US 7,419,975 B2Granted

Organic compounds

AssigneeNovartis AG

InventorsMark Gabriel Palermo, Sushil Kumar Sharma, Christopher Straub, Run-Ming Wang, Leigh Scott Zawel, Yanlin Zhang, Zhuoliang Chen, Yaping Wang, Fan Yang, Wojciech Wrona, Gang Liu, Mark G. Charest, Feng He

Life of this patent

Estimating the term…

Abstract

Novel compounds that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of the formula I

Claims10

Dependent claims

A compound according to formula I

wherein
R1 is H;
C1-C4 alkyl;
C1-C4 alkenyl;
C1-C4 alkynyl or C3-C10cycloalkyl which are unsubstituted or substituted;
R2 is H;
C1-C4 alkyl;
C1-C4 alkenyl;
C1-C4 alkynyl or C3-C10cycloalkyl which are unsubstituted or substituted;
R3 is H;
—CF3;
—C2F5;
C1-C4 alkyl;
C1-C4 alkenyl;
C1-C4 alkynyl;
—CH2-Z;
Z is H;
—OH;
F;
Cl;
—CH3;
—CF3;
—CH2Cl;
—CH2F or —CH2OH;
R4 is C1-C16 straight or branched alkyl;
C1-C16 alkenyl;
C1-C16 alkynyl;
or —C3-C10cycloalkyl;
—(CH2)1-6-Z1;
and —(CH2)0-6-het;
wherein cycloalkyl is unsubstituted or substituted;
Z1 is —N(R8)—C(O)—C1-C10alkyl;
—N(R8)—C(O)—(CH2)1-6—C3-C7cycloalkyl;
—N(R8)—C(O)—(CH2)0-6-phenyl;
—N(R8)—C(O)—(CH2)1-6-het;
—C(O)—N(R9)(R10);
—C(O)—O—C1-C10alkyl;
—C(O)—O—(CH2)1-6—C3-C7cycloalkyl;
—C(O)—O—(CH2)0-6-phenyl;
—C(O)—O—(CH2)1-6-het;
—O—C(O)—C1-C10alkyl;
—O—C(O)—(CH2)1-6—C3-C7cycloalkyl;
—O—C(O)—(CH2)0-6-phenyl;
—O—C(O)—(CH2)1-6-het;
wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;
het is a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom;
R8 is H;
—CH3;
—CF3;
—CH2OH or —CH2Cl;
R9 and R10 are each independently H;
C1-C4alkyl;
C3-C7cycloalkyl;
—(CH2)1-6—C3-C7cycloalkyl;
—(CH2)0-6-phenyl;
wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R9 and R10 together with the nitrogen form het;
R5 is H;
C1-C10-alkyl;
aryl;
phenyl;
C3-C7cycloalkyl;
—(CH2)1-6—C3-C7cycloalkyl;
—C1-C10alkyl-aryl;
—(CH2)0-6—C3-C7cycloalkyl-(CH2)0-6-phenyl;
—(CH2)0-4CH—((CH2)1-4-phenyl)2;
—(CH2)0-6—CH(phenyl)2;
-indanyl;
—C(O)—C1-C10alkyl;
—C(O)—(CH2)1-6—C3-C7-cycloalkyl;
—C(O)—(CH2)0-6-phenyl;
—(CH2)0-6—C(O)-phenyl;
—(CH2)0-6-het;
—C(O)—(CH2)1-6-het;
or R5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted;
U is a bicyclic saturated or unsaturated ring system, consisting of all carbon skeleton or with one or more heteroatoms such as O, N, S but preferably as shown in structure III:
wherein each of the ring carbons is unsubstituted, and
m is 0-3;
n=0-5;
X or N;
W is N;
V is O, F2, Cl2, Br2, I2, S, YH, H2, NH, or C1-C4 alkyl;
or pharmaceutically acceptable salts thereof.

79 more elements

A compound selected from:

N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-acetamide;
2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;
2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;
2-Methylamino-N-[2-methyl-1-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carbonyl)-propyl]-propionamide;
2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-butyramide;
2-Methylamino-N-[2-methyl-1-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-butyramide;
2-Methylamino-N-[2-methyl-1-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carbonyl)-propyl]-butyramide;
N-[1-Cyclohexyl-2-oxo-2-(7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide;
2-Methylamino-N-{2-methyl-1-[5-(3-methyl-hexa-3,5-dienyl)-6-oxo-hexahydro-pyrrolo[3,4-b]pyrrole-1-carbonyl]-propyl}-propionamide;
2-Methylamino-N-[2-methyl-1-(3-methyl-7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;
2-Methylamino-N-[2-methyl-1-(3-methyl-7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;
N-[1-(4-Benzyloxy-7-oxo-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-2-methyl-propyl]-2-methylamino-propionamide;
N-[1-Cyclohexyl-2-oxo-2-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-butyramide;
N-[1-Cyclohexyl-2-oxo-2-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-butyramide;
N-[1-Cyclohexyl-2-oxo-2-(7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-propionamide;
2-Methylamino-N-[2-methyl-1-(8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carbonyl)-propyl]-butyramide;
N-[(S)-1-(S)-Cyclohexyl-2-oxo-2-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-acetamide;
(S)-N-[(S)-1-(S)-Cyclohexyl-2-oxo-2-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-butyramide;
(S)-2-Methylamino-N-[(S)-2-methyl-1-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-propionamide;
(S)-N-[(S)-2,2-Dimethyl-1-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-2-methylamino-propionamide;
(S)-2-Methylamino-N-[(S)-2-methyl-1-((R)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-butyramide;
(S)-N-[(S)-2,2-Dimethyl-1-((3aR,7aS)-6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine-1-carbonyl)-propyl]-2-methylamino-propionamide;
(S)-N-((S)-1-Cyclohexyl-2-oxo-2-{(3aR,7aS)-6-[2-(2-trifluoromethoxy-phenyl)-ethyl]-octahydro-pyrrolo[2,3-c]pyridin-1-yl}-ethyl)-2-methylamino-propionamide;
(S)-N-((S)-1-Cyclohexyl-2-oxo-2-{(3aR,7aS)-6-[2-(3-trifluoromethoxy-phenyl)-ethyl]-octahydro-pyrrolo[2,3-c]pyridin-1-yl}-ethyl)-2-methylamino-propionamide;
(S)-N-[(S)-1-Cyclohexyl-2-oxo-2-((3aR,6aR)-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;
(S)-N-[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;
(S)-N-[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-propionamide;
(S)-N-[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;
(S)-N-[(R)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-butyramide;
(S)-N-[(S)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-propionamide;
(S)-N-[(R)-1-Cyclohexyl-2-oxo-2-((3aS,6aS)-6-oxo-5-phenethyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-ethyl]-2-methylamino-propionamide;
(S)-N-[(S)-1-(R)-Cyclohexyl-2-oxo-2-((S)-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-propionamide;
(S)-N-[(S)-1-(S)-Cyclohexyl-2-oxo-2-((R)-8-oxo-7-phenethyl-octahydro-pyrrolo[2,3-c]azepin-1-yl)-ethyl]-2-methylamino-butyramide;
and pharmaceutically acceptable salts thereof.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/099,941Filed 6 Apr 2005 · us provisional application
Priority: 7 Apr 2004
Published: US 2005/0234042 A120 Oct 2005
Granted: 2 Sep 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 207/16
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 5/26
Of the sex hormones: androgens
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application60/560,186Us provisional application · filed 7 Apr 2004
US 2005/0234042 A1Pre-grant publication · published 20 Oct 2005
US 7,419,975 B2This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

A compound according to formula I

wherein
R1 is H;
C1-C4 alkyl;
C1-C4 alkenyl;
C1-C4 alkynyl or C3-C10cycloalkyl which are unsubstituted or substituted;
R2 is H;
C1-C4 alkyl;
C1-C4 alkenyl;
C1-C4 alkynyl or C3-C10cycloalkyl which are unsubstituted or substituted;
R3 is H;
—CF3;
—C2F5;
C1-C4 alkyl;
C1-C4 alkenyl;
C1-C4 alkynyl;
—CH2-Z;
Z is H;
—OH;
F;
Cl;
—CH3;
—CF3;
—CH2Cl;
—CH2F or —CH2OH;
R4 is C1-C16 straight or branched alkyl;
C1-C16 alkenyl;
C1-C16 alkynyl;
or —C3-C10cycloalkyl;
—(CH2)1-6-Z1;
and —(CH2)0-6-het;
wherein cycloalkyl is unsubstituted or substituted;
Z1 is —N(R8)—C(O)—C1-C10alkyl;
—N(R8)—C(O)—(CH2)1-6—C3-C7cycloalkyl;
—N(R8)—C(O)—(CH2)0-6-phenyl;
—N(R8)—C(O)—(CH2)1-6-het;
—C(O)—N(R9)(R10);
—C(O)—O—C1-C10alkyl;
—C(O)—O—(CH2)1-6—C3-C7cycloalkyl;
—C(O)—O—(CH2)0-6-phenyl;
—C(O)—O—(CH2)1-6-het;
—O—C(O)—C1-C10alkyl;
—O—C(O)—(CH2)1-6—C3-C7cycloalkyl;
—O—C(O)—(CH2)0-6-phenyl;
—O—C(O)—(CH2)1-6-het;
wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;
het is a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom;
R8 is H;
—CH3;
—CF3;
—CH2OH or —CH2Cl;
R9 and R10 are each independently H;
C1-C4alkyl;
C3-C7cycloalkyl;
—(CH2)1-6—C3-C7cycloalkyl;
—(CH2)0-6-phenyl;
wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R9 and R10 together with the nitrogen form het;
R5 is H;
C1-C10-alkyl;
aryl;
phenyl;
C3-C7cycloalkyl;
—(CH2)1-6—C3-C7cycloalkyl;
—C1-C10alkyl-aryl;
—(CH2)0-6—C3-C7cycloalkyl-(CH2)0-6-phenyl;
—(CH2)0-4CH—((CH2)1-4-phenyl)2;
—(CH2)0-6—CH(phenyl)2;
-indanyl;
—C(O)—C1-C10alkyl;
—C(O)—(CH2)1-6—C3-C7-cycloalkyl;
—C(O)—(CH2)0-6-phenyl;
—(CH2)0-6—C(O)-phenyl;
—(CH2)0-6-het;
—C(O)—(CH2)1-6-het;
or R5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted;
U is a bicyclic saturated or unsaturated ring system, consisting of all carbon skeleton or with one or more heteroatoms such as O, N, S but preferably as shown in structure III:
wherein each of the ring carbons is unsubstituted, and
m is 0-3;
n=0-5;
X or N;
W is N;
V is O, F2, Cl2, Br2, I2, S, YH, H2, NH, or C1-C4 alkyl;
or pharmaceutically acceptable salts thereof.

79 more elements

Facts

Application

11/099,941Filed 6 Apr 2005 · us provisional application

Priority

7 Apr 2004

Published

US 2005/0234042 A120 Oct 2005

Granted

2 Sep 2008

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 207/16
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 5/26
Of the sex hormones: androgens
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…