US 6,306,870 B1Granted

N-cinnamoyl derivatives of beta-carboline

AssigneeICOS Corporation

InventorAgnes Bombrun

Life of this patent

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Abstract

Carboline derivatives of formula (I), are potent and selective inhibitors of cyclic guanosine 3′,5′-monophoshate specific phosphodiesterase (cGMP specific PDE) and have utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardivascular disorders.

Claims22

Dependent claims

A compound of formula (I)

wherein
R0 represents -hydrogen or -halogen;
R1 is selected from the group consisting of:
-hydrogen,
—NO2,
-trifluoromethyl,
-trifluoromethoxy,
-halogen,
-cyano,
a 5- or 6-membered heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl, furyl, tetrazolyl, imidazolyl, piperidinyl, and piperizinyl (optionally substituted by —C(═O)ORa or C1-4alkyl),
—C1-6alkyl optionally substituted by ORa,
—C1-3alkoxy,
—C(═O)Ra,
—O—C (═O)Ra,
—C(═O)ORa,
—C1-4alkyleneC(═O)ORa,
—O—C1-4alkylene-C(═O)ORa,
—C1-4alkylene-O—C1-4alkylene-C(═O)ORa,
—C(═O)NRaCO2Rc,
—C(═O)C1-4alkyleneHet, wherein Het represents 5- or 6-membered heterocyclic group as defined above,
—C1-4alkyleneNRaRb,
—C2-6alkenyleneNRaRb,
—C(═O)NRaRb,
—C(═O)NRaRc,
—C(═O)NRaC1-4alkyleneORb,
—C(═O)NRaC1-4alkyleneHet, wherein Het represents a 5- or 6-membered heterocyclic group as defined above,
—ORa,
—OC2-4alkyleneNRaRb,
—OC1-4alkylene-CH(ORa)CH2NRaRb,
—O—C1-4alkyleneHet, wherein Het represents a 5- or 6-membered heterocyclic group as defined above,
—O—C2-4alkylene-ORa,
—O—C2-4alkylene-NRa—C(═O)—ORb,
—NRaRb,
—NRaC1-4alkyleneNRaRb,
—NRaC(═O)Rb,
—NRaC(═O)NRaRb,
—N(SO2C1-4alkyl)2,
—NRa(SO2C1-4alkyl),
—SO2NRaRb, and
—OSO2trifluoromethyl;
R2 is selected from the group consisting of:
-hydrogen,
-halogen,
—ORa,
—C1-6alkyl,
—NO2, and
—NRaRb,
or R1 and R2, together form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteroatom;
a first R3 is selected from the group consisting of:
-hydrogen,
-halogen,
—NO2,
-trifluoromethoxy,
—C1-6alkyl, and
—C(═O)ORa,
and a second R3 and R4 together, and with the phenyl ring to which they are attached, form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteroatom,
Ra and Rb, which may be the same or different, are independently selected from hydrogen and C1-6alkyl;
Rc represents phenyl or C4-6cycloalkyl, which phenyl or C4-6cycloalkyl can be optionally substituted by one or more halogen atoms, one or more —C(═O)ORa or one or more —ORa;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates thereof.

58 more elements

A compound selected from the group consisting of

(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropene-1-one,
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-nitrophenyl)propene-1-one,
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-trifluoromethylphenyl)propene-1-one,
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-methoxyphenyl)propene-1-one,
(E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one,
(E)-N-[4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]acetamide
(E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropene-1-one,
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-formylphenyl)propene-1-one,
(E)-N-[4-[3-Oxo-3-(1-(4-nitrophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]acetamide
(E)-1-[1-(4-Nitrophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-1-[1-(4-Trifluoromethoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-1-[1-(4-Methylphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]benzoic acid, methyl ester,
(E)-1-[1-(2-Chlorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(3,4-methylenedioxyphenyl)-propene-1-one,
(E)-1-[1-(4-Chlorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-N-(2-Morpholin-4-ylethyl)-4-[3-oxo-3-(1-(3,4-methylene-dioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide,
(E)-N-(4-Piperidine-4-carboxylic acid, ethyl ester)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide,
(E)-N-(4-Piperidine-4-carboxylic acid)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide,
(E)-N-(2-Piperazin-1-ylethyl)-3-[3-oxo-3-(1-(3,4-methylene-dioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide,
(E)-N-(1-Ethylpyrrolidin-2-yl-methyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide,
(E)-1-[1-(4-Isopropylphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one,
(E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3(3-nitrophenyl)propene-1-one,
(E)-1-[1-(4-Methylphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one,
(E)-1-[1-(Indan-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl]propenyl]benzoic acid, methyl ester,
(E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl]propenyl]benzoic acid,
(E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl]-3-phenylpropene-1-one,
(E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl]-3-[4-pyrrolidin-1-ylphenyl]-propene-1-one,
(E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl]-3-[4-imidazol-1-ylphenyl]-propene-1-one,
(E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one,
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(1-(S)-methylpyrrolidin-2-yl-methoxy)phenyl)propene-1-one,
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-(4-methylpyperazin-1-yl)-phenyl)propene-1-one,
(E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(1-(S)-methylpyrrolidin-2-yl-methoxy)-phenyl)propene-1-one,
(E)-4-[3-Oxo-3-[1-(3,4-fluorophenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl]propenyl]benzoic acid, methyl ester,
(E)-4-[3-Oxo-3-[1-(3,4-difluorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic acid,
(E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one,
(E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl)]-3-(3-nitrophenyl)propene-1-one,
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one,
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(4-methylpiperazin-1-yl)phenylpropene-1-one,
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-piperidin-1-ylethoxy)phenyl)propene-1-one,
(E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-β-carbolin-2-yl)-3-(4-(2-piperidin-1-ylethoxy)phenyl]propene-1-one,
and pharmaceutically acceptable salts and solvates thereof.

40 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/592,514Filed 12 Jun 2000 · continuation in part
Priority: GB 960977710 May 1996
Granted: 23 Oct 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D
Heterocyclic compounds

Family

PCT/EP96/02277Parent of this continuation-in-part · filed 5 May 1997
Application09/155,811Parent of this continuation-in-part
US 6,117,881 AParent of this continuation-in-part
US 6,306,870 B1This patent

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

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Abstract

A compound of formula (I)

wherein
R0 represents -hydrogen or -halogen;
R1 is selected from the group consisting of:
-hydrogen,
—NO2,
-trifluoromethyl,
-trifluoromethoxy,
-halogen,
-cyano,
a 5- or 6-membered heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl, furyl, tetrazolyl, imidazolyl, piperidinyl, and piperizinyl (optionally substituted by —C(═O)ORa or C1-4alkyl),
—C1-6alkyl optionally substituted by ORa,
—C1-3alkoxy,
—C(═O)Ra,
—O—C (═O)Ra,
—C(═O)ORa,
—C1-4alkyleneC(═O)ORa,
—O—C1-4alkylene-C(═O)ORa,
—C1-4alkylene-O—C1-4alkylene-C(═O)ORa,
—C(═O)NRaCO2Rc,
—C(═O)C1-4alkyleneHet, wherein Het represents 5- or 6-membered heterocyclic group as defined above,
—C1-4alkyleneNRaRb,
—C2-6alkenyleneNRaRb,
—C(═O)NRaRb,
—C(═O)NRaRc,
—C(═O)NRaC1-4alkyleneORb,
—C(═O)NRaC1-4alkyleneHet, wherein Het represents a 5- or 6-membered heterocyclic group as defined above,
—ORa,
—OC2-4alkyleneNRaRb,
—OC1-4alkylene-CH(ORa)CH2NRaRb,
—O—C1-4alkyleneHet, wherein Het represents a 5- or 6-membered heterocyclic group as defined above,
—O—C2-4alkylene-ORa,
—O—C2-4alkylene-NRa—C(═O)—ORb,
—NRaRb,
—NRaC1-4alkyleneNRaRb,
—NRaC(═O)Rb,
—NRaC(═O)NRaRb,
—N(SO2C1-4alkyl)2,
—NRa(SO2C1-4alkyl),
—SO2NRaRb, and
—OSO2trifluoromethyl;
R2 is selected from the group consisting of:
-hydrogen,
-halogen,
—ORa,
—C1-6alkyl,
—NO2, and
—NRaRb,
or R1 and R2, together form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteroatom;
a first R3 is selected from the group consisting of:
-hydrogen,
-halogen,
—NO2,
-trifluoromethoxy,
—C1-6alkyl, and
—C(═O)ORa,
and a second R3 and R4 together, and with the phenyl ring to which they are attached, form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteroatom,
Ra and Rb, which may be the same or different, are independently selected from hydrogen and C1-6alkyl;
Rc represents phenyl or C4-6cycloalkyl, which phenyl or C4-6cycloalkyl can be optionally substituted by one or more halogen atoms, one or more —C(═O)ORa or one or more —ORa;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates thereof.

58 more elements

Facts

Application

09/592,514Filed 12 Jun 2000 · continuation in part

Priority

GB 960977710 May 1996

Granted

23 Oct 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D
Heterocyclic compounds