine such as triethylamine, in a polar aprotic solvent such as dichloromethane or
DMF, at a temperature of between -15°C and 40°C. Another particularly appreciated
method consists of causing these two entities to react in the presence of 0-(7-
azabenzotriazol-l-yl)-l ,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU), a
tertiary amine such as diisopropylethylamine, in a polar aprotic solvent such as
dichloromethane or DMF, at a temperature of between -15°C and 100°C.
After deprotection of the intermediate using techniques well known to those
skilled in the art (« Protective Groups in Organic Synthesis », T.W. Greene, John Wiley
& Sons, 2006 and « Protecting Groups », P.J. Kocienski, Thieme Verlag, 1994),
compound (IV) can be condensed with compound (V) following the methods and
techniques described above to lead to compound (VI) after a deprotection step. This
compound can then, after condensation with the intermediate (VII) and optional
deprotection, lead to the formation of the formula (I) compounds. Compound (VI) can
also be coupled with a compound (VIF) in which R'3 is a precursor of R3, in particular
an R3 group protected by a protective group. Coupling followed by deprotection of
group R'3 to lead to R3 can be carried out following the same procedures as described
previously.
Scheme
Scheme 2 illustrates the second general method which can be used to prepare
formula (I) compounds. In the above general formulas Ri, R2, and R3 are such as
previously defined, R4a represents an R4 group such as previously defined optionally in
protected form, R4b is a precursor of an R4 group and G is a protective group.
At the first step, compound (IX) protected on its amine function by a protective
group G is condensed with compound (VI). X may represent a leaving group e.g. a
chlorine. In this case, the first step consists of the reaction between an acid chloride and
an amine. This reaction can be performed using methods and techniques well known to
persons skilled in the art. In one particularly appreciated method the two entities are
caused to react in the presence of an organic or inorganic base such as Et3N, iPr2NEt,
pyridine, NaH, Cs2C0 3, K2C0 3 in a solvent such as THF, dichloromethane, DMF,
DMSO at a temperature notably between -20° and 100°C. X may also represent a
hydroxyl. In this case, the first step is a condensation reaction between the carboxylic
acid (IX) and the amine (VI). This reaction can be conducted following methods and
techniques well known to skilled persons. In one particularly appreciated method, the
two entities are caused to react in the presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDC), 3-hydroxy-l,2,3-benzotriazin-4(3H)-one, a tertiary amine such
as diisopropylethylamine, in a polar aprotic solvent such as dichloromethane or DMF, at
a temperature notably between -15°C and 40°C. In another particularly appreciated
method, these two entities are caused to react in the presence of diethyl
phosphorocyanidate (DEPC), a tertiary amine such as triethylamine, in a polar aprotic
solvent such as dichloromethane or DMF, at a temperature notably between -15°C and
40°C.
After deprotection of the intermediate, using techniques well known to skilled
persons, the obtained compound (VIII) can lead to the formula (I) compounds after
reaction with R4Y. In this case, Y is a leaving group such as CI, Br, I, OSO 2CH3,
OSO 2CF3 or O-Tosyl. The reaction is conducted in the presence of an organic or
inorganic base such as Et3N, iPr2NEt, NaH, Cs2C0 3, K2C0 3, in a polar anhydrous
solvent such as dichloromethane, THF, DMF, DMSO at a temperature notably between
-20° and 100°C. In another particularly appreciated method, compound (VIII) is caused
to react with an aldehyde of formula R4b-CHO where R4b corresponds to a precursor of
R4. In this case, the reaction is a reductive amination in the presence of a reducing agent
such as NaBH4, NaBH3CN, NaBH(OAc) 3, in a polar solvent such as 1,2-
dichloroethane, dichloromethane, THF, DMF, MeOH, in the optional presence of
titanium isopropoxide (IV), at a pH which can be controlled by the addition of an acid
such as acetic acid at a temperature notably between -20°C and 100°C.
In the foregoing synthesis schemes, a formula (I) compound may lead to another
formula (I) compound after an additional reaction step such as saponification for
example using methods well known to skilled persons whereby an R2 group
representing an ester, preferably a methyl ester, is changed to an R2 group representing a
carboxylic acid.
If it is desired to isolate a formula (I) compound containing at least one base
function in the state of an acid addition salt, this is possible by treating the free base of
the formula (I) compound (containing at least one base function) with a suitable acid,
preferably in equivalent quantity. The suitable acid may in particular be trifluoroacetic
acid.
A further subject of the present invention is therefore a first method for
preparing a formula (I) compound, comprising a condensation reaction between a
compound of following formula (VI):
where Ri and R2 are such as defined previously, and
a compound of following formul
where R3 is such as previously defined, R4a corresponds to a R4 group such as
previously defined optionally in protected form, and X is OH or CI.
When X = OH, the coupling reaction can be performed under peptide coupling
conditions well known to persons skilled in the art.
Said peptide coupling can be performed in the presence of a coupling agent such
as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), l-(3-dimethyl
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI),
2-( 1H-benzotriazole- 1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU),
2-(lH-benzotriazole- 1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU),
0-(7-azobenzotriazol- 1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU),
diethyl phosphorocyanidate (DEPC) or (benzotriazol-l-yloxy)
tripyrrolodinophosphonium hexafluorophosphate (PyBOP), optionally associated with a
coupling auxiliary such as N-hydroxy succinimide (NHS), N-hydroxy benzotriazole
(HOBt), 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazole (HOOBt), l-hydroxy-7-
azabenzotriazole (HAt), N-hydroxysylfo succinimide (sulfo NHS) or dimethyl
aminopyridine (DMAP). Preferably the coupling agent is HATU or DEPC.
The reaction can also be performed in the presence of a base such as DIEA
(diisopropylethylamine).
In particular, the peptide coupling is performed in the presence of HATU or
DEPC and DIEA.
Said reaction can be carried out in a polar aprotic solvent such as
dichloromethane (DCM) or dimethylformamide (DMF), in particular at a temperature of
between -15°C and 40°C.
When X = CI, the condensation reaction will be conducted in the presence of a
base which may be organic or inorganic, such as Et3N, iPr2NEt, pyridine, NaH, CS2CO3,
or K2C0 3.
The reaction can be carried out in a solvent such as tetrahydrofuran (THF),
dichloromethane (DCM), dimethylformamide (DMF), or dimethylsulfoxide (DMSO), in
particular at a temperature of between -20° and 100°C.
The compounds of formulas (VI) and (VII) can be prepared following synthesis
protocols described in the experimental part below or following techniques known to
those skilled in the art.
A further subject of the present invention is a second method for preparing a
formula (I) compound comprising a substitution reaction between a compound of
following formula (VIII):
(VIII)
where Ri, R2 an R3 are such has previously defined, and
a compound of following formula (X):
where R4a is an R4 group such as previously defined optionally in protected form,
is a leaving group such as CI, Br, I, OS0 2CH3, OS0 2CF3 or O-Tosyl.
The substitution reaction will be notably conducted in the presence of a base
which may be organic or inorganic such as Et3N, iPr2NEt, NaH, Cs2C0 3, or K2C0 3.
This reaction can be implemented in a polar solvent, preferably anhydrous, such
as DCM, THF, DMF or DMSO, in particular at a temperature of between -20° and
100°C.
The compounds of formulas (VIII) and (X) can be prepared following the
synthesis protocols described in the experimental part below or using techniques known
to those skilled in the art.
A further subject of the present invention is a third method for preparing a
formula (I) compound in which R 4 is a -CH 2R4b group with R4b representing:
■ OH, R R , a straight-chain or branched hydrocarbon chain, saturated or
unsaturated, having 1 to 7 carbon atoms (e.g. a (Ci-Cv)alkyl group) substituted
by one or more groups (in particular one) chosen from among OH and R R ,
■ -CH 2Xi(CH 2CH2X2)a2(CH2CH2X3)a (CH2CH2X4) a4(CH2CH2X5)a5R7,
■ an aryl or aryl-(Ci-C )alkyl group optionally substituted by one or more
groups (in particular one, preferably on the aryl moiety) chosen from among
the aryl, OH and NR9R10 groups, or
■ a heterocycle or heterocycle-(Ci-C 7)alkyl group optionally substituted by one
or more groups (in particular one, preferably on the heterocycle moiety) chosen
from among (Ci-Ce)alkyl, OH and NRi2Ri3 groups,
comprising a reductive amination reaction between a compound of following formula
(VIII):
where Ri, R2 and R3 are such as previously defined, and
a compound of following formula (XI):
R4b-CHO (XI)
where R4b is such as defined above.
The reductive amination reaction can be carried out in the presence of a reducing
agent such as NaBH4, NaBH3CN or NaBH(OAc)3 and optionally titanium isopropoxide
(IV).
The pH can be controlled by adding an acid such as acetic acid, in particular to
reach a pH of between 4 and 5.
This reaction can be implemented in a polar solvent such as DCE (1,2-
dichloroethane), DCM, THF, DMF or methanol, in particular at a temperature of
between -20° and 100°C.
The compounds of formulas (VIII) and (XI) can be prepared following synthesis
protocols described in the experimental part below or using techniques known to those
skilled in the art.
The compound obtained after the condensation/substitution/reductive amination
step of one of the three above methods can be subjected to additional deprotection steps
particularly concerning the substituents R2 and R4 and optionally additional
functionalization steps using methods well known to skilled persons.
When R2 represents a COOH group, the condensation/substitution/reductive
amination step mentioned above can be performed from a compound of formula (VI)
with an R2 group representing a COO-((Ci-C )alkyl) ester function, this ester function
then possibly being saponified to yield a formula (I) compound with R2 = COOH.
When the R4 group comprises a NH function, this can be protected before
performing the condensation/substitution/reductive amination reaction by substituting
the nitrogen atom by an N-protective group such as a Boc or Fmoc group.
By « protective group » in the present invention is meant a group which
selectively blocks a reactive site in a multifunctional compound such that a chemical
reaction can selectively be carried out at another non-protected reactive site in the
meaning conventionally associated therewith in chemical synthesis.
By « N-protective group » in the present invention is meant any substituent
which protects the NH group against undesirable reactions such as the N-protective
groups described in Greene, « Protective Groups In Organic synthesis », (John Wiley &
Sons, New York (1981)) and Harrison et al. « Compendium of Synthetic Organic
Methods », Vols. 1 to 8 (J. Wiley & sons, 1971 to 1996). The N-protective groups
comprise carbamates, amides, N-alkylated derivatives, amino acetal derivatives, Nbenzyl
derivatives, imine derivatives, enamine derivatives and N-heteroatom
derivatives. The N-protecting groups can be formyl; an aryl, such as a phenyl,
optionally substituted with one or several methoxy groups such as /?-methoxyphenyl
(PMP); an aryl-(Ci-C 6)alkyl, such as a benzyl, the aryl moiety being optionally
substituted with one or several methoxy groups, such as benzyl (Bn), /?-methoxybenzyl
(PMB) or 3,4-dimethoxybenzyl (DMPM); -CO-R Gpi such as acetyl (Ac), pivaloyl (Piv
or Pv), benzoyl (Bz) or /?-methoxybenzylcarbonyl (Moz); -C0 2-RGPI such as
tbutyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc),
benzyloxycarbonyl (Cbz or Z) or 9-fluorenylmethyloxycarbonyl (Fmoc); -S0 2-RGPI
such as phenylsulfonyl, tosyl (Ts or Tos) or 2-nitrobenzenesulfonyl (also called nosyl -
Nos or Ns); and the like,
with RGPI representing a (Ci-C )alkyl optionally substituted with one or several halogen
atoms such as F or CI; a (C2-Ce)alkenyl such as an allyl; an aryl, such as a phenyl,
optionally substituted with one or several groups chosen among OMe (methoxy) and
N0 2 (nitro); an aryl-(Ci-C 6)alkyl, such as a benzyl, the aryl moiety being optionally
substituted with one or several methoxy groups; or a 9-fluorenylmethyl group.
In particular, the N-protective group comprises formyl, acetyl, benzoyl, pivaloyl,
phenylsulfonyl, benzyl (Bn), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),
p-methoxybenzyloxycarbonyl, p-nitrobenzyl-oxycarbonyl, trichloroethoxycarbonyl
(TROC), allyloxycarbonyle (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl,
benzyl carbamates (substituted or not) and similar. It may in particular be a Boc
or Fmoc group.
The protection of the NH amine function by a Boc or Fmoc group and its
subsequent deprotection, after the condensation/substitution/reductive amination
reaction, are well known to persons skilled in the art and are described in particular in
the experimental part below.
The formula (I) compound obtained with one of the three methods mentioned
above can also be salified by adding a pharmaceutically acceptable base or acid, in
particular a pharmaceutically acceptable acid such as trifluoroacetic acid. Said step can
optionally be performed at the same time as another reaction step, in particular at the
same time as a deprotection step when this must be performed in an acid medium for
example.
The compound obtained with one of these three methods, optionally after
additional step(s) for deprotection, functionalization and/or salification, can be
separated from the reaction medium using methods well known to skilled persons, such
as by extraction, solvent evaporation or by precipitation and filtration.
The compound may also be purified if necessary using techniques well known to
skilled persons, e.g. by recrystallization if the compound is crystalline, by distillation,
by silica gel column chromatography or high performance liquid chromatography
(HPLC).
The following examples illustrate the invention without however limiting
scope thereof.
EXAMPLES
I - Synthesis of the compounds of the invention
The following abbreviations are used in the following examples:
aq. aqueous
ee enantiomeric excess
equiv equivalent
ESI Electrospray ionisation
LC/MS Liquid Chromatography coupled with Mass Spectrometry
HPLC High Performance Liquid Chromatography
NMR Nuclear Magnetic Resonance
sat. saturated
UV ultraviolet
Example 1
(S)-2-((S)-2-((3-aminopropyl)(methyl)amino)-3-methylbutanamido)-7V-
((3R,4S,5S)-3-methoxy-l-((S)-2-((lR,2R)-l-methoxy-2-methyl-3-oxo-3-(((S)-
2-phenyl-l-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-l-yl)-5-methyl-loxoheptan-
4-yl)-7V,3-dimethylbutanamide, bis trifluoroacetic acid
Exam 5S)-4-methyl-5-phenyl-3-propanoyl-l,3-oxazolidin-2-one
(4R, 5S)-4-methyl-5-phenyl-l,3-oxazolidin-2-one (5.8 g, 32.7 mmol, 1.00 equiv)
was dissolved in tetrahydrofuran (THF, 120 mL) in an inert atmosphere. The mixture
was cooled to -78°C and n-butyllithium (14.4 mL) was added drop-wise. After
agitation for 30 minutes at -78°C, propanoyl chloride (5.7 mL) was added. Agitation
was continued for 30 minutes at -78°C then overnight at ambient temperature. The
reaction mixture was concentrated then re-dissolved in 200 mL of water. The pH of the
solution was adjusted to 7 with sodium bicarbonate saturated aqueous solution. This
aqueous phase was extracted 3 times with 100 mL of ethyl acetate (EtOAc). The
organic phases were combined, dried over sodium sulfate, filtered and concentrated to
yield 6.8 g (89 %) of compound 1 in the form of a yellow oil.
Example IB: tert-butyl (2S)-2-[(lR,2R)-l-hydroxy-2-methyl-3-[(4R,5S)-4-
methyl-2-oxo-5-phenyl- 1,3-oxazolidin-3-yl]-3-oxopropyl]pyrrolidine- 1-carboxylate
Compound 1A (17.6 g, 75.45 mmol, 1.00 equiv) was dissolved in
dichloromethane (DCM, 286 mL) in an inert atmosphere. This solution was cooled with
an ice bath. Triethylamine (TEA, 12.1 mL, 1.15 equiv) and Bu2BOTf (78.3 mL, 1.04
equiv) were added drop-wise whilst holding the temperature of the reaction mixture
below 2°C. Agitation was continued at 0°C for 45 minutes, after which the reaction was
cooled to -78°C. A solution of tert-butyl (2S)-2-formylpyrrolidine-l-carboxylate (8.5 g,
42.66 mmol, 0.57 equiv) in DCM (42 mL) was added drop-wise. Agitation was
continued for 2 hours at -78°C, then for 1 hour at 0°C and finally 1 hour at ambient
temperature. The reaction was neutralised with 72 mL of phosphate buffer (pH = 7.2 -
7.4) and 214 mL methanol, and cooled to 0°C. A solution of 30 % hydrogen peroxide in
methanol (257 mL) was added drop-wise whilst maintaining the temperature below
10°C. Agitation was continued for 1 hour at 0°C. The reaction was neutralised with
142 mL of water, then concentrated under reduced pressure. The resulting aqueous
solution was extracted 3 times with 200 mL EtOAc. The organic phases were combined,
dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica
column with a mixture of EtOAc and petroleum ether (EtOAc:PE = 1:8) to yield
13.16 g (40 %) of compound IB in the form of a colourless oil.
Example 1C: (2R,3R)-3-[(2S)-l-[(ter t-butoxy)carbonyl]pyrrolidin-2-yl]-3-
hydroxy-2-methylpropanoic acid
Compound IB (13.16 g, 30.43 mmol, 1.00 equiv) was dissolved in THF
(460 mL) in the presence of hydrogen peroxide (30 % in water, 15.7 mL), then cooled
with an ice bath. An aqueous solution of lithium hydroxide (0.4 mol/L, 152.1 mL) was
added drop-wise whilst holding the reaction temperature below 4°C. The reaction
mixture was agitated 2.5 hours at 0°C. An aqueous solution of Na2S0 3 ( 1 mol/L,
167.3 mL) was added drop-wise whist holding the temperature at 0°C. The reaction
mixture was agitated 14 hours at ambient temperature, then neutralised with 150 mL of
cold sodium bicarbonate saturated solution and washed 3 times with 50 mL of DCM.
The pH of the aqueous solution was adjusted to 2-3 with a 1M aqueous solution of
KHSO4. This aqueous solution was extracted 3 times with 100 mL of EtOAc. The
organic phases were combined, washed once with saturated NaCl solution, dried over
sodium sulfate, filtered and concentrated to yield 7.31 g (88 %) of compound 1C in the
form of a colourless oil.
Example ID: (2R,3R)-3-[(2S)-l-[(ter t-butoxy)carbonyl]pyrrolidin-2-yl]-3-
methoxy-2-methylpropanoic acid
Compound 1C (7.31 g, 26.74 mmol, 1.00 equiv) was dissolved in an inert
atmosphere in THF (135 mL) in the presence of iodomethane (25.3 mL). The reaction
medium was cooled with an ice bath after which NaH (60 % in oil, 4.28 g) was added in
portions. The reaction was left under agitation 3 days at 0°C and then neutralised with
100 mL of sodium bicarbonate saturated aqueous solution and washed 3 times with
50 mL ether. The pH of the aqueous solution was adjusted to 3 with 1M aqueous
KHSO 4 solution. This aqueous solution was extracted 3 times with 100 mL of EtOAc.
The organic phases were combined, washed once with 100 mL of Na2S2C 3 (5 % in
water), once with NaCl-saturated solution, then dried over sodium sulfate, filtered and
concentrated to yield 5.5 g (72 %) of compound ID in the form of a colourless oil.
Example -methoxy - N-methyl-2-phenylacetamide
2-phenylacetic acid (16.2 g, 118.99 mmol, 1.00 equiv) was dissolved in
dimethylformamide (DMF, 130 mL) then cooled to -10°C. Diethyl phosphorocyanidate
(DEPC, 19.2 mL), methoxy(methyl)amine hydrochloride (12.92 g, 133.20 mmol,
1.12 equiv) and triethylamine (33.6 mL) were added. The reaction mixture was agitated
30 minutes at -10°C then 2.5 hours at ambient temperature. It was then extracted twice
with 1 litre of EtOAc. The organic phases were combined, washed twice with 500 mL
of NaHCC"3 (sat.), once with 400 mL of water, then dried over sodium sulfate, filtered
and concentrated. The residue was purified on a silica column with an EtOAc and PE
mixture (1:100 to 1:3) to yield 20.2 g (95 %) of compound IE in the form of a yellow
oil.
Example IF: 2-phenyl-l-(l ,3-thiazol-2-yl)ethan-l-one
Tetramethylethylenediamine (TMEDA, 27.2 mL) was dissolved in THF
300 mL) in an inert atmosphere, then cooled to -78°C before the drop-wise addition of
n-BuLi (67.6 mL, 2.5 M). 2-bromo-l,3-thiazole (15.2 mL) was added drop-wise and
agitation was continued 30 minutes at -78°C. Compound IE (25 g, 139.50 mmol, 1.00
equiv) dissolved in THF (100 mL) was added drop-wise. Agitation was continued for
30 minutes at -78°C then 2 hours at -10°C. The reaction was neutralised with 500 mL
of KHSO4 (sat.), then extracted 3 times with 1 litre of EtOAc. The organic phases were
combined, washed twice with 400 mL water and twice with 700 mL of NaCl (sat.), then
dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica
column with a mixture of EtOAc and PE (1:100 to 1:10) to yield 25 g (88 %) of
compound IF in the form of a yellow oil.
Example 1G: (lR)-2-phenyl-l-(l ,3-thiazol-2-yl)ethan-l-ol
In an inert atmosphere, a solution of compound IF (15 g, 73.8 mmol, 1.00
equiv.) in ether (300 mL) was added drop-wise to (+)-Bchlorodiisopinocampheylborane
((+)-Ipc 2BCl, 110.8 mL). The reaction mixture was
agitated 24 hours at 0°C, then neutralised with 300 mL of a (1:1) mixture of NaOH
(10 % in water) and H20 2 (30 % in water), and finally extracted three times with
500 mL of EtOAc. The organic phases were combined, washed twice with 300 mL of
K2CO3 (sat.) and once with 500 mL of NaCl (sat.), then dried over sodium sulfate,
filtered and concentrated. The residue was purified on a silica column with a mixture of
EtOAc and PE (1:20 to 1:2) to yield 6.3 g (42 %) of compound 1G in the form of a
white solid.
Example 1 - [(l S)-l-azido-2-phenylethyl]-l ,3-thiazole
Compound 1G (6 g, 29.23 mmol, 1.00 equiv.) was dissolved in an inert
atmosphere in THF (150 mL) in the presence of triphenylphosphine (13 g, 49.56 mmol,
1.70 equiv.), then cooled to 0°C. Diethylazodicarboxylate (DEAD, 7.6 mL) was added
drop-wise, followed by diphenylphosphorylazide (DPPA, 11 mL), the cold bath was
then removed and the solution was left under agitation 48 hours at ambient temperature.
The medium was concentrated under reduced pressure. The residue was purified on a
silica column with a mixture of EtOAc and PE (1:100 to 1:30) to yield 8 g of partly
purified compound 1H in the form of a yellow oil. Compound 1H was used as such in
the following step .
Example II: ter t-butyl N -[(lS)-2-phenyl-l-(l,3-thiazol-2-yl)ethyl] carbamate
Compound 1H (6.5 g, 28.2 mmol, 1.00 equiv) was dissolved in an inert
atmosphere in THF (100 mL) in the presence of triphenylphosphine (6.5 g, 33.9 mmol,
1.20 equiv.), and heated to 50°C for 2 hours. Ammonia (70 mL) was then added and
heating was continued for 3 hours. The reaction was cooled, neutralised with 500 mL
water, then extracted 3 times with 500 mL of EtOAc. The organic phases were
combined and extracted twice with 500 mL of IN HC1. The aqueous phases were
combined, brought to pH 8-9 by adding a sodium hydroxide solution (10 % in water),
then extracted 3 times with 500 mL of DCM. The organic phases were combined, dried
over sodium sulfate, filtered and concentrated to yield 4.8 g (83 %) of (lS)-2-phenyl-l-
(l,3-thiazol-2-yl)ethan-l-amine in the form of a yellow oil. This compound was then
protected with a Boc group ((t rt-butoxy)carbonyl) so that it could be purified. It was
dissolved in an inert atmosphere in 1,4-dioxane (40 mL), then cooled to 0°C. (Boc)20
(10.26 g, 47.01 mmol, 2.00 equiv) diluted in 20 mL of 1,4-dioxane was added dropwise.
The cold bath was removed and the solution left under agitation overnight at
ambient temperature before being neutralised with 300 mL of water and extracted twice
with 500 mL of EtOAc. The organic phases were combined, dried over sodium sulfate,
filtered and concentrated. The residue was purified on a silica column with a mixture of
EtOAc and PE ( 1:100 to 1:20, ee = 93 %). It was then recrystallized in a hexane/acetone
mixture (~ 5-10 / 1, l g / 10 mL) to yield 6 g (84 %) of compound II in the form of a
white solid (ee > 99 %).
Example 1J: ter t-butyl (2S)-2-[(lR,2R)-l-methoxy-2-methyl-2-[[(lS)-2-
phen -1-(1 ,3-thiazol-2-yl)ethyl]carbamoyl]ethyl]pyrrolidine- 1-carboxylate
Compound II (3 g, 9.86 mmol, 1.00 equiv) was dissolved in an inert atmosphere
in 10 mL DCM. Trifluoroacetic acid (TFA, 10 mL) was added and the solution left
under agitation overnight at ambient temperature, then concentrated under reduced
pressure to yield 2.0 g (64 %) of (lS)-2-phenyl-l-(l,3-thiazol-2-yl)ethan-l-amine;
trifluoroacetic acid in the form of a yellow oil. This intermediate was re-dissolved in 20
mL of DCM after which compound ID (1.8 g, 6.26 mmol, 1.05 equiv), DEPC (1.1 g,
6.75 mmol, 1.13 equiv) and diisopropylethylamine (DIEA, 1.64 g, 12.71 mmol, 2.13
equiv) were added. The reaction mixture was left under agitation overnight at ambient
temperature, then concentrated under reduced pressure. The residue was purified on a
silica column with a mixture of EtOAc and PE (1:100 to 1:3) to yield 2.3 g (81 %) of
compound 1J in the form of a pale yellow solid.
Example IK: (2R,3R)-3-methoxy-2-methyl -N-[(lS)-2-phenyl-l-(l,3-thiazol-2-
yl)ethyl]-3-[(2S)-pyrrolidin-2-yl]propanamide; trifluoroacetic acid
Compound 1J (2.25 g, 4.75 mmol, 1.00 equiv) was dissolved in an inert
atmosphere in 10 mL of DCM. TFA (10 mL) was added and the solution left under
agitation overnight at ambient temperature, then concentrated under reduced pressure to
yield 2.18 g (94 %) of compound IK in the form of a yellow oil.
Example 1L: (2S,3S)-2-(benzylamino)-3-methylpentanoic acid
(2S,3S)-2-amino-3-methylpentanoic acid (98.4 g, 750 mmol, 1.00 equiv) was
added at ambient temperature and in portions to a 2N sodium hydroxide solution
(375 mL). Benzaldehyde (79.7 g, 751.02 mmol, 1.00 equiv) was quickly added and the
resulting solution was agitated 30 minutes. Sodium borohydride (10.9 g, 288.17 mmol,
0.38 equiv) was added in small portions, whilst holding the temperature at between 5
and 15°C. Agitation was continued for 4 hours at ambient temperature. The reaction
mixture was diluted with 200 mL of water, then washed twice with 200 mL of EtOAc.
The pH of the aqueous solution was adjusted to 7 with a 2N hydrochloric acid solution.
The formed precipitate was collected by filtering and gave 149.2 g (90 %) of compound
1L in the form of a white solid.
)- 2- [benzyl(methyl)amino]- 3- meth lpentanoic acid-
Compound 1L (25 g, 112.97 mmol, 1.00 equiv) was dissolved in an inert
atmosphere in formic acid (31.2 g) in the presence of formaldehyde (36.5 % in water,
22.3 g). The solution was agitated 3 hours at 90°C then concentrated under reduced
pressure. The residue was triturated in 250 mL of acetone, then concentrated. This
trituration/evaporation operation was repeated twice with 500 mL of acetone to yield
21.6 g (81 %) of compound 1M in the form of a white solid.
Exam le IN: (2S,3 S)-2-[benzyl(methyl)amino]-3-methylpentan- 1- o1
L1AIH4 (0.36 g) was suspended in 10 mL of THF in an inert atmosphere at 0°C.
Compound 1M (1.5 g, 6.37 mmol, 1.00 equiv) was added in small portions whilst
holding the temperature at between 0 and 10°C. The reaction mixture was agitated 2
hours at 65°C, then again cooled to 0°C before being neutralised with successive
additions of 360 of water, 1 mL of 15 % sodium hydroxide and 360 of water.
The aluminium salts which precipitated were removed by filtering. The filtrate was
dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica
column with a mixture of EtOAc and PE (1:50) to yield 820 mg (58 %) of compound
IN in the form of a pale yellow oil.
Example IO: (2S,3S)-2-[benzyl(methyl)amino]-3-methylpentanal
Oxalyl chloride (0.4 mL) was dissolved in DCM (15 mL) in an inert atmosphere.
The solution was cooled to -70°C and a solution of dimethylsulfoxide (DMSO (0.5 mL)
in DCM (10 mL) was added drop-wise for 15 minutes. The reaction mixture was
agitated 30 minutes after which a solution of compound IN (820 mg, 3.70 mmol, 1.00
equiv) in DCM (10 mL) was added drop-wise for 15 minutes. The reaction mixture was
agitated a further 30 minutes at low temperature, then triethylamine (2.5 mL) was
slowly added. The reaction mixture was agitated 1 hour at -50°C, the cold bath was
then removed and the reaction neutralised with 25 mL of water whilst allowing the
temperature to return to normal. The solution was washed once with 30 mL of NaClsaturated
aqueous solution, then dried over sodium sulfate, filtered and concentrated.
The residue was purified on a silica column with a mixture of EtOAc and PE ( 1:200) to
yield 0.42 g (52 %) of compound IO in the form of a yellow oil.
Example IP: (2S,3S)-N -benzyl-l ,l-dimethoxy - N,3-dimethylpentan-2-amine
Compound lO (4.7 g, 21.43 mmol, 1.00 equiv) was dissolved in 20 mL of
methanol at 0°C. Concentrated sulfuric acid (4.3 mL) was added drop-wise and
agitation was continued for 30 minutes at 0°C. Trimethyl ortho formate (21.4 mL) was
added, the cold bath removed and the reaction medium left under agitation for 3 hours at
ambient temperature. The reaction medium was diluted with 200 mL of EtOAc,
successively washed with 100 mL of 10 % a2C03 and 200 mL of saturated NaCl, then
dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 3.4
g (60 %) of compound IP in the form of a pale yellow oil.
Example 1 : [[ l -(t rt-butoxy)ethenyl]oxy ](t rt-butyl)dimethylsilane
Diisopropylamine (20 g, 186.71 m mol, 1.08 equiv) was dissolved in 170 mL of
THF in an inert atmosphere and cooled to -78°C. nBuLi (2.4 M, 78.8 mL) was added
drop-wise and the solution agitated 30 minutes at low temperature (to give LDA-lithium
diisopropylamide) before adding t rt-butyl acetate (20 g, 172.18 mmol, 1.00 equiv).
The reaction mixture was agitated 20 minutes at -78°C before adding
hexamethylphosphoramide (HMPA, 25.8 mL) and a solution of tertbutyldimethylchlorosilane
(TBDMSCl, 28 g, 185.80 mmol, 1.08 equiv) in 35 mL of
THF. Agitation was continued for 20 additional minutes at low temperature, and the
cold bath was then removed. The solution was concentrated under reduced pressure.
The residue was re-dissolved in 100 mL of water and extracted 3 times with 100 mL of
PE. The organic phases were combined, washed once with 500 mL of NaCl-saturated
aqueous solution, dried over sodium sulfate, filtered and concentrated. The residue was
purified by distillation to yield 16.6 g (83 %) of compound 1Q in the form of a
colourless oil.
Example 1R: ter t-butyl (3R,4S,5S)-4-[benzyl(methyl)amino]-3-methoxy-5-
methyl heptanoate
Compound I P (2.0 g, 7.54 mmol, 1.00 equiv) and compound 1Q (2.6 g,
11.28 mmol, 1.50 equiv) were dissolved in 33 mL of DCM in an inert atmosphere. The
solution was cooled to 0°C. DMF ( 1.2 g) was added drop-wise together with a solution
of BF3 Et20 (2.1 g) in 7.5 mL of DCM. Agitation was continued for 24 hours at 0°C.
The reaction medium was washed once with 30 mL of sodium carbonate (10 %) and
twice with 50 mL of NaCl-saturated aqueous solution, then dried over sodium sulfate,
filtered and concentrated. The residue was purified on a silica column with a mixture of
EtOAc and PE (1:100) to yield 1.82 g (91 %) of compound 1R in the form of a yellow
oil.
Example I S: (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate
hydr hloride
Compound 1R (2.4 g, 6.87 mmol, 1.00 equiv) was dissolved in an inert
atmosphere in 35 mL of ethanol in the presence of Pd/C (0.12 g) and concentrated
hydrochloric acid (0.63 mL). The nitrogen atmosphere was replaced by a hydrogen
atmosphere and the reaction medium was left under agitation 18 hours at ambient
temperature. The reaction medium was filtered and concentrated under reduced
pressure. The residue was triturated in 50 mL of hexane and the supernatant removed
which, after drying under reduced pressure, gave 1.66 g (82 %) of compound I S in the
form of a white solid.
Example IT: tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(benzyloxy)carbonyl]amino]-
N,3-dimethylbutanamido] -3-mthox -5- methylheptanoate
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoic acid (15 g, 0.40 mmol,
1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and
bromotripyrrolidinophosphonium hexafiuorophosphate (PyBrOP, 32. 3g). The solution
was agitated 30 minutes at ambient temperature before adding compound IS (15.99g,
0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then
concentrated. The residue was purified in reverse phase (CI 8) with a mixture of
acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58 %) of
compound IT in the form of a colourless oil.
Example 1U: tert-butyl (3R,4S,5S)-4-[(2S)-2-amino -N,3-dimethylbutanamido]-
3-methoxy-5- methylheptanoate
Compound IT (76 mg, 0.15 mmol, 1.00 equiv) was dissolved in an inert
atmosphere in 10 mL of ethanol in the presence of Pd/C (0.05 g). The nitrogen
atmosphere was replaced by a hydrogen atmosphere and the reaction agitated 2 hours at
ambient temperature. The reaction medium was filtered and concentrated under reduced
pressure to yield 64 mg of compound 1U in the form of a colourless oil.
Example IV: (3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]
ami - N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoate
Compound 1U (18.19 g, 50.74 mmol, 1.00 equiv) was dissolved in 400 mL of a
1,4-dioxane/water mixture (1:1) in the presence of sodium bicarbonate (12.78 g, 152
mmol, 3.00 equiv) and 9H-fluoren-9-ylmethyl chloroformate (Fmoc-Cl, 19.69 g, 76
mmol, 1.50 equiv), then agitated 2 hours at ambient temperature. The reaction medium
was then diluted with 500 mL of water and extracted 3 times with 200 mL of EtOAc.
The organic phases were combined, washed once with 200 mL of NaCl-saturated
aqueous solution, dried over sodium sulfate, filtered and concentrated to yield 40 g of
partly purified compound I in the form of a pale yellow oil.
Example 1W: (3R,4S,5S)-4-[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]
]- ,3-dimethylbutanamido]-3-methoxy-5-methylheptanoic acid
Compound IV (40 g, 68.88 mmol, 1.00 equiv) was dissolved in a neutral
atmosphere in 600 mL of DCM. TFA (300 mL) was added. The solution was agitated 2
hours at ambient temperature, then concentrated under reduced pressure. The residue
was purified on a silica column with a mixture of methanol and DCM (1:10) to yield
23.6 g (65 %) of compound 1W in colourless oil form.
Example IX: 9H-fluoren-9-ylmethyl N-[(lS)-l-[[(3R,4S,5S)-3-methoxy-l-
[(2S)-2-[(lR,2R)-l-methoxy-2-methyl-2-[[(lS)-2-phenyl-l-(l,3-thiazol-2-
yl)ethyl]carbamoyl] ethyljpyrrolidin- 1-yl]-5-methyl- 1-oxoheptan-4-yl] (methyl)
carbamoyl]-2-methylpropyl]carbamate
Compound 1W (2.53 g, 4.82 mmol, 1.08 equiv) was dissolved in 20 mL of
DCM in the presence of compound IK (2.18 g, 4.47 mmol, 1.00 equiv), DEPC (875
mg, 5.37 mmol, 1.20 equiv) and DIEA (1.25 g, 9.67 mmol, 2.16 equiv). The reaction
mixture was left under agitation overnight at ambient temperature, then successively
washed with 50 mL of saturated KHS0 4 and 100 mL of water, dried over sodium
sulfate, filtered and concentrated. The residue was purified on a silica column with a
mixture of methanol and DCM (1:200 to 1:40) to yield 2.8 g (71 %) of compound IX in
the form of a pale yellow solid.
Example 1Y: (2S)-2-amino -N-[(3R,5S)-3-methoxy-l-[(2S)-2-[(lR,2R)-lmethoxy-
2-methyl-2- [[(1S)-2-phenyl- 1-(1,3-thiazol-2-yl)ethyl] carbamoyl] ethyl]
pyrrolidin- 1-yl] -5-methyl- 1-oxoheptan-4-yl ]-N,3-dimethylbutanamide
Compound IX (2.8 g, 3.18 mmol, 1.00 equiv) was dissolved in acetonitrile
(ACN, 12 mL) in the presence of piperidine (3 mL) and left under agitation 18 hours at
ambient temperature. The reaction was neutralised with 50 mL of water, then extracted
twice with 100 mL of DCM. The organic phases were combined, dried over sodium
sulfate, filtered and concentrated. The residue was purified on a silica column with a
mixture of methanol and DCM ( 1:100 to 1:40) to yield 1.2 g (57 %) of compound 1Y in
the form of a yellow solid.
Example IZA: (2S)-2- [[(t rt-butoxy)carbonyl] (methyl)amino] -3-methyl
butanoic acid
(2S)-2-[[(t rt-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g,
289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in
the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding
sodium hydride ( 116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture
was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation
continued for 18 hours. The reaction was neutralised with 200 mL of water and then
concentrated under reduced pressure. The residual aqueous phase was diluted with 4
litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3
and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3
times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium
sulfate, filtered and concentrated to yield 60 g (89 %) of compound IZA in the form of
a yellow oil.
Example 1ZB: benzyl (2S)-2-[[(t rt-butoxy)carbonyl](methyl)amino]-3-
methylbutanoate
Compound 1ZA (47 g, 203.21 mmol, 1.00 equiv) was dissolved in DMF
(600 mL) in the presence of L 12CO3 (15.8 g, 213.83 mmol, 1.05 equiv). The solution
was cooled to 0°C then benzyl bromide (BnBr 57.9 g, 338.53 mmol, 1.67 equiv) was
added drop-wise. The reaction mixture was left under agitation overnight before being
neutralised with 400 mL of water and filtered. The solution obtained was extracted
twice with 500 mL of EtOAc. The organic phases were combined, dried over sodium
sulfate, filtered and concentrated. The residue was purified on a silica column with a
mixture of EtOAc and PE (1:100 to 1:20) to yield 22.5 g (34 %) of compound 1ZB in
the form of a yellow oil.
Example 1 -3-methyl-2-(methylamino)butanoate hydrochloride
Compound 1ZB (22.5 g, 70.00 mmol, 1.00 equiv) was dissolved in 150 mL of
DCM. Gaseous hydrochloric acid was bubbled. The reaction was agitated 1 hour at
ambient temperature and then concentrated under reduced pressure to yield 17 g (94 %)
of compound 1ZC in the form of a yellow solid.
Examp - butylN-(3,3-diethoxypropyl)carbamate
3,3-diethoxypropan-l-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in
1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then
cooled to 0°C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4-
dioxane was added drop-wise. The solution was agitated 2 hours at 0°C then overnight
at ambient temperature before being neutralised with 10 mL of water. The pH was
adjusted to 5 with HC1 ( 1 %). The solution was extracted 3 times with 50 mL of EtOAc.
The organic phases were combined, dried over sodium sulfate, filtered and concentrated
to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
Example 1Z: tert-butyl N-(3-oxopropyl) carbamate
Compound 1ZD (8.20 g, 33.15 mmol, 1.00 equiv) was dissolved in 18.75 mL of
acetic acid and left under agitation overnight at ambient temperature. The reaction
medium was then extracted 3 times with 30 mL of EtOAc. The organic phases were
combined, washed 3 times with 30 mL of saturated NaCl solution, dried over sodium
sulfate, filtered and concentrated to yield 5 g (87 %) of compound 1ZE in the form of a
dark red oil.
Example 1ZF: (2S)-2- [(3 -[[(tert-butoxy)carbonyl] amino]propyl)(methyl)
amino]-3-methylbutanoic ac
Compound 1ZE (2.4 g, 13.86 mmol, 1.00 equiv) was dissolved in 50 mL of THF
in the presence of compound 1ZC (3.56 g, 13.81 mmol, 1.00 equiv) and DIEA
(9.16 mL, 4.00 equiv). The reaction mixture was agitated 30 minutes at ambient
temperature before adding sodium triacetoxyborohydride (5.87 g, 27.70 mmol, 2.00
equiv). Agitation was continued overnight, then the reaction was neutralised with 100
mL of water and extracted 3 times with 50 mL of EtOAc. The organic phases were
combined, dried over sodium sulfate, filtered and concentrated. The residue was partly
purified on a silica column with a mixture of EtOAc and PE (1:4). The crude product
obtained was re-dissolved in 20 mL of methanol in the presence of Pd/C (1.2 g) and
hydrogenated for 20 minutes at normal temperature and pressure. The reaction medium
was filtered and concentrated under reduced pressure to yield 200 mg (5 %) of
compound 1ZF in the form of a white solid.
Example 1ZG: tert-butyl N-(3-[[(lS)-l-[[(lS)-l-[[(3R,4S,5S)-3-methoxy-l-
[(2S)-2-[(lR,2R)-l-methoxy-2-methyl-2-[[(lS)-2-phenyl-l-(l,3-thiazol-2-yl)ethyl]
carbamoyl]thyl]pyrrolidin- 1-yl] -5-methyl- 1-oxoheptan-4yl] (methyl) carbamoyl]-2-
methylpropyl]carbamoyl]-2-methylpropyl](methyl)amino]propyl) carbamate

CLAIMS
1. A compound of following formula (I):
(I)
where:
- Ri is H or OH,
- R2 is a (Ci-C 6)alkyl, COOH, COO-((Ci-C 6)alkyl) or thiazolyl group,
- R3 is H or a (Ci-C )alkyl group, and
- R 4 is:
" a straight-chain or branched, saturated or unsaturated hydrocarbon chain having 1 to
8 carbon atoms such as a (Ci-C8)alkyl group, the said chain being substituted by one
or more groups chosen from among OH and R R with R and R each
independently of one another representing H or a (Ci-C 6)alkyl group,
■ a -(CH 2CH2X1)(CH2CH2X2)a2(CH2CH2X3 )a3 (CH2CH2 X4)a4 (CH2CH2X5)a5R group
with Xi, X2, X3, X4 and X each independently of one another representing O or NRs,
a2, a3, a4 and a5 each independently of one another representing 0 or 1, R7
representing H and R representing H or a (Ci-C 6)alkyl group,
■ an aryl-(Ci-C 8)alkyl group substituted by one or more groups chosen from among
OH and NR9R10 groups with R and Rio each independently of one another
representing H or a (Ci-C )alkyl group, or
■ a heterocycle-(Ci-C 8)alkyl group optionally substituted by one or more groups
chosen from among (Ci-C )alkyl, OH and NRi2Ri3 groups with Ri2 and R13 each
independently of one another representing H or a (Ci-C 6)alkyl group,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
2. The compound according to claim 1, characterized in that:
- Ri=OH and R2 represents a (Ci-C )alkyl group, or
- Ri=H and R2 represents a COOH, COO-(Ci-C )alkyl or thiazole group.
3. The compound according to claim 1 or 2, characterized in that Ri
represents H and R2 represents COOH or COOMe.
4. The compound according to any one of claims 1 to 3, characterized in that
R3 represents H or a methyl group.
5. The compound according to any one of claims 1 to 4, characterized in that
R4 represents one of the following groups:
- (Ci-C )alkyl substituted by a group chosen from among OH and NR5R ,
- -(CH 2CH2Xl)(CH2CH2X2)a2(CH2CH2X3) a3R7,
aryl-(Ci-C 2)alkyl substituted by one group chosen from among OH and NR9R10 , or
- heterocycle-(Ci-C 2)alkyl substituted by one group chosen from among NRi 2Ri3,
OH and (Ci-C 6)alkyl.
6. The compound according to any one of claims 1 to 5, characterized in that
R4 represents an aryl-(Ci-C 2)alkyl group substituted on the aryl moiety by one NR9R10
group.
7. The compound according to any one of claims 1 to 6, characterized in that
the aryl group is a phenyl group and the heterocycle is a saturated, unsaturated or
aromatic ring with 5 or 6 members comprising 1 or 2 nitrogen atoms, chosen in
particular from among a pyridine, a piperidine and an imidazole.
8. The compound according to claim 1, chosen from among:
an t e p armaceut ca y accepta e sa ts t ereo suc as t e sa ts orme w t
trifluoroacetic acid.
9. A compound according to any one of claims 1 to 8 for use as a medicinal
product.
10. A compound according to any one of claims 1 to 8 for use as medicinal
product intended for the treatment of cancer or benign proliferative disorders.
11. A pharmaceutical composition comprising a formula (I) compound
according to any one of claims 1 to 8 and at least one pharmaceutically acceptable
excipient.
12. The pharmaceutical composition according to claim 11, further comprising
another active ingredient, advantageously chosen from among anticancer agents, in
particular comprising cytotoxic anticancer agents such as navelbine, vinflunine, taxol,
taxoter, 5-fluorouracil, methotrexate, doxorabicin, camptothecin, gemcitabin, etoposide,
cis-platin or carmustin; and hormonal anticancer agents such as tamoxifen or
medroxyprogesterone.
13. A method for preparing a formula (I) compound according to any one of
claims 1 to 8 comprising a condensation reaction between a compound of following
formula (VI):
where Ri and R2 are as defined in claim 1,
a compound of following formul
where R3 is as defined in claim 1, R4a represents an R4 group as defined in claim 1,
optionally in protected form, and X is OH or CI.
14. A method for preparing a formula (I) compound according to any one of
claims 1 to 8 comprising a substitution reaction between a compound of following
formula (VIII):
where Ri, R2 a,d R3 are as defined in claim 1, and
a compound of following formula (X):
where R4a represents an R4 group as defined in claim 1 optionally in protected form,
Y is a leaving group such as CI, Br, I, OS0 2CH3, OS0 2CF3 or O-Tosyl.
15. A method for preparing a formula (I) compound according to any one of
claims 1 to 8 where R4 represents a -CH 2R4b group with R4b representing:
■ OH, R R , a straight-chain or branched, saturated or unsaturated hydrocarbon
group comprising 1 to 7 carbon atoms substituted by one or more groups
chosen from among OH and R R ,
■ -CH 2Xi(CH2CH2X2)a2(CH2CH2X3)a (CH2CH2 X4) a4(CH2CH2 X5)a5R7,
■ an aryl group or aryl-(Ci-Cv)alkyl group substituted by one or more groups
chosen from among OH and NR9R10 groups, or
■ a heterocycle or heterocycle-(Ci-Cv)alkyl group optionally substituted by one
or more groups chosen from among (Ci-C6)alkyl, OH and NRi2Ri3 groups,
comprising a reductive amination reaction between a compound of following formula
(VIII):
where Rl R2 and R3 are as defined in claim 1, and
a compound of following formula (XI):
where R4b is as previously defined.