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Title:
PYRIDO' 1,2-ALPHA PYRAZINE AND PIPERIDINE DERIVATIVES AS LIGANDS FOR THE NEUROPEPTIDE Y Y5 RECEPTOR
Document Type and Number:
WIPO Patent Application WO/2001/085730
Kind Code:
A1
Abstract:
Compounds of formula (I) R¿1?—A—R¿2? wherein R¿1? and R¿2? are selected from the following combinations: R¿1? is R¿4? —and R¿2? is —SO¿2? —R¿5?, R¿1? is R¿4? —SO¿2?— and R¿2? is—R¿5?, R¿1? is R¿5?— and R¿2? is—SO¿2?—R¿4?; and R¿1? is R¿5?—SO¿2?—and R¿2? is—R¿4?; A is selected from Group 1a, Group 1b, Group 1c or Group 1d and B, R¿3?, R¿4?, R¿5?, p, q and n are as described within, and their pharmaceutically-acceptable salts, pro-drugs and solvates are described. Also described are processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by the neuropeptide Y5 receptor.

Inventors:
BLOCK MICHAEL HOWARD (GB)
SCHOFIELD PAUL (GB)
Application Number:
PCT/GB2001/001961
Publication Date:
November 15, 2001
Filing Date:
May 04, 2001
Export Citation:
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Assignee:
ASTRAZENECA AB (SE)
ASTRAZENECA UK LTD (GB)
BLOCK MICHAEL HOWARD (GB)
SCHOFIELD PAUL (GB)
International Classes:
C07D401/12; C07D471/04; (IPC1-7): C07D471/04; A61K31/505; A61P3/04; C07D403/12
Domestic Patent References:
WO1999055667A11999-11-04
WO1997019682A11997-06-05
WO2001009120A12001-02-08
Foreign References:
EP0783503A11997-07-16
Attorney, Agent or Firm:
Bryant, Tracey (Global Intellectual Property P.O. Box 272, Mereside, Alderley Par, Macclesfield Cheshire SK10 4GR, GB)
Download PDF:
Description:
Claims 1. A compound of formula (I) : RlAR2 formula (I) wherein: R, and R2 are selected from the following combinations: R, is R4 - and R2 is -SO2-R5, R, is R4-SO2-and R2 is -R5, Ri is Rs-and RZ is-SOZ-R4 ; and Ri is R5-SO2- and R2 is -R4 ; A is selected from Group la, Group lb, Group le or Group Id Group la Group 1b Group lc Group ld B is a direct bond, methylene or carbonyl; R3 is hydrogen, Cl 4alkyl or phenylC1-4alkyl; R4 is a monocyclic nitrogen-containing heteroaryl substituted with an amino group, a bicyclic nitrogen-containing heteroaryl, naphthyl or a carbocyclic ring, wherein any monocyclic heteroaryl, the bicyclic heteroaryl, the naphthyl and carbocyclic ring are optionally substituted by one or more substituents independently selected from halo, amino or Cl 4alkyl, wherein the Cl 4alkyl is optionally substituted by 3 substituents independently selected from halo and Cl 4alkoxy ; R, is Cl 6alkyl, aryl, arylCI 2alkyl, N-CI 4alkylamino or N, N-di-CI 4alkylamino, wherein any aryl is optionally substituted by one or more substituents independently selected from halo, alkyl, cyano, C1-4alkoxy, C1-4alkanoyl and amino; and

pis 1 or 2; q is 1 or 2 ; and n is 1 or 2; or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

2. A compound of formula (I) according to claim 1 wherein A is Group la or Group lb or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

3. A compound of formula (I) according to claim 1 wherein A is Group le or Group ld or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

4. A compound of formula (I) according to any one of claims 1-3 wherein R, is R4-and R2 is-SO2-Rs or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

5. A compound of formula (1) according to any one of claims 1-4 wherein R4 is quinolinyl, quinazolinyl or 1,2,3,4-tetrahydronaphthyl, optionally substituted by one or more substituents independently selected from halo, amino or C, 4alkyl, wherein the Cl 4alkyl is optionally substituted by 3 substituents independently selected from halo and Cl 4alkoxy or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

6. A compound of formula (I) according to any one of claims 1-5 wherein R4 is optionally substituted by one or more substituents independently selected from chloro, fluoro, methyl, ethyl, trifluoromethyl or amino or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

7. A compound of formula (1) according to any one of claims 1-6 wherein p is 1, q is 1 and n is 1 or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

8. A compound of formula (I) according to any one of claims 1-7 wherein B is a direct bond or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

9. A compound of formula (I) according to any one of claims 1-8 wherein Rs is naphthyl, optionally substituted by one or more substituents independently selected from halo, alkyl, cyano, Cl 4alkoxy, Cl 4alkanoyl and amino or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

10. A compound of formula (I) according to any one of claims 1-9 wherein R3 is hydrogen, benzyl or Cl 4allçyl or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

11. A compound of formula (I) selected from : trans-2- (naphth-1-ylsulphonyl)-7- [ (4-aminoquinazolin-2-yl) aminometllyl] octahydro-2H- pyrido [1, 2-a] pyrazine; trans-1-benzyl-2-(naphth-1-ylsulphonylaminomethyl)-5-[(2-met hylquinolin-4- yl) aminomethyl] piperidine ; trans-2-phenylsulphonylaminomethyl-5-[(2-methylquinolin-4-yl ) aminomethyl] piperidine ; trans-2- (naphth-1-ylsulphonyl)-7- [ (1,2,3,4-tetrahydronaphth-2- yl) methylaminomethyl] octahydro-2H-pyrido [1, 2-a] pyrazine; trans-2- (naphth-1-ylsulphonyl)-7- [ (4-aminoquinazolin-2-yl) aminomethyl] octahydro-2H- pyrido [1, 2-a] pyrazine; and trans-1-benzyl-2- (phenylsulphonylaminomethyl)-5- [ (4-aminoquinazolin-2- yl) aminomethyl] piperidine; or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

12. A compound of formula (I) selected from: trans-1-ethyl-2-(naphth-1-ylsulphonylaminomethyl)-5-[(2-meth ylquiolin-4- yl) aminomethyl] piperidine; trans-2- (naphth-1-ylsulphonyl)-7- [ (2-methyl-7-chloroquinolin-4-yl) aminomethyl] octahydro- 2H-pyrido [1, 2-a] pyrazine ; trans-2-(naphth-1-ylsulphonyl)-7-[(2-methyl-4-fluoroquinolin -4-yl)aminomethyl] octahydro- 2H-pyrido [1,2-a] pyrazine; trans-2-(naphth-1-ylSulphonyl)-7-[(2-methylquinolin-4-yl) aminomethyl] octahydro-2H- pyrido [1, 2-a] pyrazine ; and

trans-1-ethyl-2-phenylsulphonylaminomethyl-5-[(2-methylquino lin-4- yl) aminomethyl] piperidine; or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.

13 A process for preparing a compound of formula (I) wherein Rl, R2, R3, R4, Rs A, B, n, p and q are, unless otherwise specified as defined in claim 1 which comprises: (a) reacting an amine of formula (II), wherein B is a direct bond and R2is selected from <BR> <BR> <BR> <BR> -SOz-R4 or-SOz-Rs<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> H-A-R2 formula (II) with a compound of the formula R, L wherein L is a displaceable group; (b) reacting an amine of formula (III) wherein R, is selected from R4or Rs R-A-H formula (III) with a sulphonyl compound of the formula LR2, wherein L is a displaceable group and R2 is selected from -SO2-R4 or -SO2-R5 ; (c) for a compound of formula (I) wherein A is Group la or Group lb and R3 is other than hydrogen, reacting a group of formula (I) wherein A is Group la or Group lb and R3 is hydrogen, with a group of the formula LR3 wherein L is a displaceable group; (d) for a compound of formula (I) wherein A is Group lc or Group ld and B is carbonyl, reacting an amine of formula (IV) H2N-A'-SO2-R2 formula (IV) wherein A'is selected from Group 1 c'or Group ld' Group1e' Group 1d' with an acid of formula (V)

formula (V) or an activated derivative thereof ; (e) for a compound of formula (I) wherein A is Group lc or Group ld and B is methylene, reacting a compound of formula (I) wherein A is Group lc or Group ld and B is carbonyl with a suitable reducing agent; And thereafter if necessary (i) converting a compound of formula (I) into another compound of formula (I) ; (ii) removing any protecting groups; (iii) forming a pharmaceutically-acceptable salt.

14. The use of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, as a medicament.

15. A pharmaceutical composition which comprises a compound of the formula (I) or a phannaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, in association with a pharmaceutically-acceptable diluent or carrier.

16. A method of treatment, in a warm-blooded animal, of disorders mediated by the neuropeptide Y5 receptor comprising administering to said wann-blooded animal a therapeutically effective amount of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12.

17. The use of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, in the manufacture of a medicament for the treatment of a disorder mediated by the neuropeptide Y5 receptor, in a warm blooded animal.

18. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims

1-12, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of a warm-blooded animal, in need of treatment, of disorders mediated by the neuropeptide Y5 receptor.

19. A method of treatment, in a wann-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12.

20. The use of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, in the manufacture of a medicament for the treatment of eating disorders in a warm-blooded animal.

21. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, in admixture with a pharmaceutically-acceptable diluent or carrier for the treatment of eating disorders in a warm-blooded animal.

22. The method, use or composition, according to claims 19-21 wherein the eating disorders are obesity and related disorders, bulimia or anorexia, wherein the related disorders are diabetes dyslipidaemia, hypertension and sleep disturbances.

23. A method of promoting weight loss, in a warm-blooded animal, comprising administering a therapeutically effective amount of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12.

24. The use of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, in the manufacture of a medicament for promoting weight loss in a warm-blooded animal.

25. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt, pro-drug or solvate thereof, according to any one of claims 1-12, in admixture with a pharmaceutically-acceptable diluent or carrier for promoting weight loss in a warm-blooded animal.