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WO2001085730A1 - Pyrido' 1,2-alpha pyrazine and piperidine derivatives as ligands for the neuropeptide y y5 receptor - Google Patents

Pyrido' 1,2-alpha pyrazine and piperidine derivatives as ligands for the neuropeptide y y5 receptor Download PDF

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Publication number
WO2001085730A1
WO2001085730A1 PCT/GB2001/001961 GB0101961W WO0185730A1 WO 2001085730 A1 WO2001085730 A1 WO 2001085730A1 GB 0101961 W GB0101961 W GB 0101961W WO 0185730 A1 WO0185730 A1 WO 0185730A1
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PCT/GB2001/001961
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Michael Howard Block
Paul Schofield
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU52405/01A priority Critical patent/AU5240501A/en
Publication of WO2001085730A1 publication Critical patent/WO2001085730A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Rj and R 2 are selected from the following combinations: Rj is R 4 — and R 2 is — SO 2 — R 5 , Rj is R 4 — SO 2 — and R 2 is — R 5 , Rj is R 5 — and R 2 is — SO 2 — R 4 ; and
  • Ri is R 5 — SO 2 — and R 2 is — R 4 ;
  • A is selected from Group la, Group lb, Group lc or Group Id
  • B is a direct bond, methylene or carbonyl
  • R 3 is hydrogen, C M alkyl or phenylC M alkyl
  • R 4 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 C M alkyl, wherein the C M alkyl is optionally substituted by 3 substituents independently selected from halo and C M alkoxy; Rs is C M alkyl, aryl, arylC ⁇ alkyl, N-C alkylamino or N,N-di-C M aUtylamino, wherein any aryl is optionally substituted by one or more substituents independently selected from halo, alkyl, cyano, C M alkoxy, and amino; and p is 1 or 2; q is 1 or 2; and n is 1 or 2; or a pharmaceutical
  • R 4 is quinolinyl, quinazolinyl or 1,2,3,4-tetrahydronaphthyl, optionally substituted by one or more substituents independently selected from halo, amino or C,. 4 alkyl, wherein the C ⁇ court 4 alkyl is optionally substituted by 3 substituents independently selected from halo and or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
  • R 4 is optionally substituted by one or more substituents independently selected from chloro, fluoro, methyl, ethyl, trifluoromethyl or amino or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
  • R 5 is naphthyl, optionally substituted by one or more substituents independently selected from halo, alkyl, cyano, C M alkoxy, C M alkanoyl and amino or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
  • a compound of formula (I) according to any one of claims 1 -9 wherein R 3 is hydrogen, benzyl or C alkyl or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.
  • a compound of formula (I) selected from: 25 trans-l-ethyl-2-(naphth-l-ylsulphonylaminomethyl)-5-[(2-methylquinolin-4- yl)aminomethyl]piperidine; trans-2-(naphth-l-ylsulphonyl)-7-[(2-methyl-7-chloroquinolin-4-yl)aminomethyl]octahydro-
  • R —.
  • a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt, pro-drag or solvate thereof, according to any one of claims 1-12, in association with a pharmaceutically-acceptable diluent or carrier.
  • a method of treatment, in a warm-blooded animal, of disorders mediated by the 20 neuropeptide Y5 receptor comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drag or solvate thereof, according to any one of claims 1-12.
  • a pharmaceutical composition comprising a compound of formula (I), or a
  • a method of treatment, in a warm-blooded animal, of eating disorders comprising administering a therapeutically effective amount of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drag or solvate thereof, according to any one of claims 1-12.
  • a pharmaceutical composition comprising a compound of formula (I), or a
  • disorders are obesity and related disorders, bulimia or anorexia, wherein the related disorders are diabetes dyshpidaemia, hypertension and sleep disturbances.
  • a method of promoting weight loss, in a warm-blooded animal comprising administering a therapeutically effective amount of a compound of formula (I) or
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt, pro-drag 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of formula (I) R1—A—R2 wherein R1 and R2 are selected from the following combinations: R1 is R4 —and R2 is —SO2 —R5, R1 is R4 —SO2— and R2 is—R5, R1 is R5— and R2 is—SO2—R4; and R1 is R5—SO2—and R2 is—R4; A is selected from Group 1a, Group 1b, Group 1c or Group 1d and B, R3, R4, R5, 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.

Description

Claims
A compound of formula (I):
R— A— R2 formula (I) wherein:
Rj and R2 are selected from the following combinations: Rj is R4 — and R2 is — SO2 — R5, Rj is R4 — SO2 — and R2 is — R5, Rj is R5— and R2 is — SO2— R4; and
Ri is R5 — SO2 — and R2 is — R4; A is selected from Group la, Group lb, Group lc or Group Id
Figure imgf000052_0001
Group la Group lb
Figure imgf000052_0002
Group lc Group Id
B is a direct bond, methylene or carbonyl; R3 is hydrogen, CMalkyl or phenylCMalkyl;
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 CMalkyl, wherein the CMalkyl is optionally substituted by 3 substituents independently selected from halo and CMalkoxy; Rs is CMalkyl, aryl, arylC^alkyl, N-C alkylamino or N,N-di-CMaUtylamino, wherein any aryl is optionally substituted by one or more substituents independently selected from halo, alkyl, cyano, CMalkoxy,
Figure imgf000052_0003
and amino; and p is 1 or 2; q is 1 or 2; and n is 1 or 2; or a pharmaceutically-acceptable salt, pro-drag 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 lc or Group Id or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
4. A compound of formula (I) according to any one of claims 1-3 wherein Rλ is R4- and R2 is -SO2-R5 or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
5. A compound of formula (I) 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 Cι„4alkyl is optionally substituted by 3 substituents independently selected from halo and
Figure imgf000053_0001
or a pharmaceutically-acceptable salt, pro-drag 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-drag or solvate thereof.
7. A compound of formula (I) 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-drag 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-drag or solvate thereof. 9. A compound of formula (I) according to any one of claims 1-8 wherein R5 is naphthyl, optionally substituted by one or more substituents independently selected from halo, alkyl, cyano, CMalkoxy, CMalkanoyl and amino or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
5
10. A compound of formula (I) according to any one of claims 1 -9 wherein R3 is hydrogen, benzyl or C alkyl or a pharmaceutically-acceptable salt, pro-drug or solvate thereof.
10 11. A compound of formula (I) selected from: trans-2-(naphth-l-ylsulphonyl)-7-[(4-aminoquinazolin-2-yl)aminomethyl]octahydro-2H- pyrido[l ,2---]pyrazine; trans-l-benzyl-2-(naphth-l-ylsulphonylaminomethyl)-5-[(2-methylquinolin-4- yl)aminomethyl]piperidine; 15 trans -2-phenylsulphonylaminomethyl-5-[(2-methylquinolin-4-yl)aminomethyl]piperidine; trans-2-(naphth-l-ylsulphonyl)-7-[(l,2,3,4-tetrahydronaphth-2- yl)methylaminomethyl]octahydro-2H-pyrido[l,2-α]pyrazine; trans-2-(naphth-l-ylsulphonyl)-7-[(4-aminoquinazolin-2-yl)aminomethyl]octahydro-2H- pyrido[l,2-Ω]pyrazine; and 20 trans-l-benzyl-2-(phenylsulphonylaminomethyl)-5-[(4-aminoquinazolin-2- yl)aminomethyl]piperidine; or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
12. A compound of formula (I) selected from: 25 trans-l-ethyl-2-(naphth-l-ylsulphonylaminomethyl)-5-[(2-methylquinolin-4- yl)aminomethyl]piperidine; trans-2-(naphth-l-ylsulphonyl)-7-[(2-methyl-7-chloroquinolin-4-yl)aminomethyl]octahydro-
2H-pyrido[l ,2-α]pyrazine; trflns-2-(naphth-l-ylsulphonyl)-7-[(2-methyl-4-fluoroquinolin-4-yl)aminomethyl]octahydro- 30 2H-pyrido[l,2-a]pyrazine; trans-2-(naphth-l-ylsulphonyl)-7-[(2-methylquinolin-4-yl)aminomethyl]octahydro-2H- pyrido[l,2-α]pyrazine; and trans-l-ethyl-2-phenylsulphonylaminomethyl-5-[(2-methylquinolin-4- yl)aminomethyl]piperidine; or a pharmaceutically-acceptable salt, pro-drag or solvate thereof.
13 A process for preparing a compound of formula (I) wherein R R2, R3, R4, R5, A, B, n, p and q are, unless otherwise specified as defined in claim 1 which comprises:
(a) reacting an amine of fonnula (II), wherein B is a direct bond and R2 is selected from
Figure imgf000055_0001
H— A— R2 formula (II) with a compound of the formula R^ wherein L is a displaceable group;
(b) reacting an amine of formula (III) wherein Rj is selected from R4 — or R5 —
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 Id and B is carbonyl, reacting an amine of formula (IV)
HjN-A'-SO^ — R2 formula (IV) wherein A is selected from Group lc' or Group Id'
Figure imgf000055_0002
,
Group lc' Group Id' with an acid of formula (V)
Figure imgf000056_0001
formula (V) or an activated derivative thereof;
(e) for a compound of formula (I) wherein A is Group lc or Group Id and B is methylene, 5 reacting a compound of formula (I) wherein A is Group lc or Group Id 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; 10 (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 15. A pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt, pro-drag 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 20 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-drag 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 25 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
30 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.
5 19. A method of treatment, in a warm-blooded animal, of eating disorders, comprising administering a therapeutically effective amount of a compound of formula (I) or pharmaceutically-acceptable salt, pro-drag or solvate thereof, according to any one of claims 1-12.
10 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
15 pharmaceutically-acceptable salt, pro-drag or solvate thereof, according to any one of claims l-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
20 disorders are obesity and related disorders, bulimia or anorexia, wherein the related disorders are diabetes dyshpidaemia, 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
25 pharmaceutically-acceptable salt, pro-drag 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-drag or solvate thereof, according to any one of claims 1-12, in the manufacture of a medicament for
30 promoting weight loss in a warm-blooded animal. 25. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt, pro-drag 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.
PCT/GB2001/001961 2000-05-09 2001-05-04 Pyrido' 1,2-alpha pyrazine and piperidine derivatives as ligands for the neuropeptide y y5 receptor WO2001085730A1 (en)

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