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1. WO2004101546 - DERIVES DE PIPERAZINE ET LEUR UTILISATION DANS LE TRAITEMENT DE MALADIES NEUROLOGIQUES ET PSYCHIATRIQUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:



(I)
wherein:
R1 represents aryl, heteroaryl, -aryl-X-C3-7 cycloalkyl, -heteroaryl-X-C3-7 cycloalkyl, -aryl-X-aryl, -aryl-X-heteroaryl, -aryl-X-heterocyclyl, -heteroaryl-X-heteroaryl, -heteroaryl-X-aryl or -heteroaryl-X-heterocyclyl;
wherein said aryl, heteroaryl and heterocyclyl groups of R1 may be optionally substituted by one or more (eg. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloC1-6 alkyl, polyhaloC1-6 alkyl, haloC1-6 alkoxy, polyhaloC1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkoxyC1-6 alkyl, C3-7 cycloalkylC1-6 alkoxy, -COC1-6 alkyl, -COC-ι.6 alkyl-halogen, -COC1-6 alkyl-cyano, C1-6 alkoxycarbonyl, C -6 alkylsulfonyl, C-i-6 alkylsulfinyl, C1-6 alkylsulfonyloxy, C1-6 alkylsulfonylC1-6 alkyl, C -6 alkylsulfonamidoC1-6 alkyl, C1-6 alkylamidoC1-6 alkyl, aryl, arylsulfonyl, arylsulfonyloxy, aryloxy,
arylsulfonamido, arylcarboxamido, aroyl, or a group NR15R16, -CONR15R16, -NR15COR16, -C(R15)=NOR16, -NR15SO2R16 or -SO2NR15R16, wherein R15 and R16 independently represent hydrogen or C1-6 alkyl or together form a heterocyclic ring;
X represents a bond, O, CO, SO2, OCH2 or CH2O;
each R2 and R4 independently represents C1-4 alkyl;
R3 represents C3.8 alkyl, C3.6 alkenyl, C3-6 alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl or -C-,. 4alkyl-C3-6 cycloalkyl;
wherein said C3.6 cycloalkyl groups of R3 may be optionally substituted by one or more (eg. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, C- alkyl or trifluoromethyl groups;
m and n independently represent 0, 1 or 2;
p and q independently represent 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) as defined in claim 1 wherein R1 represents
-aryl optionally substituted by 1 , 2 or 3 halogen, C1-6 alkyl, polyhaloC1-6 alkyl, C1-6 alkoxy, polyhaloC1-6 alkoxy, -COC1-6 alkyl, -C(R15)=NOR16, -NR15COR16, -COC1-6 alkyl-halogen, -COC1-6 alkyl-cyano, cyano or C1-6 alkoxycarbonyl groups;
-aryl-X-C3-7 cycloalkyl;

-aryl-X-aryl;
-aryl-X-heterocyclyl optionally substituted by 1 , 2 or 3 halogen or oxo groups;
-aryl-X-heteroaryl optionally substituted by a C1-6 alkyl or aryl group;
-heterocyclyl optionally substituted by 1 , 2 or 3 C1-6 alkyl or -COC -6 alkyl groups; heteroaryl optionally substituted by 1 , 2 or 3 cyano, halogen, polyhaloC1-6 alkyl,

-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl or -CONR15R16 groups;
-heteroaryl-X-aryl optionally substituted by 1 , 2 or 3 cyano or C1-6 alkylsulfonyl groups;
-heteroaryl-X-heterocyclyl; or
-heteroaryl-X-heteroaryl.

3. A compound of formula (I) as defined in claim 2 wherein R1 represents
phenyl, naphthyl or indanone optionally substituted by 1 , 2 or 3 halogen, C1-6 alkyl, polyhaloC1-6 alkyl, C1-6 alkoxy, polyhaloC1-6 alkoxy, -COCι.6 alkyl, -C(R15)=NOR16, -NR15COR16, -COC1-6 alkyl-halogen, -COC1-6 alkyl-cyano, cyano or C-i-6 alkoxycarbonyl groups;
-phenyl-CO-cyclopropyl or -phenyl-CO-cyclobutyl;
-phenyl-thiazolyl, -phenyl-oxadiazolyl, -phenyl-pyrrolyl, -phenyl-oxazolyl or -phenyl-isoxaxolyl optionally substituted by a C1-6 alkyl or aryl group; or
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl or benzothiazolyl optionally substituted by 1 , 2 or 3 cyano, halogen, polyhaloCι-6 alkyl, Cι-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl or -CONR15R16 groups.

4. A compound of formula (I) as defined in claim 3 wherein R1 represents
phenyl optionally substituted by 1 , 2 or 3 halogen, polyhaloC1-6 alkyl, - NR15COR16, -COC1-6 alkyl or cyano groups;
-phenyl-CO-cyclopropyl;
-phenyl-oxadiazolyl or -phenyl-oxazolyl optionally substituted by a C1-6 alkyl or aryl group; or
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or quinolinyl optionally substituted by 1 , 2 or 3 halogen, polyhaloC1-6 alkyl, C1-6 alkyl or cyano groups.

5. A compound of formula (I) as defined in claim 4 wherein R1 represents
phenyl optionally substituted at the 4-position by a -COMe, -COEt or cyano group; or
pyridyl or quinolinyl optionally substituted by a methyl or CF3 group.

6. A compound of formula (I) as defined in claim 5 wherein R1 represents
- 6-CF3-pyridin-3-yl.

7. A compound of formula (I) as defined in any one of claims 1 to 6 wherein X represents a bond, O or CO.

8. A compound of formula (I) as defined in claim 7, wherein X represents a bond or CO.

9. A compound of formula (I) as defined in any one of claims 1 to 8 wherein m represents 0.

10. A compound of formula (I) as defined in any one of claims 1 to 9 wherein n represents 0, 1 or 2.

11. A compound of formula (I) as defined in claim 10 wherein n represents 0 or 1.

12. A compound of formula (I) as defined in claim 10 or claim 11 wherein R2 represents methyl.

13. A compound of formula (I) as defined in claim 11 wherein n represents 0.

14. A compound of formula (I) as defined in any one of claims 1 to 13 wherein q represents 1.

15. A compound of formula (I) as defined in any one of claims 1 to 14 wherein R3 represents C3-8 alkyl or C3-6 cycloalkyl.

16. A compound of formula (I) as defined in claim 15 wherein R3 represents isopropyl, isobutyl or cyclobutyl.

17. A compound of formula (I) as defined in claim 16 wherein R3 represents isopropyl or cyclobutyl.

18. A compound of formula (I) as defined in claim 17 wherein R3 represents isopropyl.

19. A compound of formula (I) as defined in claim 1 which is a compound of E1-E198 or a pharmaceutically acceptable salt thereof.

20. A compound of formula (I) as defined in claim 1 which is
1-lsopropyl-4-[1-(5-cyano-pyridin-2-yl)-piperidine-4-carbonyl]-piperazine;
1-lsopropyl-4-[1-(5-methoxycarbonyl-4-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]-piperazine;
1 -lsopropyl-4-[1 -(4-ethoxycarbonylphenyl)-piperidine-4-carbonyl]-piperazine;
1-Cyclobutyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine;
1-Cyclobutyl-4-[1-(4-cyano-3-fluorophenyl)-piperidine-4-carbonyl]-piperazine;

1-Cyclobutyl-4-[1-(4-cyano-2,6-difluorophenyl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(4-cyano-3-trifluoromethylphenyl)-piperidine-4-carbonyl]-piperazine; 1 -Cyclobutyl-4-[1 -(4-cyano-naphthalen-1 -yl)-piperidine-4-carbonyl]-piperazine;
1-Cyclobutyl-4-[1-(5-cyanopyridin-2-yl)-piperidine-4-carbonyl]-piperazine;
1-Cyclobutyl-4-[1-(6-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(5-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(3-chloro-5-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]-piperazine;
1-lsopropyl-4-{1-[5-(4-methylsulfonylphenyl)-pyrimidin-2-yl]-piperidine-4-carbonyl}-piperazine;
1-lsopropyl-4-{1-[4-(morpholino-carbonyl)-phenyl]-piperidine-4-carbonyl}-piperazine; 1-Cyclopentyl-4-[1-(4-cyano-phenyl)-piperidine-4-carbonyl]-piperazine;
(2f?,6S)-1-Cyclobutyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-2,6-dimethylpiperazine;
1-lsopentyl-4-[1-(5-cyano-pyridin-2-yl)-piperidine-4-carbonyl]-piperazine;
1 -Cyclobutyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -Cyclobutyl-4-[1 -(5-cyanopyridin-2-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(4-cyano-2,5-difluorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-cyano-3-chlorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-cyano-3-fluoro-phenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-cyano-2,6-difluoro-phenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-cyano-2-fluoro-phenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-cyano-3-trifluoromethyl-phenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(4-trifluoromethyl-phenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1-lsopropyl-4-[1-(4-cyano-naphthalen-1-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(3,4-dichlorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1-lsopropyl-4-[1-(4-trifluoromethoxyphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-difluoromethoxyphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1 -(4-phenoxyphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(6-methoxypyridin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -lsopropyl-4-[1-(4-cyano-2,3-difluorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1 -lsopropyl-4-[1 -(4-cyano-2-chlorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -Cyclobutyl-4-[1 -(4-cyano-2-chlorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -Cyclobutyl-4-[1 -(4-cyano-3-chlorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -Cyclobutyl-4-[1 -(4-cyano-3-fluorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; 1 -Cyclobutyl-4-[1 -(4-cyano-3-trif luoromethylphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -Cyclobutyl-4-[1 -(4-cyano-2,5-difluorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; (S)-1-lsopropyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-2-methylpiperazine;
(S)-1 -lsopropyl-4-[1 -(6-cyanopyridin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine; (S)-1 -lsopropyl-4-[1 -(5-cyanopyridin-2-yl)-piperidine-4-carbonyl]-2-methyl piperazine;

(S)-1-lsopropyl-4-[1-(5-trifluoromethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-2-methyl piperazine;
(S)-1-lsopropyl-4-[1-(6-trifluoromethyl-pyridazin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine;
1 -lsopropyl-4-{1 -[4-(5-phenyl-1 ,3,4-oxadiazol-2-yl)phenyl]-piperidine-4-carbonyl} piperazine;
1 -lsopropyl-4-[1 -(quinolin-6-yl)-piperidine-4-carbonyl] piperazine;
1-Cyclobutyl-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl] piperazine;
1-lsopropyl-4-[1-(5-trifluoromethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-piperazine;
(S)-1-lsobutyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine;
1-lsopropyl-4-[1-(4-cyclopropylcarbonylphenyl)-piperidine-4-carbonyl]-piperazine;
1-lsopropyl-4-[1-(2-methyl-quinolin-6-yl)-piperidine-4-carbonyl]-piperazine;
1-lsopropyl-4-[1-(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-piperazine;
1 -Cyclobutyl-4-[1 -(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;

1 -Cyclobutyl-4-[1 -(2-cyanopyridin-4-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(6-trifluoromethylpyridazin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;

1 -lsopropyl-4-[1 -(5-trifluoromethylpyrazin-2-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;

1-lsopropyl-4-{1 -[4-(2-methyl-1 ,3-oxazol-5-yl)phenyl]-piperidine-4-carbonyl}-[1 ,4]-diazepane;
1 -Isopropyl-4-{1 -[4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]-piperidine-4-carbonyl}-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(4-acetamido-3-fluorophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;

1 -Cyclobutyl-4-[1 -(4-acetylphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -Cyclobutyl-4-[1 -(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(2-methyl-quinolin-4-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1-lsopropyl-4-{1-[4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]-piperidine-4-carbonyl}-piperazine;

1 -lsopropyl-4-[1 -(2-trifluoromethylpyrimidin-5-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane; or a pharmaceutically acceptable salt thereof.

21. A compound of formula (I) as defined in claim 1 which is
1-Isopropyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine;
1 -lsopropyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
(S)-1-lsopropyl-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine;
1 -lsopropyl-4-[1 -(4-acetylphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
1 -lsopropyl-4-[1 -(4-propanoylphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;
or a pharmaceutically acceptable salt thereof.

22. A compound of formula (I) as defined in claim 1 which is
1-Isopropyl-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-piperazine;
1 -lsopropyl-4-[1 -(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane;

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition which comprises the compound of
formula (I) as defined in any one of claims 1 to 22 or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

24. A compound as defined in any one of claims 1 to 22 for use in therapy.

25. A compound as defined in any one of claims 1 to 22 for use in the
treatment of neurological diseases.

26. Use of a compound as defined in any one of claims 1 to 22 in the
manufacture of a medicament for the treatment of neurological diseases.

27. A method of treatment of neurological diseases which comprises administering to a host in need thereof an effective amount of a compound of formula (I) as defined in any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition for use in the treatment of neurological diseases which comprises the compound of formula (I) as defined in any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.

29. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:

(a) reacting a compound of formula (II)



(II)

or an optionally activated or protected derivative thereof, wherein R2, R4, m, n, p and q are as defined in claim 1 and R3a is as defined for R3 in claim 1 or a group convertible to R3, with a compound of formula R1-L1, wherein R1 is as defined in claim 1 and L1 represents a suitable leaving group, such as a halogen atom followed by a deprotection reaction as necessary; or (b) reacting a compound of formula (III)



(III)

wherein R1, R4, m and q are as defined in claim 1 and L2 represents OH or a suitable leaving group, such as a halogen atom, with a compound of formula (IV)



(iv)
wherein R2, n and p are as defined in claim 1 R3a is as defined for R3 in claim 1 or a group convertible to R3; or

(c) deprotecting a compound of formula (I) or converting groups which are protected; and optionally thereafter

(d) interconversion to other compounds of formula (I).