Title of Invention

ACYLAMINOTHIAZOLE DERIVATIVE COMPOUNDS

Abstract Acylaminothiazole derivative compounds of formula (I) in the form of a base, of an addition salt with an acid, of a hydrate or of a solvate. The invention also relates to a method to prepare these compounds, and to its therapeutic applications, for example for its beta-amyloid peptide production inhibiting effects.
Full Text ACYLAMINOTHIAZOLE HIAZOLE DERIVATIVE COMPOUNDS
The subject of the invention is acylamino-
thiazole derivatives, their preparation and their
therapeutic use.
The first subject of the invention is
compounds corresponding to the general formula (I):

in which,
X represents an oxygen or sulphur atom;
R1 represents a C1-10 alkyl group optionally substituted
with a C3-7 cycloalkyl, a phenyl, a thienyl; or R1
represents a C3-7 cycloalkyl, thienyl, pyridinyl or
pyrimidinyl group;
the thienyl groups being optionally substituted with
one to 3 C1-3 alkyl groups; the phenyl group being
optionally substituted with one to 5 halogen atoms or
C1-3 alkyl, C1-3 alkoxy, C1-3 fluoroalkyl or C1-3
fluoroalkcxy groups;
R2 represents a C1_6 alkyl group optionally substituted
with a C3-7 cycloalkyl, phenyl, C1-3 alkoxy, hydroxyl
group; or R2 represents a C3-7 cycloalkyl, piperidinyl,
phenyl or pyridinyl group;
the C3-7 cycloalkyl and piperidinyl groups being
optionally substituted with one or more C1-3 alkyl, C1-3
alkoxy, hydroxyl, C1-3 fluoroalkyl or C1-3 fluroalkoxy
groups;
the phenyl and pyridinyl groups being optionally
substituted with one or more halogen atoms or CN,
C1-3 alkyl, C1-3 alkoxy, hydroxyl, C1-3 fluroalkyl or C1-3
fluoroalkoxy groups;
R3 represents a hydrogen atom or a C1-6 alkyl group
optionally substituted with a C3-7 cycloalkyl group;
R4 represents a hydrogen atom or a C1-6 alkyl group;
R5 and R5' represent, independently of each other, a
hydrogen or halogen atom, a hydroxyl or C1-3 alkyl
group; or R5 and R5' form together an oxo or oxime group
such as:

where R7 represents a hydrogen atom or a C1-3 alkyl;
n represents an integer ranging from 0 to 3; and
R6 represents independently of each other when n = 2 or
3, a hydrogen or halogen atom, a hydroxyl, C1-3 alkyl,
C1-3 alkoxy, C1-3 fluoroalkyl or C1-3 fluoroalkoxy group.
Among the compounds of general formula (I), a
sub-group of preferred compounds consists of the
compounds for which:
• X represents an oxygen or sulphur atom; and/or
• R1 represents a C= alkyl group, preferably a methyl,
ethyl, l-methylethyl, 1,1-dimethylethyl, propyl,
l-methylpropyl, 2-methylpropyl, l-ethylpropyl,
optionally substituted with a phenyl, a thienyl; or
R1 represents a C3-7 cycloalkyl group, preferably a
cyclohexyl, a thienyl or pyridinyl group; the thienyl
groups being optionally substituted with one or two
C1-3 alkyl groups, preferably a methyl; the phenyl
group being optionally substituted with one or two
halogen atoms, preferably chlorine or fluorine;
and/or
R2 represents a C1-6 alkyl group, preferably an ethyl,
1-methylethyl; or R2 represents a C3-7 cycloalkyl
group, preferably a cyclohexyl, phenyl or pyridinyl;
the phenyl group being optionally substituted with
one to three CN groups, C1-3 alkyl groups, preferably
methyl or ethyl, C1-3 alkoxy groups, preferably
methoxy, ethoxy or hydroxyl, fluoroalkoxy groups,
preferably trifluoromethoxy, or halogen atoms,
preferably chlorine or fluorine; and/or
• R3 represents a C1-6 alkyl group, preferably a methyl,
ethyl or propyl group; and/or
R4 represents a hydrogen atom or a C1-6 alkyl group,
preferably a methyl or a 4-methylflentyl; and/or
• R5 and R5 represent, independently of each other, a
hydrogen atom or a hydroxyl; or R5\ and R5, form
together an oxo group; and/or
• R6 represents a hydrogen or halogeh atom, preferably
chlorine or fluorine, a C1-3 alkyl, preferably a
methyl, a C1-3 alkoxy, preferably a methoxy or an
ethoxy; and/or
• n is equal to 0 or 1.
The compounds for which X, Rl, R2, R3, R4, R5,
R5, R6 and n are all as defined above in the subgroup
of preferred compounds are particularly preferred and
more specifically among these the compounds for which:
X represents an oxygen atom; and/or
the C1-4 alkylene group is a methylene; and/or
the carbon bearing the R3 group is of (S) configuration.
By way of example of preferred compounds, the
following compounds may be mentioned*
1. (2S) -2-{ [ (2R) -2-cyclohexyl-2-hydroxyacetyl] amino}-
N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-
1,3-thiazol-2-yl)pentanamide
2. (2S)-2-{ [ (2S)-2-cyclohexyl-2-hytiroxyacetyl]amino}-
N-(5-{2-[(cyclohexyloxy)methyl] phenyl}-
1,3-thiazol-2-yl)pentanamide
3. (2S)-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-
1, 3-thiazol-2-yl) -2-{ [2- (3-pyripinyl) acetyl] -
amino}pentanamide
4. N-((lS)-l-{[(5-{2-[(cyclohexyloxy)methyl]phenyl}-
1,3-thiazol-2-yl)amino]carbonyl}butyl)-2-hydroxy-
4-methylpentanamide
5. (2S)-N-{5-[2-(isopropoxymethyl)phenyl]-4-methyl-
l,3-thiazol-2-yl}-2-{[2-(3-thienyl)acetyl]amino}-
pentanamide
6. (2S) -N-{5-[2-(isopropoxymethyl)phenyl]-
1,3-thiazol-2-yl}-2-{[2-(3-thienyl)acetyl]amino}-
pentanamide
7. (25)-N-{5-[2-(isopropoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[3-(3-
thienyl)propanoyl]amino}pentanamide
8. (2S)-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}-2-{[2-(3-thienyl)acetyl]amino}pentanamide
9. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
10. (2S)-N- {5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}-2-{[2-(2-thienyl)acetyl]amino}butanamide
11. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[2-(isopropoxymethyl)phenyl]-
1,3-thiazol-2-yl}pentanamide
12. (2S)-N-{5-[2-(isopropoxymethyl)phenyl]-
l,3--thiazol-2-yl}-2-{ [2- (2-thienyl) acetyl] amino}-
pentanamide
13. (2S)-2-[(3,3-dimethylbutanoyl)amino]-N-{5-[2-
(isopropoxymethyl)phenyl]-1,3-thiazol-2-yl}-
pentanamide
14. N-{(lS)-l-[({5-[2-(isopropoxymethyl)phenyl]-
1,3-thiazol-2-yl}amino)carbonyl]butyl}-3-methyl-
2-oxopentanamide
15. (2S)-W-{5-[2-(ethoxymethyl)phenyl]-l,3-thiazol-
2-yl>-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}pentanamide
16. (2S)-2-{[2-(2,5-dimethyl-3-thienyl)acetyl]amino}-
JV-{5- [2- (ethoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
17. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-[5-(2-{[3-(trifluoromethoxy)phenoxy]-
methyl}phenyl)-1,3-thiazol-2-yl]pentanamide
18. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[4-methoxy-2-(phenoxymethyl)phenyl]-
1,3-thiazol-2-ylJpentanamide
19. (2S)-N-(5-{2-[(2-fluorophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
20. (2S) -N-(5-{2-[(2-ethylphenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
21. (2S)-2-{[3-(2,4-dichlorophenyl)propanoyl]amino}-W-
{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-y1}pentanamide
22. (2S)-2-{[2-(5-methyl-2-thienyl)acetyl]amino}-N-
{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
23. (25)-N-(5-{2-[(2,3-dimethoxyphenoxy)methyl]-
phenyl}-l,3-thiazol-2-yl)-2-{[(25)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
24. (25)-2-{[(25)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-[5-(2-{[2-(trifluoromethoxy)phenoxy]-
methyl}phenyl)-1,3-thiazol-2-yl]pentanamide
25. (25) -N-(5-{2-[(3, 5-dimethoxyphenoxy)methyl]-
phenyl}-l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-
dimethylbutanoyl]amino}pentanamide
26. (25)-N-(5-{2-[(2, 3-dimethylphenoxy)methyl]phenyl}
l,3-thiazol-2-yl)-2-{[(25)-2-hydroxy-
3,3-dimethylbutanoyl]aminoJpentanamide
27: (25)-N-(5-{2-[(3,4-dimethylphenoxy)methyl]phenylj
l,3-thiazol-2-yl)-2-{[(25)-2-hydroxy-
3,3-dimethylbutanoyl]aminoJpentanamide
28. (25)-N-(5-{2-[(2,6-dimethylphenoxy)methyl]phenyl;
l,3-thiazol-2-yl)-2-{[(25)-2-hydroxy-
3,3-dimethylbutanoyl]aminoJpentanamide
29. (2S)-N- (5-{2-[(3-chlorophenoxy)methyl]phenyl}-
l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
30. (2S)-N- (5-{2-[(3,4-dimethoxyphenoxy)methyl]-
phenyl}-l,3-thiazol-2-yl)-2-{[(25)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
31. (2S) -N-(5-{2-[(2,6-dimethoxyphenoxy)methyl]-
phenyl}-l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoy1]amino}pentanamide
32. (2S)-N-(5-{2-[(2,4-dimethylphenoxy)methyl]phenyl}-
l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
33. (2S)~N-(5-{2-[(2,5-dimethylphenoxy)methyl]phenyl}-
l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
34. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-iV-{ 4-methyl-5- [2- (phenoxymethyl) phenyl] -
1,3-thiazol-2-yl}pentanamide
35. {2R)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
36. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-(5-{2-[(2-methylphenoxy)methyl]phenyl}-
1,3-thiazol-2-yl}pentanamide
37. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-W-
{5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
38. (2S)-2-[(2-hydroxy-3,3-dimethylbutanoyl)amino]-N-
(5-{2-[(2-methoxyphenoxy)methyl]phenyl}-
1,3-thiazol-2-yl}pentanamide
39. (2S)-N-(5-{2-[(2-ethoxyphenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-[(2-hydroxy-
3,3-dimethylbutanoyl)amino]pentanamide
40 . (2S) -2-[(2-hydroxy-3-phenylpropanoyl)amino]-N-
{5- [2- (phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
41. (2S)-N-(5-{2-[(2,6-dichlorophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-[(2-hydroxy-
3,3-dimethylbutanoyl)amino]pentanamide
42. (2iR)~3-ethyl-2-hydroxy-N-{ (lS)-l-[ ({5-[2-
(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)-
carbonyl]butyl}pentanamide
43. (2S)-3-ethyl-2-hydroxy-N-{(lS)-l-[({5-[2-
(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)-
carbonyl]butyl}pentanamide
44. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[2-(isopropoxymethyl)-
4-methoxyphenyl]-1,3-thiazol-2-yl}pentanamide
45. (2S)-N- (5-{2-[(2-(chloro-6-methylphenoxy)methyl]-
phenyl}-l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
46. (2S)-W-(5-{2-[(2,6-difluorophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
47. (2S)-N-{5-[4-chloro-2-(phenoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
48. (2S)-N-{5-[4-fluoro-2-(phenoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
49. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-
{5-[4-methoxy-2-(phenoxymethyl)phenyl]-
1,3-thiazol-2-yl}pentanamide
50. (2S)-N-(5-{2-[(3,4-dichlorophenoxy)methyl]phenyl}-
l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
51. (2S)-N-((lS)-l-{[(5-{2-[(cyclohexyloxy)methyl]-
phenyl}-l,3-thiazol-2-yl)amino]carbonyl}butyl)-
2-hydroxy-4-methylpentanamide
52. (2S)-N-{5-[4-ethoxy-2-(phenoxymethyl)phenyl]-
1,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
53. (2S) -N-{5-[4-ethoxy-2- (phenoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3-methylbutanoyl]amino}pentanamide
54. (2S)-N-{5-[5-fluoro-2-(phenoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
55. (2S)-N-{5-[5-chloro-2-(phenoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
56. (2S)-N-{5-[5-fluoro-2-(phenoxymethyl)phenyl]-
l,3-thiazol-2-yl}-2-{[(2S)-2-hydroxy-
3-methylbutanoyl]amino}pentanamide
57 . (2S) -N- (5-{2-[(cyclohexyloxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
58. (2S)-2-hydroxy-3,3-dimethyl-N-[(IS)-1-methyl-
2-OXO-2-({5-[2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}amino)ethyl]butanamide
59. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[4-methyl-2-(phenoxymethyl)phenyl]-
1,3-thiazol-2-yl}pentanamide
60. (2S)-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-
{5-[5-methyl-2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
61. (2S)-N-(5-{2-[(3-cyanophenoxy)methyl]phenyl}-
l,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
62. (2S)-N-(5-{2-[(3-fluorophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]aminoJpentanamide
63. (25)-N-(5-{2-[(3-fluorophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3-m€>thylbutanoyl] amino Jpentanamide
64. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{5-[5-methyl-2-(phenoxymethyl)phenyl]-
1,3-thiazol-2-yl}pentanamide
65. (2S}-2-{[(2S)-2-hydroxy-3-methylbutanoyl]amino}-N-
{5-[4-methyl-2-(phenoxymethyl)phenyl]-1,3-thiazol-
2-yl}pentanamide
66. (2S)-N-{(lS)-2-[(5-{2-[(cyclohexyloxy)methyl]-
phenyl}-l,3-thiazol-2-yl)amino]-1-methyl-
2-oxoethyl}-2-hydroxy-3,3-dimethylbutanamide
67. {2S)-N-(5-{2-[(2-chloro-5-methylphenoxy)methyl]-
phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
68. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-(5-{2-[(3-methylphenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)pentanamide
69. (2S)-N-(5-{2-[(2-cyanophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]aminojpentanamide
70. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-(5-{2-[(4-pyridinyloxy)methyl]phenyl}-
1,3-thiazol-2-yl)pentanamide
71. (2S)-N-(5-{2-[(2-chloro-4,5-dimethylphenoxy)-
methyl]phenyl}-l,3-thiazol-2-yl)-2-{[(2S)-
2-hydroxy-3,3-dimethylbutanoyl]amino}pentanamide
72. (2S)-N-(5-{2-[(4-chloro-3-methylphenoxy)methyl]-
phenyl}-lf3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]aminojpentanamide
73. (2S)-N-(5-{2-[(2,3-dichlorophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
74. (2S)-N-(5-{2-[(2,3-difluorophenoxy)methyl]phenyl}-
1,3~thiazol-2-yl)-2-{[(2S)-2-hydroxy-
3,3-dimethylbutanoyl]amino}pentanamide
75. (2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]-
amino}-N-{4-(4-methylpentyl)-5-[2-(phenoxymethyl)-
phenyl]-1,3-thiazol-2-yl)pentanamide
The subject of the invention is also, among
the compounds of general formula (I), compounds
corresponding to general formula (I'):

in which,
X represents an oxygen or sulphur atom;
R1 represents a C1-10 alkyl group optionally substituted
with a C3-7 cycloalkyl, a phenyl or a thienyl; or R1
represents a C3-7 cycloalkyl, thienyl, pyridinyl or
pyrimindinyl group;
the thienyl groups being optionally substituted with
one to 3 C1-3 alkyl groups; the phenyl group being
optionally substituted with one to 5 halogen atoms or
C1-3 alkyl, C1-3 alkoxy, C1-3 fluoroalkyl or C1-3
fluoroalkoxy groups;
R2 represents a C1-6 alkyl group optionally substituted
with a C3-7 cycloalkyl, phenyl, C1-3 alkoxy or hydroxyl.
group; or R2 represents a C3_7 cycloalkyl, piperidinyl,
phenyl or pyridinyl group;
the C3-7 cycloalkyl and piperidinyl groups being
optionally substituted with one or more C1-3 alkyl, C1-3
alkoxy, hydroxyl, C1-3 fluoroalkyl or C1-3 fluoroalkoxy
groups;
the phenyl and pyridinyl groups being optionally
substituted with one or more halogen atoms or C1-3
alkyl, C1-3 alkoxy, hydroxyl, C1-3 fluoroalkyl or C1-3
fluoroalkoxy groups;
R3 represents a hydrogen atom or a C1-6 alkyl group
optionally substituted with a C3-7 cycloalkyl group;
R4 represents a hydrogen atom or a C1-4 alkyl group;
R5 and R5 represent, independently of each other, a
hydrogen or halogen atom, a hydroxyl or C1-3 alkyl
group; or R5 and R5 form together an oxo or oxime group
such as:
where R7 represents a hydrogen atom or a C1-3 alkyl;
n represents an integer ranging from 0 to 3; and
R6 represents independently of each other when n = 2 or
3, a hydrogen or halogen atom, a hydroxyl, C1-3 alkyl,
C1-3 alkoxy, C1-3 fluoroalkyl or C1-3 fluoroalkoxy group.
Among the compounds of general formula (I'),
a sub-group of preferred compounds consists of the
compounds for which:
• X represents an oxygen or sulphur atom; and/or
• R1 represents a C1-5 alkyl group, preferably a methyl,
ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl,
1-methylpropyl, 2-methylpropyl, 1-ethylpropyl,
optionally substituted with a phenyl, a thienyl; or
R1 represents a C3-7 cycloalkyl group, preferably a
cyclohexyl, a thienyl or pyridinyl group; the thienyl
groups being optionally substituted with one or two
^0R7
^y = xV or Vy
C1-3 alkyl groups, preferably a methyl; the phenyl
group being optionally substituted with one or two
halogen atoms, preferably chlorine or fluorine;
and/or
• R2 represents a C1-6 alkyl group, preferably an ethyl,
1-methylethyl; or R2 represents a C3-7 cycloalkyl
group, preferably a cyclohexyl or phenyl;
the phenyl group being optionally substituted with 1
or 2 C11-3 alkyl groups, preferably methyl or ethyl,
C1-3 alkoxy groups, preferably methoxy, ethoxy or
hydroxyl, fluoroalkoxy groups, preferably
trifluoromethoxy, or with one or two halogen atoms,
preferably chlorine or fluorine; and/or
• R3 represents a C1-6 alkyl group, preferably an ethyl
or propyl; and/or
• R4 represents a hydrogen atom or a C1-4 alkyl group,
preferably a methyl; and/or
• R5 and R5' represent, independently of each other, a
hydrogen atom or a hydroxyl; or R5 and R5' form
together an oxo group; and/or
• R6 represents a hydrogen or halogen atom, preferably
a chlorine or a fluorine, a C1-3 alkoxy, preferably a
methoxy; and/or
• n is equal to 0 or 1
In the context of the invention, the
expression:
- Ct-Z where t and z may take the values from 1 to 10,
is understood to mean a carbon chain which may have
from t to z carbon atoms, for example C1-3 a carbon
chain which may have from 1 to 3 carbon atoms, C3-6 a
carbon chain which may have from 3 to 6 carbon atoms;
and the like;
- alkyl is understood to mean a linear or branched
saturated aliphatic group, for example a C1-6 alkyl
group represents a linear or branched carbon chain of
from 1 to 6 carbon atoms, more particularly a methyl,
ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,
2-methylpropyl, 1,1-dimethylethyl, and the like,
preferably a methyl, ethyl, propyl or 1-methylethyl;
- alkylene is understood to mean a divalent alkyl
group;
- cycloalkyl is understood to mean a cyclic alkyl
group, for example a C3_7 cycloalkyl group represents a
carbon cycle of from 3 to 7 carbon atoms, more
particularly a cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, preferably a cyclopentyl or
cyclohexyl;
- alkoxy is understood to mean an -O-alkyl group where
the alkyl group is as defined above;
- fluoroalkyl is understood to mean an alkyl group in
which one or more hydrogen atoms have been substituted
with a fluorine atom;
- fluoroalkoxy is understood to mean an alkoxy group in
which one or more hydrogen atoms have been substituted
with a fluorine atom; and
- halogen atom is understood to mean a fluorine, a
chlorine,, a bromine or an iodine.
The compounds of general formula (I) may
contain one or more asymmetric carbons. They may
therefore exist in the form of enantiomers or of
diastereoisomers. These enantiomers or diastereo-
isomers, and mixtures thereof, including the racemic
mixtures, form part of the invention.
The compounds of formula (I) may exist in the
form of bases or of addition salts with acids. Such
addition salts form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, but the salts of
other useful acids, for example, for the purification
or the isolation of the compounds of formula (I), also
form part of the invention.
The compounds of general formula (I) may
exist in the form of hydrates or of solvates, namely in
the form of associations or combinations with one or
more molecules of water or with a solvent. Such
hydrates and solvates also form part of the invention.
In the text which follows, the expression
leaving group is understood to mean a group which can
be easily cleaved from a molecule, with departure of an
electron pair, by the breaking of a heterolytic bond.
This group may thus be easily replaced by another group
during a substitution reaction for example. Such
leaving groups are, for example, halogens, or an
activated hydroxyl group such as a mesylate, tosylate,
triflate, acetyl and the like. Examples of leaving
groups and references for their preparation are given
in "Advanced Organic Chemistry", J. March, 3rd Edition,
Wiley Interscience, p. 310-316.
The expression protecting group is understood
to mean a group which makes it possible to prevent the
reactivity of a functional group or a position, during
a chemical reaction which may effect it, and which
releases the molecule after cleavage according to
methods known to persons skilled in the art. Examples
of protecting groups and methods of protection and
deprotection are given, inter alia, in Protective
groups in Organic Synthesis, Greene et al., 2nd Ed.
(John Wiley & Sons, Inc., New York).
The second subject of the invention is
methods for preparing the compounds of formula (I).
Thus, these compounds may be prepared by
methods, illustrated in the schemes which follow, whose
operating conditions are conventional for persons
skilled in the art.
According to Scheme 1, the compound of
formula (I) may be obtained by peptide coupling of the
amine of formula (XI) with the acid of formula (XII)
according to conditions known to persons skilled in the
art, for example in the presence of benzotriazol-1-
yloxy-tris(dimethylamino)phosphonium hexafluoro-
phosphate (BOP) and N-ethylmorpholine or N-methyl-
morpholine in an inert solvent such as dimethyl-
formamide, acetonitrile or dichloromethane at a
temperature which may range from 0°C to room
temperature.
The amine of formula (XI) is obtained by
peptide coupling of the amine of formula (VIII) with
the amino acid of formula (IX), in which Pg represents
a protecting group, under conditions as described
above, to give the compound of formula (X). The amino
acid of formula (IX) is, for example, protected by
means of an N-tert-butyloxycarbonyl (Boc). The compound
(X) is then deprotected according to methods known to
persons skilled in the art, to give the amine of
formula (XI). For example, if the protecting group used
is Boc, the latter may be deprotected by acid
hydrolysis, in the presence of anhydrous gaseous
hydrochloric acid.
The compound of formula (VIII) may be
prepared according to Scheme 2.
According to this scheme, the aralkyl of formula (II),
in which Y represents a leaving group, preferably a
halogen atom such as bromine and Z represents a halogen
atom such as bromine, is condensed with an alkali metal
thiolate or alcoholatef for example of formula R2X" Na+
in which X represents an oxygen or sulphur atom. The
reaction is carried out in an inert solvent such as
dimethylformamide at a temperature which may range from
0°C to 50°C, to give the compound of formula (III). The
aryl or formula (III) is converted to boronic acid of
formula (IV) according to an adaptation of the method
described by Schoevaars, J. Am. Chenu Soc, 1999, 121,
9550-9561. The conversion may, for example, be carried
out by prior formation of the anion of the compound of
formula (III), for example by the action of a strong
base such as butyllithium, in an ethereal solvent such
as tetrahydrofuran, at temperatures which may range
from -50°C to -80°C. This anion is then reacted with a
borate such as trimethyl borate to give, after
hydrolysis, the boronic acid of formula (IV).
The coupling of the boronic acid (IV) with
the 5-bromothiazole of formula (VI) in which Pg
represents a protecting group, such as an imino, for
example a diphenyl ketone imine, may be carried out
according to the Suzuki reaction, by adaptation of the
method described by Wolfe, J. Org. Chem., 1997, 62,
4943-4948, to give the 5-phenylthiazole of formula
(VII). The coupling is carried out, for example, in an
ethereal solvent such as dioxane in the presence of
tripotassium phosphate trihydrate and a catalyst such
as tetrakis(triphenylphosphine)palladium (0) at a
temperature which may range from room temperature to
the reflux temperature of the solvent. The 5-
phenylthiazole of formula (VII) thus prepared is then
deprotected according to methods known to persons
skilled in the art to generate the 5-phenyl-2-amino-
thiazole of formula (VIII).
The 5-bromothiazole of formula (VI) is
obtained by protecting the amino functional group of
the corresponding compound of formula (V). Preferably,
it is protected in the form of a diphenyl ketone imine
under conditions known to persons skilled in the art.
The starting compounds, in particular the
compounds of formula (II), (V), (IX) and (XII) are
commercially available or are described in the
literature, or may be prepared by methods which are
described therein or which are known to persons skilled
in the art.
For example, 5-bromo-2-aminothiazole (V) may be
obtained by bromination of the corresponding 2-amino-
thiazole according to an adaptation of the method
described by Kaye, J. Chem. Soc. Perkin I, 1981,
2335-2339.
For example, the compound of formula (XII) may be
obtained by adaptation of the methods described by
Middleton et al., J. Org. Chem., 45, 14, 1980, 2883-
2887 and by Miyamoto et al., J. Amer. Chem. Soc, 114,
15, 1992, 6256-6257.
The meanings of X, R1, R2, R3, R4, R5, R5', R6
and n in the compounds of formula (II) to (XII) are as
defined for the compounds of formula (I).
The following examples describe the
preparation of some compounds in accordance with the
invention. These examples are not limiting and only
illustrate the invention. The exemplified compound
numbers refer to those given in the Table below. The
elemental microanalyses and the NMR, IR or mass spectra
confirm the structure of the compounds obtained.
Example 1 (Compound No. 9)
(2S)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}-N-
{5-[2-(phenoxymethyl)phenyl]-l,3-thiazol-2-
yl}pentanamide
1.1 l-bromo-2-(phenoxymethyl)benzene
1.2 g of sodium hydride (at 50% in suspension
in oil) are added at 5°C, in portions, to 20.2 g of
phenol in solution in 150 ml of dimethylformamide. The
mixture is stirred at room temperature and 37.2 g of 2-
bromobenzyl bromide in solution in 15 ml of dimethyl-
formamide are introduced at 5°C. After 2 hours at 20°C,
the reaction medium is poured over ice-cold water and
extracted with ethyl acetate. The organic phase is
dried over anhydrous sodium sulphate and concentrated
to give 36 g of oil.
XH NMR: 8 in ppm (DMSO d6) : 5.22 (s, 2H); 7.09-7.67
(unresolved complex, 9H).
1.2 2-(phenoxymethyl)phenylboronic acid
90 ml of n-butyllithium (1.6 M) in solution
in hexane are added dropwise at -700C to 36 g of 1-
bromo-2-(phenoxymethyl)benzene, obtained in step 1.1,
in solution in 150 ml of tetrahydrofuran. After 2 hours
at -70°C, 16 ml of trimethyl borate are introduced
dropwise. The temperature of the reaction medium is
allowed to rise to -30°C. The medium is hydrolysed with
a saturated ammonium chloride solution, and then
extracted with ethyl acetate and the organic phase is
dried with anhydrous sodium sulphate. After
evaporation, 33 g of a white solid are obtained.
1H NMR: 8 in ppm (DMSO d6) : 5.25 (s, 2H) ; 6.85-7.67
(unresolved complex, 11H).
1.3 5-bromo-N-(diphenylmethylene)-1,3-thiazol-2-amine
26 g of benzophenone imine are added to 34 g
of 5-bromo-l,3-thiazol-2-amine hydrobromide, in
suspension in 300 ml of 1,2-dichloroethane. The mixture
is kept under reflux for 18 hours. The precipitate
formed is filtered and the filtrate is concentrated to
give 37.2 g of solid,
m.p. = 109°C
1E NMR: 8 in ppm (DMSO d6) : 7.34 (m, 2H); 7.50-7.76
(unresolved complex, 9H).
1.4 5-{2-[(phenoxy)methyl]phenyl}-N-(diphenyl-
methylene) -1,3-thiazol-2-axnine
15 g of tripotassium phosphate dihydrate,
10.5 g of 5-bromo-N-(diphenylmethylene)-1,3-thiazol-2-
amine, obtained in step 1.3, and 1.5 g of
tetrakis(triphenylphosphine)palladium(0) are
successively introduced into 14.8 g of 2-
(phenoxyrnethyl)phenylboronic acid, obtained in step
1.2, in solution in 250 ml of 1,4-dioxane, and the
mixture is kept under reflux for 1 hour. The reaction
medium is evaporated to dryness, the residue is taken
up in ethyl acetate and washed with water. The organic
phase is dried over anhydrous sodium sulphate and the
solvates are concentrated. The residue is
chromatographed on a silica gel column, eluting with
dichloromethane to give 35 g of a yellow oil.
1H NMR: 5 in ppm: 4.81 (s, 2H); 7.17-7.83 (unresolved
complex, 20H).
1.5 5-{2-[(phenoxy)methyl]phenyl}-l,3-thiazol-2-amine
150 ml of an aqueous hydrochloric acid
solution (1 M) are added to 35 g of 5-{2-
[(phenoxy)methyl]phenyl}-N-(diphenylmethylene)-1,3-
thiazol-2-amine, obtained in step 1.4, in solution in
250 ml of methanol, and the mixture is stirred for 18
hours at 20°C. The mixture is evaporated to dryness,
the residue is taken up in diethyl ether and washed
with an aqueous sodium hydroxide solution (0.5 M). The
organic phase is dried over anhydrous sodium sulphate
and concentrated. The residue is chromatographed on a
silica gel column, eluting with a
dichloromethane/methanol 98/2 (v/v) mixture, to give
15 g of a beige solid,
m.p. = 154°C
1H NMR: 8 in ppm (DMSO d6) : 5.07 (s, 2H); 6.98-7.65
(unresolved complex, 10H).
1.6 tert-butyl (lS)-l-[({5-[2-(phenoxymethyl)phenyl]-
1,3-thiazol-2-yl}amino)carbonyl]butylcarbamate
7.1 g of benzotriazol-1-yloxytris(dimethyl-
amino)phosphonium hexafluorophosphate are added at 0°C
to 3.35 g of (2S)-2-[(tert-butyloxycarbonyl)amino]-
pentanoic acid in solution in 35 ml of
dimethylformamide, followed dropwise by 2.1 ml of N-
methylmorpholine. After 15 minutes at 0°C, 4 g of 5-{2-
[(phenoxy)methyl]phenyl}-l,3-thiazol-2-amine, obtained
in step 1.5, are introduced and the mixture is stirred
for 18 hours at room temperature. The medium is taken
up in ethyl acetate and washed twice with water. The
organic phase is dried over anhydrous sodium sulphate
and concentrated. The residue is chromatographed on a
silica gel column, eluting with a
dichloromethane/methanol 98/2 (v/v) mixture to give
5.2 g of a colourless oil.
lH NMR: 5 in ppm (DMSO d6) : 0.88 (t, 3H); 1.22-1.65
(unresolved complex, 13H); 4.24 (q, 1H); 5.09 (s, 2H);
6.94-7.67 (unresolved complex, 10H); 12.23 (s, 1H).
1.7 (2S)-2-amino-N-(5-{2-[(phenoxy)methyl]phenyl}-1,3-
thiazol-2-yl)pentanamide hydrochloride
25 ml of a solution of gaseous hydrochloric
acid (4.5 M) in ethyl acetate are added dropwise at 0°C
to 5 g of tert-butyl (IS)-2-[(5-{2-[(phenoxy)-
methyl]phenyl}-l,3-thiazol-2-yl)amino]-l-propyl-2-
oxoethylcarbamate, obtained in step 1.6, in solution in
60 ml of ethyl acetate. The mixture is stirred for 18
hours at 20°C. The precipitate formed is filtered,
rinsed twice with diethyl ether and dried to give 3 g
of a white solid,
m.p. = 148°C
1 H NMR: 5 in ppm (DMSO d6) : 0.90 (t, 3H); 1.39 (m, 2H);
1.85 (m, 2H); 4.18 (q, 1H); 5.08 (s, 2H); 6.94-7.68
(unresolved complex, 10H); 8.65 (s, 3H).
1.8 (2S)-2-{[(2S)-2-hydroxy-3,3-
dimethylbutanoyl]amino}-N-{5-[2-phenoxymethy1)pheny1]-
1,3-thiazol-2-yl}pentanam±de
1.36 g of benzotriazol-1-yloxy-
tripyrrolidinephosphonium hexafluorophosphate and
0.7 ml of N-ethylmorpholine are added successively at
0°C to 0.32 g of (2S)-2-hydroxy-3,3-dimethylbutanoic
acid in solution in 25 ml of dimethylformamide. After
20 minutes at 0°C, 0.88 g of (2S)-2-amino-N-(5-{2-
[(phenoxy)methyl]phenyl}-l,3-thiazol-2-yl)pentanamide
hydrochloride, obtained in step 1.7, is introduced and
the mixture is stirred for 18 hours at room
temperature. The reaction medium is taken up in ethyl
acetate and washed with water. The organic phase is
dried over anhydrous sodium sulphate and concentrated.
The residue is chromatographed on a silica gel column,
eluting with a dichloromethane/methanol 99/1 (v/v)
mixture to give, after crystallization from isopropyl
ether, 0.83 g of a white solid,
m.p. = 84°C
lH NMR: 8 in ppm (DMSO d6) : 0.89 (t, 3H) ; 0.93 (s, 9H);
1.33 (m, 2H); 1.71 (q, 21H); 3.57 (d, 1H); 4.61 (q,
1H); 5.09 (s, 2H); 5.61 (d, 1H); 6.97-7.02 (unresolved
complex, 3H); 7.28-7.67 (unresolved complex, 7H); 7.81
(d, 1H); 12.28 (s, 1H).
[a]^,0 = -81.8 (c = I/CH3OH) .
Example 2 (Compound No. 16)
(2S)-2-{[2-(2,5-dimethyl-3-thienyl)acetyl]amino}-N-{5-
[2-(ethoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanamide
2.1 2-(2,5-dimethyl-3-thienyl)-1-(4-morpholinyl)-1-
ethanethione
1.68 g of sulphur and 6.5 ml of morpholine
are added to 5 g of 2,5-dimethyl-3-acetylthiophene, and
the mixture is heated under reflux for 10 hours. The
mixture is brought to 20°C and poured over an aqueous
hydrochloric acid solution (IN). The medium is
extracted with ethyl acetate. The organic phase is
dried over anhydrous sodium sulphate and it is
concentrated. The residue is purified by chromatography
on a silica gel column, eluting with a cyclohexane/-
ethyl acetate 8/2 (v/v) mixture to give 6.8 g of an
orange-coloured oil.
1H NMR: 8 in ppm (DMSO d6) : 2.30 (2, 3H); 2.34 (s, 3H) ;
3.47 (t, 2H); 3.65 (m, 4H); 4.07 (s, 2H); 4.20 (t, 2K);
6.56 (s, 1H).
2.2 2-(2,5-Dimethyl-3-thienyl)acetic acid
2-(2,5-Dimethyl-3-thienyl)acetic acid is
prepared according to a method described in Heterocycl.
Chem; EN; 25; 1988; 1571-1581.
21 ml of an aqueous sodium hydroxide solution (50% by
mass) are added to 6.7 g of 2-(2,5-dimethyl-3-thienyl)-
1-(4-morpholinyl)-1-ethanethione obtained in step 2.1,
in solution in 70 ml of methanol, and the mixture is
heated for 6 hours under reflux. After evaporation of
the methanol, the residue is diluted with water and
acidified with an aqueous hydrochloric acid solution
(6N). The precipitate formed is filtered and then it is
chromatographed on a silica gel column, eluting with
dichloromethane to give 3.6 g of beige crystals,
m. p. = 6 5 ° C
lE NMR: 8 in ppm (DMSO d6) : 2.26 (s, 3H) ; 2.34 (s, 3H) ;
3.39 (s, 2H); 6.56 (s, 1H).
2.3 (2S)-2-{[(2,5-Dimethyl-3-thienyl)acetyl]amino}-
-N--{5-[2-(ethoxymethyl)phenyl]-l,3-thiazol-2-yl}pentan-
amide
The procedure is carried out in the same
manner as in step 1.8 of Example 1, replacing (2S)-2-
hydroxy-3,3-dimethylbyutanoic acid with 2-(2,5-
dimethyl-3-thienyl)acetic acid, obtained in step 2.2.
0.67 g of white crystals is obtained,
m.p. = 84°C
1R NMR: 5 in ppm (DMSO d6) : 0.89 (t, 3H); 1.16 (t, 3H);
1.29 (m, 2H); 1.65 (m, 2H); 2.25 (s, 3H); 2.30 (s, 3H);
3.33 (m, 2H); 3.47 (q, 2H); 4.44 (s, 2H) ; 4.49 (q, 1H) ;
4.55 (s, 1H); 7.35-7.55 (unresolved complex, 5H); 8.32
(d,- 1H) ; 12.28 (s, 1H) .
[a]2D0 = -103 (c = I/CH3OH) .
Example 3 (Compound No. 22)
(2S)-2-{ |:2-(5-Methyl-2-thienyl)acetyl]amino}-N-{5-[2-
(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanamide
3.1 2-(5-Methyl-2-thienyl)-1-(4-morpholinyl)-1-
ethanethione
2-(5-Methyl-2-thienyl)-1-(4-morpholinyl)-4-
ethanethione is prepared according to a method similar
to that described in Example 2.1.
1H NMR: 5 in ppm (DMSO d6) : 2.40 (s, 3H); 3.49 (t, 2H);
3.64 (t, 2H); 3.81 (t, 2H); 4.19 (t, 2H); 4.40 (s, 2H);
6.49 (d, 1H); 6.77 (d, 1H).
3.2 2-(5-Methyl-2-thienyl)acetic acid
2-(5-Methyl-2-thienyl)acetic acid is prepared
according to a method similar to that described in
Example 2.2.
m.p. = 54°C
1E NMR: 8 in ppm (DMSO d6) : 2.38 (s, 3H); 3.72 (s, 3H);
6.61 (d, 1H); 6.69 (d, 1H).
3.3 (2S)-2-{[2-(5-Methyl-2-thienyl)acetyl]amino}-N-{5-
[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanamide
The procedure is carried out in the same
manner as in step 1.8 of Example 1, replacing (2S)-2-
hydroxy-3,3-dimethylbutanoic acid with 2-(5-methyl-2-
thienyl)acetic acid, obtained in step 3.2. 0.73 g of
beige crystals is obtained,
m.p. = 81°C
1H NMR: 5 in ppm (DMSO d6) : 0.87 (t, 3H); 1.32 (m, 2H);
1.64 (m, 2H); 2.36 (s, 3H); 3.62 (q, 2H); 4.48 (q, 1H);
5.07 (s, 2H); 6.59 (d, 1H); 6.67 (d, 1H); 6.95-7
(unresolved complex, 3H); 7.27-7.73 (unresolved
complex, 7H); 8.41 (d, 1H); 12.30 (s, 1H).
[a]2D0 = -91.7 (c = 1/CH3OH) .
Example 4 (Compound No. 7)
(2S)-N-{5-[2-(Isopropoxymethyl)phenyl]-1,3-thiazol-2-
yl}-2-{[3-(3-thienyl)propanoyl]amino}pentanamide
4.1 (E)-3-(3-Thienyl)-2-propenoic acid
46 g of malonic acid and 2 ml of piperidine
are added to 25 g of 3-thienaldehyde in solution in
100 ml of pyridine, and the mixture is heated at 100°C
for 4 hours. The reaction medium is cooled to 30°C and
it is poured over an aqueous hydrochloric acid solution
(2N). The precipitate formed is filtered and it is
rinsed with isopropyl ether to give, after drying, 30 g
of a white solid.
m.p. = 152°C
1H NMR: 6 in ppm (DMSO d6) : 6.36 (d, 1H); 7.51-7.62
(unresolved complex, 3H); 7.93 (d, 1H); 12.27 (s, 1H).
4.2 Ethyl (E)-3-(3-thienyl)-2-propenoate
11.5 g of potassium carbonate and 6.8 ml of
iodoethane are added to 11 g of (E)-3-(3-thienyl)-2-
propenoic acid, obtained in step 4.1, in solution in
50 ml of dimethylformamide, and the mixture is stirred
for 4 8 hours at 20°C. The medium is taken up in ethyl
acetate and it is washed with water. The organic phase
is dried over anhydrous sodium sulphate and it is
concentrated to give 12.5 g of oil.
1H NMR: 8 in ppm (DMSO d6) : 1.26 (t, 3H) ; 4.17 (q, 2H) ;
6.47 (d, 1H); 7.57-7.71 (unresolved complex, 3H); 8.01
4.3 Ethyl 3-(3-thienyl)-2-propanoate
4 g of 10% palladium on carbon are added to
12.5 g of ethyl (E)-3-(3-thienyl)-2-propenoate,
obtained in step 4.2, in solution in 100 ml of ethanol,
and the mixture is stirred for 24 hours at 60cC under
5 bar of hydrogen. The catalyst is filtered and the
filtrate is concentrated to give 11 g of oil.
1H NMR: 5 in ppm (DMSO d6) : 1.20 (t, 3H); 2.62 (t, 2H);
2.88 (t, 2H); 4.07 (q, 2H); 7.02 (d, 1H); 7.18 (m, 1H);
7.45 (m, 1H).
4.4 3-(3-Thienyl)propanoic acid
75 ml of an aqueous sodium hydroxide solution
(2N) are added to 11 g of ethyl 3-(3-thienyl)-2-
propanoate, obtained in step 4.3,.in solution in 100 ml
of ethanol. The mixture is stirred for 18 hours at
20°C. After evaporation of the solvents, the residue is
acidified. The precipitate formed is filtered and dried
under vacuum to give 6.3 g of a beige solid,
m.p. = 59°C
1H NMR: 8 in ppm (DMSO d6) : 2.56 (t, 2H); 2.85 (t, 2H) ;
7.02 (t, 1H); 7.18 (s, 1H); 7.45 (m, 1H); 12.14 (s,
1H) .
4.5 (2S)-N-{5-[2-Isopropoxymethyl)phenyl]-1,3-thiazol-
2-yl}-2-{[3-(3-thienyl)propanoyl]amino}pentanamide
The procedure is carried out in the same
manner as in step 1.8 of Example 1, replacing (2S)-2-
hydroxy-3,3-dimethylbutanoic acid with 3- (3-thienyl)-
propanoic acid, obtained in step 4.4. 0.75 g of beige
crystals is obtained,
m.p. = 1C1°C
1H NMR: 5 in ppm (DMSO d6) : 0.87 (t, 3H); 1.13 (d, 6H);
1.33 (m, 2H); 1.62 (m, 2H); 2.48 (t, 2H); 2.82 (t, 2H);
3.67 (m, 1H); 4.45 (s, 2H); 4.54 (q, 1H); 6.98 (d, 1H);
7.12 (d, 1H); 7.35-7.57 (unresolved complex, 6H); 8.21
(d, 1H); 12.26 (s, 1H).
[afo = -71 (c = I/CH3OH) .
Example 5
(2R) -3-Ethyl-2-hydroxy-N-{ (1S) -1- [ ({5- [2- (phenoxy-
methyl)phenyl]-1/3-thiazol-2-yl}amino)carbonyl]butyl}-
pentanamide (Compound No. 42) and
(2S)-3-Ethyl-2-hydroxy-N-{(IS)-1-[({5-[2-(phenoxy-
methyl)phenyl]-l,3-thiazol-2-yl}amino)carbonyl]butyl}-
pentanamide (Compound No. 43)
5.1 3-Ethyl-2-hydroxypentanoic acid
1.5 ml of trimethylsilyl cyanide are
carefully added to a solution of 1.24 ml of 2-ethyl-
butyraldehyde in 18 ml of anhydrous dichloromethane,
followed by a catalytic quantity of zinc iodide. The
reaction medium is stirred for 2 hours at room
temperature and then at 60°C for 3.5 hours. The
reaction medium is cooled to 0°C and 3.5 ml of
concentrated hydrochloric acid are added. The reaction
medium is stirred for 18 hours at room temperature and
then for 1 hour under reflux. After cooling, the
reaction mixture is poured into water and extracted
twice with 50 ml of ethyl acetate. The combined organic
phases are extracted with 100 ml of sodium hydroxide
(7.5N) at 4°C. After separation, the aqueous phase is
washed with 3 times 50 ml of ethyl acetate. The aqueous
phase is acidified with 70 ml of hydrochloric acid
(12N) and extracted with 3 times 50 ml of ethyl
acetate. The pooled organic phases are dried and the
solvent is evaporated,
m.p. = 84°C
5.2 (2J?)-3-Ethyl-2-hydroxy--N--{(IS)-1-[({5-[2-(phenoxy-
methyl)phenyl]-l,3-thiazol-2-yl}amino)carbonyl]butyl}-
pentanamide and (2S)-3-ethyl-2-hydroxy-N-{(IS)-1-[({5-
[2-(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}amino)-
carbonyl]butyl}pentanamide
The procedure is carried out in the same
manner as in step 1.8 of Example 1, replacing (2S)-2-
hydroxy-3,3-dimethylbutanoic acid with 3-ethyl-2-
hydroxypentanoic acid, obtained in step 5.1. 0.78 g of
white solid is obtained.
Compound No. 42 (SR):
m.p. = 67.4°C
1H NMR: 6 in ppm (DMSO d6) : 0.74 (t, 3H); 0.84-0.90
(unresolved complex, 6H); 1.26-1.71 (unresolved
complex, 9H); 3.94 (m, 1H); 4.57 (q, 1H); 5.07 (s, 2H);
5.40 (s, 1H); 6.94-6.99 (unresolved complex, 3H); 7.26-
7.93 (unresolved complex, 7H); 7.91 (d, 1H); 12.27 (s,
1H) .
[a]2D0 = -41.5 (c = I/CH3OH) .
Compound No. 43 (SS):
m.p. = 122.5°C
1H NMR: 8 in ppm (DMSO d6) : 0.78-0.89 (unresolved
complex, 9H); 1.18-1.38 (unresolved complex, 6H); 1.55
(m, 1H); 1.68 (q, 2H); 3.92 (m, 1H); 4.60 (q, 1H); 5.07
(s, 2H); 5.49 (d, 1H); 6.95-7 (unresolved complex, 3H);
7.26-7.62 (unresolved complex, 7H); 7.87 (d, 1H); 12.27
(s, 1H) .
[a]2D0 = -72.6 (c = 1/CH3OH) .
Example 6 (Compound No. 40)
(2S)-2-[(2-Hydroxy-3-phenylpropanoyl)amino]-N-{5-[2-
(phenoxymethyl)phenyl]-1,3-thiazol-2-yl}pentanamide
6.1 3-Phenyl-2-hydroxypropionic acid
A solution of 0.829 g of sodium nitrite in
4.2 ml of water is added dropwise at 0°C to a
suspension of 1.6 g of phenylalanine in 5.3 ml of
sulphuric acid (2.5N). The reaction mixture is stirred
for 2 hours at 0°C and then for 17 hours at room
temperature. The reaction mixture is extracted with
twice 100 ml of ethyl acetate. The pooled organic
phases are washed with 100 ml of a saturated sodium
chloride solution in water. 1.2 g of yellow crystals
are obtained after drying,
m.p. = 97°C
6.2 2-[(2-Hydroxy-3-phenylpropanoyl)amino]-N- {5-[2-
(phenoxymethyl)phenyl]-l,3-thiazol-2-yl}pentanamide
The procedure is carried out in the same
manner as in step 1.8 of Example 1, replacing (2S)-2-
hydroxy-3,3-dimethylbutanoic acid with 3-phenyl-2-
hydroxypropionic acid, obtained in step 6.1. 0.8 g of
white solid is obtained,
m.p. = 86°C
1H NMR: 8 in ppm (DMSO d6) : 0.85 (t, 3H) ; 1.24 (m, 2H) ;
1.63 (m, 2H); 2.70 (m, 1H); 2.57 (m, 1H); 4.17 (m, 1H);
4.56 (q, 1H); 5.08 (s, 2H); 6.94-7.63 (unresolved
complex, 15H); 8.02 (m, 1H); 12.25 (s, 1H).
[a]2D0 = -28 (c = 1/CH3OH) .
Example 7 (Compound No. 70)
(2S)-2-{[(2S)-2-Hydroxy-3,3-dimethylbutanoyl]amino}-N-
(5-{2-[(4-pyridinyloxy)methyl]phenyl}-l,3-thiazol-2-
7.1 2-(2-Amino-l,3-thiazol-5-yl)phenylmethanol
70 ml of a 3M aqueous hydrochloric acid
solution are added to 29.86 g of 5-[2-(tert-butoxy-
methyl)phenyl]-N-diphenylmethylene)-1,3-thiazol-2-
amine, prepared according to a method similar to that
described in steps 1.1 to 1.4 of Example 1, in solution
in 140 ml of methanol, and the mixture is kept at room
temperature for 18 hours and then heated under reflux
for 4 hours. The methanol is evaporated. The residue is
taken up in a 6M aqueous hydrochloric acid solution and
extracted with diethyl ether. The aqueous phase is
brought to a basic pH while cooling it, and it is
extracted with ethyl acetate. The ethyl acetate phase
is dried over anhydrous sodium sulphate and
concentrated. The residue is concreted with diisopropyl
ether to give 6 g of a beige solid,
m.p. = 145°C
7.2 tert-Butyl 5-[2-(hydroxymethyl)phenyl]-l,3-
thiazol-2-ylcarbaraate
1.17 g of magnesium oxide and 29 ml of a 2M
aqueous sodium hydroxide solution are added
successively to 6 g of 2-(2-amino-1,3-thiazol-5-yl)-
phenylmethanol, obtained in step 7.1, in solution in
80 ml of 1,4-dioxane, followed at 0°C, in portions, by
7.6 g of di-tert-butyl dicarbonate (BOC2O) . The mixture
is left for 48 hours at room temperature, and then the
medium is concentrated, it is taken up in water and it
is extracted with ethyl acetate. The organic phase is
washed with a 5% potassium hydrogen sulphate solution,
it is dried over anhydrous sodium sulphate and it is
concentrated. The residue is chromatographed on a
silica gel column, eluting with a dichloromethane/
methanol 99/1 (V/V) mixture to give 2.3 g of oil which
is concreted with diisopropyl ether,
m.p. = 180.7°C
7.3 tert-Butyl 5-{2-[(4-pyridinyloxy)methyl]phenyl}-
1,3-thiazol-2-ylcarbamate
4.15 g of diisopropyl azodicarboxylate (DIAD)
are added, in portions at 0°C, to 5.24 g of triphenyl-
phosphine in solution in 60 ml of. tetrahydrofuran.
After 30 minutes at about 10°C, 1.96 g of 4-hydroxy-
pyridine are added in portions, the mixture is left for
30 minutes at about 10°C and 4.2 g of tert-butyl 5-[2-
(hydroxymethyl)phenyl]-1,3-thiazol-2-ylcarbamate,
obtained in step 7.2, are introduced. The mixture is
left for 4 days at room temperature. The medium is
concentrated, it is taken up in a saturated sodium
carbonate solution and extracted with dichloromethane.
The organic phase is dried over anhydrous sodium
sulphate and it is concentrated. The residue is
chromatographed on a silica gel column, eluting with a
mixture cf increasing polarity dichloromethane/methanol
99/1 (V/V) up to dichloromethane/methanol 90/10 (V/V)
to give 1 g of oil.
1H NMR: 8 in ppm (DMSO d6): 1.52 (s, 9H); 5.27 (s, 2H);
6.10 (q, 2H); 7.05 (m, 1H); 7.41-7.54 (unresolved
complex, 6H); 11.60 (s, 1H) .
7.4 5-{2-[(4-Pryidinyloxy)methyl]phenyl}-l,3-
thiazolamine
20 ml of a 4M gaseous hydrochloric acid
solution in ethyl acetate are added to 1 g of tert-
butyl 5-{2-[(4-pyridinyloxy)methyl]phenyl}-1,3-thiazol-
2-ylcarbamate, obtained in step 7.3, in 20 ml of
dichloronethane. The mixture is left for 4 hours at
room temperature. The reaction medium is concentrated
and it is brought to a basic pH with a 5% sodium
hydrogen sulphate solution. The precipitate formed is
filtered and chromatographed on a silica gel column,
eluting with a dichloromethane/methanol 95/5 (V/V)
mixture to give 0.58 g of a beige foam.
:H NMR: 8 in ppm (DMSO d6): 5.25 (s, 2H); 6.10 (d, 2H);
6.98-7.55 (unresolved complex, 9H)
7.5 (2S)-2-{[(2S)-2-hydroxy-3,3-diraethylbutanoyl]-
amino}-N- (5-{2-[(4-pyridinyloxy)methyl]phenyl}-l,3-
thiazol-2-yl)pentanam±de
The procedure is carried out in the same
manner as in steps 1.6 to 1.8 of Example 1, replacing
5-{2-[(phenoxy)methyl]phenyl}-1,3-thiazol-2-amine with
5-{2-[(4-pyridinyloxy)methyl]phenyl}-1,3-thiazolamine,
obtained in step 7.4.
0.4 g is obtained in the form of crystals,
m.p. = 112.7°C
1H NMR: 6 in ppm (DMSO d6): 0.89 (t, 3H); 0.92 (s, 9H);
1.34 (m, 2H); 1.68 (q, 2H); 3.58 (d, 1H); 4.61 (q, 1H);
5.24 (s, 2H); 5.61 (d, 1H); 6.09 (d, 2H); 7.04 (m, 1H);
7.41-7.53 (unresolved complex, 6H); 7.80 (d, 1H); 12.36
(s, 1H) .
Compounds No. 61 ((2S) -N-(5-{2-[(3-cyano-
phenoxy)methyl]phenyl}-l,3-thiazol-2-yl)-2-{[(2S)-2-
hydroxy-3,3-dimethylbutanoyl]amino}pentanamide) and
No. 69 ((2S)-N-(5-{2-[(2-cyanophenoxy)methyl]phenyl}-
1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethyl-
butanoyl] amino}pentanamide) may be prepared according
to the method described in Example 1, replacing
4-hydroxypyridine with 3-cyanophenol or 2-cyanophenol,
respectively.
The following table illustrates the chemical
structures and the physical properties of a few of the
compounds of the invention.
In this table:
- m.p. (°C) represents the melting point of the
compound in degrees Celsius;
- [aD] (c = 1, CH3OH) represents the optical rotation of
the compound at the concentration of 1 g/l in methanol;
- (S) or (R) in columns "R3" and "R5, R5'" indicate the
stereochemistry of the asymmetric carbons, carrying R3
or R5 respectively, in formula (I). For the carbon
carrying R5, the indication (S) or (R) does not relate
to the case where R5 and R5' form together an oxo or
amine group.
The compounds described in this table were
prepared according to the methods described above.
The compounds of the invention have been the
subject of pharmacological trials which have shown
their value as active substances in therapy.
They have in particular been tested for their
ß-amyloid peptide (p-A4) production inhibiting effects.
P-Amyloid peptide (ß-A4) is a fragment of a
larger precursor protein called APP (amyloid precursor
protein). The latter is produced and is present in
various cells of animal or human tissue. At the
cerebral level, its cleavage by protease-type enzymes
leads to the formation of the ß-A4 peptide which
accumulates in the form of an amyloid plaque. The two
proteases responsible for the production of the amyloid
peptide are known by the name of beta- and gamma-
secretases;s (Wolfe MS, Secretase targets for Alzheimer' s
disease: identification and therapeutic potential, J.
Med. Chem., 2001 June 21; 44(13), 2039-60).
However, it has been demonstrated that this
gradual deposition of the ß-A4 peptide is neurotoxic
and could play an important role in Alzheimer's
disease.
Thus, the compounds of the present invention,
as inhibitor of the production of P-amyloid peptide
(p-A4) by inhibition of gamma-protease, can be used in
the treatment of pathologies such as senile dementia,
Alzheimer's disease, Down's syndrome, Parkinson's
disease, amyloid angiopathy, cerebrovascular disorders,
frontotemporal dementia and Pick's disease, post-
traumatic dementia, pathologies linked to
neuroinflammatory processes, Huntington's disease and
Korsakov's syndrome.
The tests were carried out according to the
protocol described below.
For the p-amyloid cellular trial, the CHO-K1
line coexpressing the CT100 of APP and PS1 M146L clone
30-12 is used. The line targets the inhibition of
gamma-secretase. Presenilin is linked to the gamma-
secretase activity (Wolfe MS, Haass C, The Role of
presenilins in gamma-secretase activity, J. Biol.
Chem., 2001 Feb. 23, 276(8), 5413-6) and its
coexpression with the amyloid protein or its N-terminal
fragment causes an increase in the secretion of the
Al-42 peptide (P~A4) thus generating a pharmacological
tool which makes it possible to evaluate inhibition by
the compounds of formula (I) of the production of the
p-A4 peptide. The inoculation of the 96-well culture
plates is carried out at the rate of 1 x 105 cells per
well in 150 |il of incubation medium. The presence of a
minimum percentage (1.3% final) of serum allows
cellular adhesion to the plastic after 2-3 hours of
incubation at 37°C, in the presence of 5% CO2. The
products (15 µl) are tested at 10 µM DMSO 1% final and
are incubated for 24-25 h at 37CC in the presence of 5%
CO2 and of 100% humidity. After this incubation of
24-25 h, the cellular supernatants (100 µl) are
transferred to the ELISA plates, treated with the
capture antibody 6E10 (6E10, epitope: aa1-17,
INTERCHIM/SENETEK 320-10), to determine the amount of
amyloid peptides secreted by the cells in the presence
of compounds according to the invention. A series for a
synthetic control peptide, "peptide 1-40", at 5 and
10 ng/ml is treated in parallel. The ELISA plates are
incubated overnight at 40C.
The quantity of bound peptide is detected in
an indirect manner in the presence of a competitor
corresponding to the truncated peptide, peptide 1-28
coupled to biotin which is then detected with
streptavidin coupled to alkaline phosphatase. The
substrate, p-Nitrophenyl Phosphate (pNPP FAST
p-Nitrophenyl Phosphate, Sigma N2770), gives a yellow
soluble reaction product which can be read at 405 nm.
The reaction is stopped with a 0.1M EDTA solution. For
that, after attachment of the amyloid peptide in the
ELISA plate, 50 µl of biotinylated peptide 1-28 are
added to 100 µl of cell supernatant and incubated for
30 minutes at room temperature. The ELISA plates are
then washed 3 times. After drying by inverting on
absorbent paper, 100 µl of streptavidin-Alkaline
Phosphatase (Interchim/Jackson ImmunoResearch
Laboratories 016-050-084), are added per well and
incubated for 1 hour at room temperature. The plates
are again washed and then alkaline phosphatase
substrate (pNPP 1 mg/ml) is added in an amount of
100 µl per well. After incubating for 30 minutes at
room temperature, the reaction is stopped by the
addition of 100 µl per well of 0. 1M EDTA and the
reading is carried out at 405 nm.
The compounds of formula (I) according to the
invention showed an EC50 (50% effective concentration)
of less than 500 nM. In particular, compound No. 50 in
the Table showed an EC50 equal to 2 95 nM. The compounds
for formula (I) according to the invention showed more
> particularly an EC50 of less than 100 nM.
The results of the biological tests show that
the compounds are inhibitors of the formation of the ß-
amyloid peptide (ß-A4).
Thus, these compounds may be used in the
treatment of pathologies in which an inhibitor of the
formation of the ß-amyloid peptide (ß-A4) provides a
therapeutic benefit. In particular, such pathologies
are senile dementia, Alzheimer's disease, Down's
syndrome, Parkinson's disease, amyloid angiopathy,
cerebrovascular disorders, frontotemporal dementia and
Pick's disease, post-traumatic dementia, pathologies
linked to neuroinflammatory processes, Huntington's
disease and Korsakov's syndrome.
The use of the compounds according to the
invention,, in the form of base, salt, hydrate or
pharmaceutically acceptable solvate, for the
preparation of a medicament for treating the
abovementioned pathologies forms an integral part of
the invention.
The subject of the invention is also
medicaments which comprise a compound of formula (I),
or an addition salt thereof with a pharmaceutically
acceptable acid or alternatively a hydrate or a solvate
of the compound of formula (I). These medicaments find
their use in therapy, in particular in the treatment of
the abovementioned pathologies.
According to another of its aspects, the
present invention relates to pharmaceutical
compositions containing, as active ingredient, at least
one compound according to the invention. These
pharmaceutical compositions contain an effective dose
of a compound according to the invention, or a
pharmaceutically acceptable salt, a hydrate or a
solvate of the said compound, and optionally one or
more pharmaceutically acceptable excipients.
The said excipients are chosen, according to
the pharmaceutical dosage form and the desired mode of
administration, from the usual excipients which are
known to persons skilled in the art.
In the pharmaceutical compositions of the
present invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local,
intratracheal, intranasal, transdermal or rectal
administration, the active ingredient of formula (I)
above, or its optional salt, solvate or hydrate, may be
administered in unit form for administration, as a
mixture with conventional pharmaceutical excipients, to
animals and to human beings for the prophylaxis or the
treatment of the above disorders or diseases.
The appropriate unit forms for administration
comprise the forms for oral administration such as
tablets, soft or hard gelatine capsules, powders,
granules, chewing gums and oral solutions or
i suspensions, the forms for sublingual, buccal,
intratracheal, intraocular or intranasal administration
or for administration by inhalation, the forms for
1000 mg, preferably from 0.1 to 500 mg, of active
ingredient in combination with one or more
pharmaceutical excipients. This unit dose may be
administered 1 to 5 times per day so as to administer a
daily dosage of 0.5 to 5000 mg, preferably of 0.5 to
2500 mg.
The present invention according to another of
its aspects also relates to a method for treating the
pathologies indicated above which comprises the
administration of a compound according to the
invention, of a pharmaceutically acceptable salt, of a
solvate or of a hydrate of the said compound.
WE CLAIM:
1. Acylaminothiazole derivative compounds corresponding to the general formula (I) :

in which,
X represents an oxygen or sulphur atom;
P1 represents, a C1-10 alkyl group optionally
substituted with a C3-7 cycloalkyl, a pheny.1. or a
thienyl; or R1 represents a C3-7 cycloalkyl, thienyl,
pyridinyl or pyrimindinyl group;
the thienyl groups being optionally substituted
with one to 3 C1-3 alkyl groups; the pheny.1 group
being optionally substituted with one to 5 halogen
atoms or C1-3 alkyl, C1-3 alkoxy, C1-3 fluoroalkyl or
C1-3 fluoroalkoxy groups;
R1 represents a C1-3 alkvl qroup optionally substi-
tuted with a C3-7 cycloalkyl, phenyl, C1-3 alkoxy,
hydroxyl group; or R2 represents a C3-7 cycloalkyl,
piperidinyl, phenyl or pyridinyl group;
the C3-1 cycloalkyl and piperidinyl groups beiny
optionally substituted with one or more C1-3 alkyl,
C1-3 alkoxy, hydroxyl, C1-3 fluoroalkyl or C1-3
fluoroalkoxy groups;
the phenyl and pyridinyl groups being optionally
substituted with one or more halogen atoms or
C1-3 alkyl, C1-3 alkoxy, hydroxyl, C1-3 fluoroalkyl
or C1-3 fluoroalkoxy;
R3 represents a hydrogen atom or a C1-6 alkyl group
optionally substituted with a C3.7 cycloalkyl
group/
R:, represents a hydrogen atom or a C1-6 alkyl group;
R5 and R5 represent, independently of each other,
a hydrogen or haloyen atom, a hydroxyl or C1-0
alkyl group; or R5 and R5 form together an oxo or
oxime group such as:

where R7 represents a hydrogen atom or a C1-3 alkyl;
n represents an integer ranging from 0 to 3; and
R6 represents independently of each other when
n - 2 01: 3, a hydrogen or haloyen atom, a
hydroxyl, C1-3 alkyl, C1-3 alkoxy, C1-3 fluoroalkyl
or C1-3 fluoroalkoxy group;
in the form of a base.
2. Compound corresponding to the general formula (I);

in which X, R1, R3, R4/ R5, R'5 and R6 are as
defined in Claim 1 and R2 represents a C1-6 alkyl
group substituted with a phenyl group or R2
represents a phenyl or pyridinyl group, the said
phenyl and pyridinyl groups being substituted with
one or more CN groups.
3. Compound of formula (I) as claimed in claim 1, wherein
X represents an oxygen or 3ulphur atom;
R1 represents a C1-5 alkyl group, optionally
substituted with a phenyl or a thianyl; or R1
rnpresents a C3-7 cycloalkyl group, a thienyl or
pyridinyl group; the thianyl groups being
optionally substituted with one or two C1-3 allcyl
groups; the phenyl group being optionally substi-
tuted with one or two halogen atoms';
R2 represents a C1-6 alkyl, C3-7 cycloalkyl phenyl
or pyridinyl group;
the phenyl group being optionally substituted with
one to three C1-5 allcyl, C1-5 alkoxy, hydroxyl or
fluoroallcoxy groups, or halogen atoms;
R3 represents a C1-6 alkyl group;
R1 represents a hydrogen atom or a C1-3 alkyl group;
R5 and R5 repre-sent, indepandontly of oach oilier,
a hydrogen atom or a hydroxyl/ or R5 and R5 form
together an oxo group;
R6 represents a hydrogen or halogen atom, a C1-j
alkyl, a C1-3 alkoxy? and
n is 0 or 1;
in the form of a base-
4. Compound as claimed in claim 2, wherein
R2 represents a phenyl group, the said phenyl
group being substituted with one to three CN
groups, and X, R1, R3, R4, R5, R's and Rs are as
defined in Claim 3.
5. Compound of formula (I) as claimed in claim 1 or 3, wherein
X represents an oxygen atom;
R1 represents a methyl, ethyl, 1-methylethyl,
1,1-dimethylethyl, propyl, 1-methylpropyl,
2-methylpropyl or 1-ethylpropyl, optionally sub-
stituted with a phenyl or with a thienyl; or R1
represents a cyclohexyl, thienyl or pyridinyl
group; the thienyl groups being optionally
substituted with one or two methyl groups; the
phenyl group being optionally substituted with one
or two chlorine or fluorine atoms;
R2 represents an ethyl, 1-methylethyl, cyclohexyl,
phony! on pynidinyi group;
the phenyl group being optionally substituted with
one to three methyl' ethyl, methoxy, ethoxy,
hydroxyl or trifluoromethoxy groups, or chlorine
or fluorine atoms/
R3 represents a methyl, ethyl or propyl group;
R4 represents a hydrogen atom or a methyl or
4-methylpentyl group;
R5 and R5 represent, indipendently of each other,
a hydrogen atom, a hydroxyl; or R5 and R5 form
together an oxo group;
R5 represents a hydrogen, chlorine or fluorine
atom, a methyl, a methoxy or an ethoxy;
n is 0 or 1; and
the C1-4 alkylene group is a methylene;
in the form of a base.
6. Compound as claimed in claim 2 or 4, wherein
R2 represents a phenyl group, the said
phenyl group being substituted with one to three
CN groups and X, Rj, R3, R4, R5, R'j and Rg are as
defined in Claim 5.
7. Method for preparing a compound of formula (I)
as claimed in any one of claims 1 to 6, by peptide
coupling of an amine of formula (XI)

with an acid of formula (XII)

in which X, Rl R2, Ra, R4, R$, R5'/ R5 and n are as
defined in formula (I) according to Claim 1.
0. Pharmaceutical composition containing at least one
compound of formula (T) as claimed in any one of
Claima 1 to 6, in the form of a pharmaceutically
acceptable base and optionally one or more
pharmaceutically acceptable excipents .
9. Compound of formula (I) as claimed in any one of
Claima 1 to 6, in the form of a pharmaceutically
acceptable base, for its use as a medicament.
10. A compound of formula (I) as claimed in any
one of Claims 1 to 6, in the form of a pharma-
ceutically acceptable base for the preparation of a
medicament for treating a pathology in which an inhibitor
of the formation of ß-amyloid peptide p-A4 offers a
therapeutic benefit.
11. A compound of formula (I) as claimed in: any
one of claims 1 to 6, in the form of a pharmaceutically
acceptable base, for the preparation of a medicament for
treating senile dementia, Alzheimer's disease,
Down's syndrome, Parkinson's disease, amyloid
angiopathy, cerebrovascular disorders, frontotem-
poral dementia and Pick's disease, post-traumatic
dementia, pathologies linked to neuroinflammation
processes, -Huntington'-s disease and/or Korsakov's
syndrome.
Acylaminothiazole derivative compounds of formula (I)

in the form of a base, of an addition salt with an acid, of a hydrate or of a solvate. The
invention also relates to a method to prepare these compounds, and to its therapeutic
applications, for example for its beta-amyloid peptide production inhibiting effects.

Documents:

1249-kolnp-2005-granted-abstract.pdf

1249-kolnp-2005-granted-assignment.pdf

1249-kolnp-2005-granted-claims.pdf

1249-kolnp-2005-granted-correspondence.pdf

1249-kolnp-2005-granted-description (complete).pdf

1249-kolnp-2005-granted-examination report.pdf

1249-kolnp-2005-granted-form 1.pdf

1249-kolnp-2005-granted-form 13.pdf

1249-kolnp-2005-granted-form 18.pdf

1249-kolnp-2005-granted-form 3.pdf

1249-kolnp-2005-granted-form 5.pdf

1249-kolnp-2005-granted-gpa.pdf

1249-kolnp-2005-granted-reply to examination report.pdf

1249-kolnp-2005-granted-specification.pdf

1249-kolnp-2005-granted-translated copy of priority document.pdf


Patent Number 233851
Indian Patent Application Number 1249/KOLNP/2005
PG Journal Number 16/2009
Publication Date 17-Apr-2009
Grant Date 16-Apr-2009
Date of Filing 28-Jun-2005
Name of Patentee SANOFI AVENTIS
Applicant Address 174 AVENUE DE FRANCE, F-75013 PARIS
Inventors:
# Inventor's Name Inventor's Address
1 DESPEYROUSX, PIERRE 472, ROUTE DE LAGARDELLE, F-31860 LABARTHE SUR LEZE
2 FREHEL, DANIEL LE BURGET, F-31160, ESTADENS
3 SCHOENTJES, BRUNO 185 RUE GUILLAUME DE NORMANDIE, F-76230 BOIS-GUILLAUME
4 VAN DORSSELAER, VIVIANE 8, RUE DE-LA-GROSSAU, F-67100 STRASBOURG
PCT International Classification Number A61P 25/16, 25/28
PCT International Application Number PCT/FR2004/000140
PCT International Filing date 2004-01-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03/00703 2003-01-23 France