US 7,067,657 B2Granted

Thiazolopyrimidine derivatives and use thereof as antagonists of the CX3 CR1 receptor

AssigneeAstraZeneca AB

InventorsSverker Hanson, Gunnar Nordvall

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Abstract

Provided herein is a compound having the formula (Ia): wherein said compounds are useful for the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease and pain.

Claims1

Dependent claims

A compound selected from:

R)-2-[5-phenylmethylthio-7-(1-hydroxymethyl-3-methyl-butylamino)-thiazolo[4,5-d]pyrimidin-2-ylamino]acetamide;
(R)-2-[5-phenylmethylthio-2-(piperidin-4-ylamino)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-chlirophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-bromophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-bromophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-bromophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-iodophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,4-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,5-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,6-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3,4-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3,5-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(3-chloro-2-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(2-chloro-6-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(4-bromo-2-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(2-bromo-5-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,3-dichlorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-chloro-4,5-methylenedioxyphenylmethylthio)-thiazolo [4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-fluoro-3-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-fluoro-3-trifluoromethylphenylmethylthio)-thiazolo [4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-bromo-3-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-trifluoromethylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-trifluoromethylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-cyanophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-cyanophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-trifluoromethylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-cyanophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methyl-2-nitrophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1ol;
N-(2-amino-5-phenylmethylthio-thiazolo[4,5-d]pyrimidin-7-1-hydroxymethyl-cyclopentylamine;
(±)-2-[2-amino-5-(2,3-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino ]hexan-1-ol;
or a pharmaceutically acceptable salt, enantiomer or raccmate thereof.

36 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/472,992Filed 26 Mar 2002
Priority: SE 010108227 Mar 2001
Published: US 2004/0106628 A13 Jun 2004
Granted: 27 Jun 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61P 25/00
Drugs for disorders of the nervous system

Family

US 2004/0106628 A1Pre-grant publication · published 3 Jun 2004
US 7,067,657 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Provided herein is a compound having the formula (Ia): wherein said compounds are useful for the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease and pain.

A compound selected from:

R)-2-[5-phenylmethylthio-7-(1-hydroxymethyl-3-methyl-butylamino)-thiazolo[4,5-d]pyrimidin-2-ylamino]acetamide;
(R)-2-[5-phenylmethylthio-2-(piperidin-4-ylamino)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-chlirophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-bromophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-bromophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-bromophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-iodophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,4-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,5-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,6-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3,4-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3,5-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(3-chloro-2-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(2-chloro-6-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(4-bromo-2-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[-2-amino-5-(2-bromo-5-fluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2,3-dichlorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-chloro-4,5-methylenedioxyphenylmethylthio)-thiazolo [4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-fluoro-3-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-fluoro-3-trifluoromethylphenylmethylthio)-thiazolo [4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-bromo-3-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methoxyphenylmethylthio)thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-trifluoromethylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-trifluoromethylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-cyanophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(4-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-cyanophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(2-methylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-trifluoromethylphenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-cyanophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1-ol;
(R)-2-[2-amino-5-(3-methyl-2-nitrophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino]-4-methyl-pentan-1ol;
N-(2-amino-5-phenylmethylthio-thiazolo[4,5-d]pyrimidin-7-1-hydroxymethyl-cyclopentylamine;
(±)-2-[2-amino-5-(2,3-difluorophenylmethylthio)-thiazolo[4,5-d]pyrimidin-7-ylamino ]hexan-1-ol;
or a pharmaceutically acceptable salt, enantiomer or raccmate thereof.

36 more elements

Facts

Application

10/472,992Filed 26 Mar 2002

Priority

SE 010108227 Mar 2001

Published

US 2004/0106628 A13 Jun 2004

Granted

27 Jun 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61P 25/00
Drugs for disorders of the nervous system