US 7,067,519 B2Granted

7,8,9,10-tetrahydro-6H-azepino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro-2H-pyrrolo[2,1-b]-quinazolinone derivatives

OwnerHamed Aissaoui, Martine Clozel +4inventors

InventorsHamed Aissaoui, Martine Clozel, Walter Fischli, Ralf Koberstein, Thierry Sifferlen, Thomas Weller

Life of this patent

Estimating the term…

Abstract

The invention relates to novel 7,8,9,10-tetrahydro-6H-azepino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro-2H-pyrrolo[2,1-b]-quinazolinone derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.

Claims8

Dependent claims

Compounds of the general formula (I)

wherein:
X is O or S;
n is the integer 1, 2, or 3;
m is the integer 0, 1, 2, 3;
R1, R2, R3, R4 independently represent cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R8CO—, NR9R10CO—, R9R10N—, R8OOC—, R8SO2NH—, R11—CO—NH—;
or
R5 represents aryl, aralkyl, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl;
R6 represents hydrogen, lower alkyl, trifluoromethyl, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—CO2H, —(CH2)m—CO2-lower alkyl, —(CH2)mCONH2, —(CH2)m—CONH-lower alkyl, or —(CH2)m—CON-(lower alkyl)2, or —(CH2)m—N-(lower alkyl)2;
R7 represents aryl, aralkyl, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl;
R8 represents lower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
R9 and
R10 independently represent hydrogen, alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
R11 represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R9R10N— or R8O—;
and
optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.

12 more elements

A compound selected from the

group consisting of 1-(9-Oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
3-Biphenyl-2-yl-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
3-(2-Ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
3-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
3-Naphthalen-1-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
3-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
3-Biphenyl-2-yl-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-phenyl-ethyl)-urea;
1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-propyl-phenyl)-urea;
1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;
1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea;
1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
3-Biphenyl-2-yl-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
3-(2-Ethyl-phenyl)-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
1-(6-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;
1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea;
1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;
1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
3-Biphenyl-2-yl-1-(7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;
1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
3-Biphenyl-2-yl-1-(8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;
1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1-(1-phenyl-ethyl)-urea;
3-Biphenyl-2-yl-1-(6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;
1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;
3-Biphenyl-2-yl-1-butyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;
1-Butyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-n-propyl-phenyl)-urea;
1-Benzyl-3-biphenyl-2-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;
1-Benzyl-3-(2-ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;
1-Benzyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-n-propyl-phenyl)-urea;
3-Biphenyl-2-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
3-(2-Ethyl-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
3-(2-Ethoxy-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
3-Naphthalen-1-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
3-Biphenyl-2-yl-1-(2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;
1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethoxy-phenyl)-1-(1-phenyl-ethyl)-urea;
3-Biphenyl-2-yl-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
1-(3-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
3-(2-Ethoxy-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
3-(2-Ethyl-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
3-(2-Ethyl-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
3-(2-Ethoxy-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
3-Biphenyl-2-yl-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;
1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-naphthalen-1-yl-1-(1-phenyl-ethyl)-urea;
1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
3-Biphenyl-2-yl-1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1((S)-1-phenyl-ethyl)-urea;
1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
1-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;
1-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;
3-(2-Ethyl-phenyl)-1-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea;
and
3-Biphenyl-1-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea.

61 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/489,350Filed 8 Jul 2003
Priority: WO PCT/EP02/076089 Jul 2002
Published: US 2005/0009852 A113 Jan 2005
Granted: 27 Jun 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 471/04
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 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

US 2005/0009852 A1Pre-grant publication · published 13 Jan 2005
US 7,067,519 B2This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

Facts

Application

10/489,350Filed 8 Jul 2003

Priority

WO PCT/EP02/076089 Jul 2002

Published

US 2005/0009852 A113 Jan 2005

Granted

27 Jun 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 471/04
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 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 9/00
Drugs for disorders of the cardiovascular system