IP Library › Granted Patent US 10,065,961
Granted Patent B2
US 10,065,961 · App. 15/259,922 · Granted Sep 4, 2018

Chiral N-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof

Inventors: Hamid R. Hoveyda (Brussels, BE); Guillaume Dutheuil (Vedrin, BE); Graeme L. Fraser (Bousval, BE); Marie-Odile Roy (Paris, FR); Mohamed E. Bousmaqui (Aul-Noy-lez-Valenciennes, FR); Frederic Batt (Lyon, FR)
Assignee: Ogeda SA.
C07D487/04Y02P20/55
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Quick Facts
Patent No.
US 10,065,961
App. No.
15/259,922
Granted
Sep 4, 2018
Kind
B2
Abstract

The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.

Claims (172)

1. A compound of Formula III

or salts or solvates thereof, wherein

the solid line with a star indicates that the individual enantiomers are meant, excluding racemic mixtures thereof;

R 1′ is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl, each of said alkyl or cycloakyl groups, groups being optionally substituted by one or more group(s) selected from halo or esters;

Ar 2′ is of general Formula (i), (ii) or (iii):

wherein

X 1 is N or C—R 6 wherein R 6 is H, fluoro or methyl;

X 2 is O or S;

X 3 is N, or X 3 is CH under the condition that X 1 is N and X 2 is N—R 7 wherein R 7 is linear or branched C1-C3 alkyl or cyclopropyl;

R 2′ is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl, di(C1-C2 alkyl)amino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl or N-morpholinyl;

X 4 is N or C—R 8 wherein R 8 is H or C1-C2 alkyl,

X 5 is O or S,

X 6 is N or X 6 is CH under the condition that X 4 is N and X 5 is N—R 9 wherein R 9 is C1-C2 alkyl or C3 alkyl or C3 cycloalkyl, or X 4 is N, X 5 is N—R 9 wherein R 9 is methyl and X 6 is CH;

R 3′ is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl, di(C1-C2 alkyl)amino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl or N-morpholinyl;

R 4′ is cyano, C2 alkyl or hydroxyl;

R 11 is H or an N-sp 3 protective group;

with the proviso that the compound of Formula III is not

(R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole hydrochloride,

(R)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole hydrochloride salt,

(S)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,

(S)-4-(4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine.

2. The compound of claim 1 or a salt or solvate thereof, wherein

R 11 is H or

wherein

R 12 , R 12′ , R 13 , R 13′ and R 14 are H, or R 14 is methoxy and R 12 , R 12′ , R 13 and R 13 are H, or R 12 and R 14 are methoxy and R 12′ , R 13 and R 13′ are H, or R 12 , R 12′ and R 14 are methoxy and R 13 and R 13′ are H; and

R 1′ and Ar 2′ are as defined in claim 1 .

3. The compound of claim 1 , wherein R 1′ is C1-C2 alkyl optionally substituted by one ester group.

4. The compound of claim 1 selected from the group consisting of

Compd n°

Structure

Chemical name

1

(R)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

2

(S)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

3

(R)-2-ethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

4

(S)-2-ethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

5

(R)-4-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole

6

(S)-4-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole

7

(R)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

8

(S)-2-methyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

9

(R)-2-isopropyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

10

(S)-2-isopropyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

11

(R)-2-cyclopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

12

(S)-2-cyclopropyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

13

(R)-2,5-dimethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

14

(S)-2,5-dimethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

15

(R)-N,N-dimethyl-4-(8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazol-2-amine

16

(S)-N,N-dimethyl-4-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazol-2-amine

17

(R)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

18

(S)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

19

(R)-4,5-dimethyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

20

(S)-4,5-dimethyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)thiazole

21

(R)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)-1,2,4-oxadiazole

22

(S)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)-1,2,4-oxadiazole

23

(R)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)-1,2,4-thiadiazole

24

(S)-3-methyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)-1,2,4-thiadiazole

25

(R)-3-isopropyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)-1,2,4-thiadiazole

26

(S)-3-isopropyl-5-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)-1,2,4-thiadiazole

27

(R)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

28

(S)-4-methyl-2-(8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

29

(R)-3-(1,3-dimethyl-1H-pyrazol-5-yl)- 8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine

30

(S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)- 8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine

33

(R)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)pyridin-2-ol

34

(S)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)pyridin-2-ol

35

(R)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)picolinonitrile

36

(S)-6-(8-methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)picolinonitrile

37

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methylthiazole

38

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methylthiazole

39

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- ethylthiazole

40

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- ethylthiazole

41

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole

42

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- vinylthiazole

43

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methyloxazole

44

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- methyloxazole

45

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- isopropyloxazole

46

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- isopropyloxazole

47

(R)-2-cyclopropyl-4-(7-(2,4- dimethoxybenzyl)-8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

48

(S)-2-cyclopropyl-4-(7-(2,4- dimethoxybenzyl)-8-methyl-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3- a]pyrazin-3-yl)oxazole

49

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,5- dimethylthiazole

50

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,5- dimethylthiazole

51

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)- N,N-dimethylthiazol-2-amine

52

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)- N,N-dimethylthiazol-2-amine

53

(R)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methylthiazole

54

(S)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methylthiazole

55

(R)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4,5- dimethylthiazole

56

(S)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4,5- dimethylthiazole

57

(R)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-oxadiazole

58

(S)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-oxadiazole

59

(R)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-thiadiazole

60

(S)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- methyl-1,2,4-thiadiazole

61

(R)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- isopropyl-1,2,4-thiadiazole

62

(S)-5-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- isopropyl-1,2,4-thiadiazole

63

(R)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methyloxazole

64

(S)-2-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4- methyloxazole

65

(R)-7-(2,4-dimethoxybenzyl)-3-(1,3- dimethyl-1H-pyrazol-5-yl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine

66

(S)-7-(2,4-dimethoxybenzyl)-3-(1,3- dimethyl-1H-pyrazol-5-yl)-8-methyl- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine

69

(R)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)pyridin-2-ol

70

(S)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)pyridin-2-ol

71

(R)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)picolinonitrile

72

(S)-6-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)picolinonitrile

73

(R)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- (4-fluorophenyl)thiazole

74

(S)-4-(7-(2,4-dimethoxybenzyl)-8- methyl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2- (4-fluorophenyl)thiazole.

5. A compound according to claim 1 , or a salt or solvate thereof, as intermediate for the synthesis of a pharmaceutical active ingredient.

Assignments (1)
CHANGE OF NAME Recorded Apr 4, 2017
From: EUROSCREEN SA
To: OGEDA SA
Reel/Frame 042157/0125 →
Priority Claims (4)
EP 11183678 · Oct 3, 2011 · regional
EP 11183679 · Oct 3, 2011 · regional
EP 11183681 · Oct 3, 2011 · regional
EP 11183692 · Oct 3, 2011 · regional
Continuity (3)
Division 14349595
Provisional Application 61543611 · Oct 5, 2011
Related Publication 20170029429A1 · Feb 2, 2017