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US 6,281,194 B1Granted
Cycloalkyl inhibitors of protein farnesyltransferase
AssigneeWarner-Lambert Company
InventorsAnnette M. Doherty, James S. Kaltenbronn, Daniele M. Leonard, Dennis J. McNamara
Life of this patent
Estimating the term…
Abstract
Novel inhibitors of protein farnesyltransferase enzymes are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in controlling tissue proliferative diseases, including cancer, restenosis, atherosclerosis, psoriasis and endometriosis.
Claims20
A compound having the Formula I
- wherein
- RQ is
- x is 0 or 1;
- each R14 is independently hydrogen or C1-C6 alkyl;
- A is —CORa, —CO2Ra′, —CONHRa′, —CSRa,
- —C(S)ORa′, —C(S)NHRa′, —SO2Ra, or —CONRaRa″;
- Ra, Ra′, and Ra″ are independently C1-C6 alkyl, —(CR14R14)m-cycloalkyl, —(CR14R14)m-aryl, or —(CR14R14)m-heteroaryl;
- each m is independently 0 to 3;
- R1, R2, and R4 are independently hydrogen or C1-C6 alkyl;
- R3 is
- C1-C6 alkyl, C2-C6 alkenyl, —(CR14R14)m-naphthyl, —(CH2)vCO2R14, —(CH2)tNR14R14, —(CH2)v—O—C1-C6 alkyl, —(CH2)t—OH, —(CH2)t-morpholino,
- —(CR14R14)m-(phenyl substituted with Rb), or —(CR14R14)m-(heteroaryl substituted with Rb);
- t is 2 to 6;
- v is 1 to 6;
- Rb is —O-phenyl, —O-benzyl, halogen, C1-C6 alkyl, hydrogen, —OC1-C6 alkyl, —NH2, —NHRa,
- —O(CH2)yNRaRa′, —CF3, —NO2,
- —OPO3H2, —CF2CF3, —SO2Ra, —SO2NRaRa′, —CHO, —OCOCH3, —O(CH2)m-aryl, —O(CH2)m-cycloalkyl, —(CH2)m-aryl, —(CH2)m-cycloalkyl, —(CH2)m-heteroaryl, or —CH═CHC6H5, or —O(CH2)m-heteroaryl;
- y is 2 or 3;
- R5 is
- each n is independently 2, 3, or 4;
- Ri, Rg, and Rh are independently hydrogen, halogen, —OC1-C6 alkyl, C1-C6 alkyl, —CN, —OPO3H2, —CH2PO3H2, —O-phenyl, —O-benzyl,
- —O(CH2)yNRaRa′, —NH2, —NHRa,
- —CF2CF3, —SO2Ra, —SO2NRaRa′, —CHO, or —OCOCH3;
- and
- Rc and Rd are independently C1-C6 alkyl, —(CH2)m-cycloalkyl or hydrogen, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
22 more elements
A compound having the Formula II
- wherein
- R6 is —O-benzyl,
- —N(C1-C6 alkyl)-benzyl, or —SCH2-phenyl;
- R8 is hydrogen, halogen, C1-C6 alkyl, —O-benzyl, —OCH2-pyridyl, —OC1-C6 alkyl, —CF3, —OH, or -phenyl;
- R10 and R13 are independently hydrogen or C1-C6 alkyl;
- each n is independently 2, 3, or 4;
- R12 is
- and
- R14 is hydrogen or methyl;
- Rj, Rk, and Rl are independently hydrogen, —NH2, —NHRa, halogen, —OC1-C6 alkyl or C1-C6 alkyl, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
7 more elements
A compound having the Formula III
- wherein
- each n is 2, 3, or 4;
- X is NH, O, or —NCH3;
- R15 is —O-benzyl, —CF3, hydrogen, halogen, —OH, -phenyl, —C1-C6 alkyl, —O-CH2-pyridyl, or —OC1-C6 alkyl;
- and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
2 more elements
A compound having the Formula IV
- wherein
- X is NH, O, or —NCH3;
- R14 is hydrogen or C1-C6 alkyl;
- Rm is C1-C6 alkyl, C2-C6 alkenyl, —(CH2)tNR14R14, —(CH2)v—O—C1-C6 alkyl, —(CH2)t—OH, —(CH2)t-morpholino,
- n is 2, 3, or 4;
- m is 0 to 3;
- t is 2 to 6;
- and
- v is 1 to 6.
6 more elements
The compounds:
- (S)-[1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-[1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclopropylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-[1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclopentylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-[1-((4-Phenyl-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-[1-((4-Methoxy-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-[1-((4-Methyl-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-N-(4-Benzyloxy-benzyl)-2-(3-benzyl-ureido)-3-(1H-imidazol-4-yl)-N-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-propionamide;
- (S)-2-(3-Benzyl-3-methyl-ureido)-N-(4-benzyloxy-benzyl)-3-(1H-imidazol-4-yl)-N-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-propionamide;
- (S)-[1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-thiocarbamic acid S-benzyl ester;
- (S)-(2-(1H-Imidazol-4-yl)-1-{{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-[4-(pyridin-2-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
- (S)-(1-((Cyclohexyl-methyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- and
- (S)-(1-((Isobutyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester.
10 more elements
The compounds:
- (S)-2-(3-Benzyl-3-methyl-ureido)-3-(1H-imidazol-4-yl)-N-(4 methyl-benzyl)-N-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-propionamide;
- (S)-[1-[(4-Benzyloxy-benzyl)-({[1-(2,6-dichloro-phenyl)-cyclobutylmethyl]-carbamoyl}-methyl)-carbamoyl]-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- [(S)-trans]-[1-(But-2-enyl-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
- (S)-[2-(3H-Imidazol-4-yl)-1-({[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-propyl-carbamoyl)-ethyl]-carbamic acid benzyl ester;
- Benzyl N-((1S)-1-(1H-4-imidazolylmethyl)-2-oxo-2-(2-oxo-2-[(1-phenylcyclobutyl)methyl]-aminoethyl)[(1S)-1-phenylethyl]aminoethyl)-carbamate;
- and
- (S)-[1-((1,1-Dimethyl-2-phenylethyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester.
4 more elements
The compounds:
- Benzyl N-[(1S)-2-[(2-hydroxyethyl)(2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-1-(1H-4-imidazolylmethyl)-2-oxoethyl]carbamate;
- 3-[[(2S)-2-[(Benzyloxy)carbonyl]amino-3-(1H-4-imidazolyl)propanoyl](2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]propanoic acid;
- Methyl 3-[[(2S)-2-[(benzyloxy)carbonyl]amino-3-(1H-4-imidazolyl)propanoyl](2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]propanoate;
- Benzyl N-[(1S)-2-[(2-aminoethyl)(2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-1-(1H-4-imidazolylmethyl)-2-oxoethyl]carbamate;
- Benzyl N-(1S)-1-(1H-4-imidazolylmethyl)-2-[[2-(methylamino)ethyl](2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-2-oxoethylcarbamate;
- Benzyl N(1S)-1-(1H-4-imidazolylmethyl)-2-[(2-(methoxyethyl)(2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-2-oxoethylcarbamate;
- Benzyl N-(1S)-1-(1H-4-imidazolylmethyl)-2-[(2-(morpholinoethyl)(2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-2-oxoethylcarbamate;
- Benzyl N-(1S)-1-(1H-4-imidazolylmethyl)-2-[(2-(methyl-2-phenylpropyl)(2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-2-oxoethylcarbamate;
- and
- 1-Phenylethyl N-[(1S)-2-[[4-(benzyloxy)-1,5-cyclohexadienyl]methyl(2-oxo-2-[(1-phenylcyclobutyl)methyl]aminoethyl)amino]-1-(1H-4-imidazolylmethyl)-2-oxoethyl]carbamate.
7 more elements
Dependencies are inferred from the claim text.