US 6,242,494 B1Granted

Substituted β-amino acid inhibitors of methionine aminopeptidase-2

AssigneeAbbott Laboratories

InventorsRichard A. Craig, Jack Henkin, Megumi Kawai, Linda M. Lynch, Jyoti Patel, George S. Sheppard, Jieyi Wang

Life of this patent

Estimating the term…

Abstract

A class of substituted b-amino acids are potent inhibitor of methionine aminopeptidase type 2 (MetAP2) and are thus useful in inhibiting angiogenesis and disease conditions which depend upon angiogenesis for their development such as diabetic retinopathy, tumor growth, and conditions of inflammation. Pharmaceutical compounds containing the compounds and methods of inhibiting methionine aminopeptidase-2, and angiogenesis are also disclosed.

Claims15

Dependent claims

A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein the small numerals denote chrial centers in the compound;
m is 1-3;
R1 is selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) carboxaldehyde,
(4) alkanoyl, where the alkanoyl can be optionally substituted with hydroxyl,
and
(5) —(CH2)nCO2R4, where n is 0-6, and R4 is selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) aryl,
and
(f) arylalkyl,
where (c) and (d) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkoxy,
and
(iii) aryl,
and
where (e) and (f) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) —CO2R4,, where R4, is selected from the group consisting of,
(a) hydrogen,
(b) alkyl,
(c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) eryl,
and
(f) arylalkyl,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) arylsulfonylalkyl,
(xiv) aryloylalkyloxycarbonylalkyl,
(xv) —NR6R6′, where R6 and R6′ are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl optionally substituted with alkoxy,
(3) aryl,
(4) arylalkyl,
and
(5′) a nitrogen-protecting group,
(xvi) —SO2NR6R6′, where R6 and R6′ are defined above,
and
(xvii) —C(O)NR6R6′, where R6 and R6′ are defined above;
R2 is selected from the group consisting of
(1) alkyl,
(2) cycloalkyl,
(3) (cycloalkyl)alkyl,
(4) —C(H)(SR15)(SR15′), where R15 and R15′ are alkyl, or R15 and R15′, together with the sulfurs to which they are attached, are a 1,3-dithiolane ring of a 1,3-dithiane ring,
(5) aryl,
(6) arylalkyl,
and
(7) —SR5, where R5 is selected from the group consisting of
(a) alkyl,
(b) cycloalkyl,
(c) (cycloalkyl)alkyl,
and
(d) benzyl, where the benzyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) —CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) —NR6R6,, where R6 and R6′ are defined above,
(xiv) —SO2NR6R6′, where R6 and R6′ are defined above,
and
(xv) —C(O)NR6R6′, where R6 and R6′ are defined above;
R3 is selected from the group consisting of
(1) and aminoacyl group optionally capped with a carboxyl protecting group,
(2) —N(R6)(CH2)pR7, where p is 0-6, R6 is defined above, and R7 is selected from the group consisting of
(a) hydrogen,
(b) alkyl, where the alkyl can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
(i) oxo,
(ii) thioxo,
(iii) alkoxy,
(iv) —CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) —NR6R6,, where R6 and R6′ are defined above,
(xiv) —SO2NR6R6′, where R6 and R6′ are defined above,
(xv) —C(O)NR6R6′, where R6 and R6′ are defined above,
(xvi) aryl, and
(xvii) hydroxy,
(c) cycloalkyl, where the cycloalkyl can be optionally substituted with 1, 2, or 3 substituents indepdently selected from the group consisting of
(i) alkyl,
(ii) halo,
(iii) oxo, and
(iv) aryl,
(d) aryl, where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) —CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxyaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) —NR6R6,, where R6 and R6′ are defined above,
(xiv) —SO2NR6R6′, where R6 and R6′ are defined above,
(xv) —C(O)NR6R6′, where R6 and R6′ are defined above,
(xvi) aryloxy,
(xvii) arylalkoxy,
(xvi) aryl, and
(xvii) hydroxy,
(e) —CO2R4, where R4 is defined above,
(f) —CONR6R8, where R6 is defined above, and R8 is selected from the group consisting of
(i) hydrogen
(ii) alkyl, and
(iii) aryl,
where (ii) and (iii) can be optionally substituted with one, two, or three groups independently selected from the group consisting of
(1′) alkyl,
(2′) alkanoyl,
(3′) alkoxy,
(4′) —CO2R4, where R4 is defined above,
(5′) alkanoyloxy,
(6′) carboxyaldehyde,
(7′) cycloalkyl,
(8′) cycloalkenyl,
(9′) halo,
(10′) nitro,
(11′) perfluoroalkyl,
(12′) perfluoroalkoxy,
(13′) —NR6R6,, where R6 and R6′ are defined above,
(14′) —SO2NR6N6′, where R6 and R6′ are defined above,
(15′) —C(O)NR6R6′, where R6 and R6′ are defined above,
(16′) aryloxy,
(17′) arylalkoxy,
(18′) aryl, and
(19′) hydroxy,
(g) —NR6R8, where R6 and R8 are defined above, and
(h) —N(R6)SO2R12, where R6 is defined previously, and R12 is selected from the group consisting of
(i) alkyl,
(ii) aryl, and
(iii) arylalkyl,
where (ii) and (iii) can be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of
(1′) alkyl,
(2′) alkanoyl,
(3′) alkoxy,
(4′) —CO2R4, where R4 is defined above,
(5′) alkanoyloxy,
(6′) carboxaldehyde,
(7′) cycloalkyl,
(8′) cycloalkenyl,
(9′) halo,
(10′) nitro,
(11′) perfluoroalkyl,
(12′) perfluoroalkoxy,
(13′) —NR6R6,, where R6 and R6′ are defined above,
(14′) —SO2NR6R6′, where R6 and R6′ are defined above,
(15′) —C(O)NR6R6′, where R6 and R6′ are defined above,
(16′) aryloxy,
(17′) arylalkoxy,
(18′) aryl, and
(19′) hydroxy,
and
(3) —O(CH2)pR7 are defined above;
with the proviso that at least one of R1, R2, or R3 has contained therein an aryl or cycloalkyl group;
X is hydroxyl or sulfhydryl;
and
Y is hydrogen;
or
X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl;
with the proviso that when X is hydroxyl;
Y is hydrogen;
R3 is —N(R6)(CH2)pR7 wherein is hydrogen, p is 0-6, and R7 is alkyl, alkoxycarbonyl, carboxyl, or phenyl;
and R2 is phenyl, m is not 1;
and
with the proviso that when X and Y, together with the carbon atom to which they are attached, are carbonyl;
R3 is —N(R6)(CH2)pR7 wherein R6 is hydrogen, p is 0-6, and R7 is alkyl, alkoxycarbonyl, carboxyl, or phenyl;
and R2 is phenyl, m is not 1.

194 more elements

A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

(2RS,3R)-N-((2-phenylethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-((3-phenylpropyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)N-(2-(4-methoxyphenyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(2-(4-sulfonamidophenyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(2-(4-phenoxyphenyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(4-phenyl)butyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carbobenzyloxy)ethyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-butanamide,
(2RS,3R)-N-(3-carboethoxy)propyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R,1′S)-N-((1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-cyclohexylbutanamide,
(2RS,3R)-N-(2-carboethoxy)ethyl)-3-amino-2-hydroxy-4-cyclohexylbutanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cyclohexylbutanamide,
(2RS,3R,1′S)-N-((1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-phenylbutanamide,
(2RS,3R)-3-amino-2-hydroxy-N-(4-methoxyphenethyl)-5-(methylthio)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-acetylamino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-3-amino-2-hydroxy-N-methyl-5-(methylthio)-N-phenethylpentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-tert-butoxycarbonylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-formylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-hydroxymethylcarbonylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R,1′R)-N-((1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R)-N-((1-methyl-1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R1′S)-N-((1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-benzylthio)butanamide,
(2RS,3R,1′S)-N-((2-hydroxy-1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,1′S)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2′S)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2′S)-N-((2benzoyloxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2′R)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2′R)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2′R)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,1′S)-N-((1-benzyloxycarbonylethyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R)-N-(monodansylcadaverenyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R)-N-(3-O-methyl-dopaminyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(3-O-methoxydopamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-hydroxy-5-nitrophen-1-yl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(4-nitro-2-hydroxyphen-1-yl)amide,
ethyl(2RS,3R,2′S)-2-((-3-(acetylamino)-4-cyclohexyl-2-hydroxybutanoyl)amino)propanoate,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-benzyloxycarbonylamino)butylamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-beta-alaninebenzylester,
(2RS,3R)-N-(monodansylcadaverenyl)-3-amino-2-hydroxy-5-ethylthio)pentanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-(4-toluenesulfonyl)aminobutyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-4-toluenesulfonylaminoethyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-aminobutyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-aminoethyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-(((3,4-dimethoxyphenyl)sulfonyl)amino)butyl)-2-hydroxybutanamide,
(2RS,3R)-N-(4-(((4-acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-((2-naphthylsulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-4-sulfonamidebenzylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alaninebenzylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alaninecyclohexylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-2-((phenylsulfonyl)methyl)benzylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alaninecyclopropylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-4-tert-butylbenzylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-4-methoxycarbonylbenzylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-4-trifluoromethylbenzylester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-(4-(methyl)phenylaceticacidphenacylester),
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N--(3-methoxyphenyl)butanamide,
methyl(2RS,3R,2′R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-4-methylpentanoate,
(2RS,3R,1′RS)-3-amino-4-cyclohexyl-2-hydroxy-N-(1-(1-naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(1,2-dimethylpropyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenylbutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1,2,3,4-tetrahydro-1-naphthalenyl)butanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)cyclohexyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethylhexyl)-2-hydroxybutanamide,
butyl(2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-5-(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-decyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-((1R,4S)bicyclo(2.2.1)hept-2-yl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(1-(4-fluorophenyl)ethyl)-2-hydroxybutanamide,
tert-butyl(2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate,
methyl(2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-phenylpropopanoate,
methyl(2RS,3R,2′S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-methylpentanoate,
methyl(2RS,3R,2′S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)hexanoate,
methyl(2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino-3-methylbutanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((1S)-1-(2-naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((1R)-1-(2-naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((1S)-1-(1-naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((1R)-1-(1-naphthyl)ethyl)butanamide,
ethyl(2RS,3R,2′R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-fluoropropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-hydroxy-1-(hydroxymethyl)ethyl)butanamide,
4-(tert-butyl)benzyl(2RS,3R,2′R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoate,
4-nitrobenzyl(2RS,3R,2′S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoate,
3-nitrobenzyl(2RS,3R,2′S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoate,
4-(trifluoromethyl)benzyl(2RS,3R,2′S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoate,
3-(trifluoromethoxy)benzyl(2RS,3R,2′S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)phenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-bromophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-N-(2-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-nitrophenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenoxyphenyl)butanamide,
(((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)(2,5-dimethoxybenzyl)chloronium,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dichlorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3-fluorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3amino-N-(3,4-bis(benzyloxy)phenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-(trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methylphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dimethylphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-iodo-2-methylphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-anilino-2-methoxyphenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-chloro-2-methoxy-5-methylphenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-N-(5-(acetylamino)-2-methoxyphenyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(5-chloro-2,4-dimethoxyphenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-diethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-phenoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methyl-5-nitrophenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxybenzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylbenzyl)butanamide,
(2RS,3R)-3-amino-N-(3-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxybenzyl)butanamide,
(2RS,3R)-3-amino-N-(4-bromobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methylbenzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenethylbutanamide,
(2RS,3R)-3-amino-N-(4-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(trifluoromethyl)phenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-bromophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-N-(1-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-N-(2-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2R,3R)-3-amino-N-cycloheptyl-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(cyclohexylmethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-4-dicyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-cyclopentyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-cyclobutyl-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1-methyl-3-phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1-methyl-2-(3-(trifluoromethyl)phenyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(1,5-dimethylhexyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1-methylhexyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isopropoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isobutoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,3-diphenylpropyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(1,4-dimethylpentyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-(1-naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-((1S)-1-(1-naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy(1,1′-biphenyl)-3-yl)butanamide,
(2RS,3R)-3-amino-N-(3-(benzyloxy)phenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3-ethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3,4,5-trimethoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-(2-fluorophenyl)-1-methylethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-(4-fluorophenyl)-1,1-dimethylethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro-1H-inden-1-yl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((1S,2R)-2-phenylcyclopropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1,1,3,3-tetramethylbutyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(1,3-dimethylbutyl)-2-hydroxybutanamide,
(2RS,3R)-N-(1-(1-adamantyl)ethyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-2-hydroxy-4-ethylthio)butanoyl-((S)-(−)-(1-naphthyl)ethyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1-naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(trifluoromethoxy)benzyl)butanamide,
(2RS,3R)-3-amino-N-(3,5-bis(trifluoromethyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-(trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(trifluoromethoxy)benzyl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2-methoxyphenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-methylphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-4-methylphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy-2-naphthyl)butanamide,
(2RS,3R)-3-amino-N-butyl-4-cyclohexyl-2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N,N-bis(methoxymethyl)butanamide,
(2RS,3R)-3-amino-N-benzyl-N-butyl-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-4-cyclohexyl-2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-N-ethyl-2-hydroxybutanamide, and
ethyl 3-propanoate.

203 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/303,807Filed 30 Apr 1999 · us provisional application
Priority: 1 May 1998
Granted: 5 Jun 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07D 207/27
With only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms: with substituted…
C07C 235/16
The carbon skeleton being acyclic and saturated: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a…
C07C 237/12
The carbon skeleton being acyclic and saturated: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon…
C07C 237/14
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton being saturated and…

Family

Application60/085,877Us provisional application · filed 1 May 1998
US 6,242,494 B1This patent

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

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Abstract

A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein the small numerals denote chrial centers in the compound;
m is 1-3;
R1 is selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) carboxaldehyde,
(4) alkanoyl, where the alkanoyl can be optionally substituted with hydroxyl,
and
(5) —(CH2)nCO2R4, where n is 0-6, and R4 is selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) aryl,
and
(f) arylalkyl,
where (c) and (d) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkoxy,
and
(iii) aryl,
and
where (e) and (f) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) —CO2R4,, where R4, is selected from the group consisting of,
(a) hydrogen,
(b) alkyl,
(c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) eryl,
and
(f) arylalkyl,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) arylsulfonylalkyl,
(xiv) aryloylalkyloxycarbonylalkyl,
(xv) —NR6R6′, where R6 and R6′ are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl optionally substituted with alkoxy,
(3) aryl,
(4) arylalkyl,
and
(5′) a nitrogen-protecting group,
(xvi) —SO2NR6R6′, where R6 and R6′ are defined above,
and
(xvii) —C(O)NR6R6′, where R6 and R6′ are defined above;
R2 is selected from the group consisting of
(1) alkyl,
(2) cycloalkyl,
(3) (cycloalkyl)alkyl,
(4) —C(H)(SR15)(SR15′), where R15 and R15′ are alkyl, or R15 and R15′, together with the sulfurs to which they are attached, are a 1,3-dithiolane ring of a 1,3-dithiane ring,
(5) aryl,
(6) arylalkyl,
and
(7) —SR5, where R5 is selected from the group consisting of
(a) alkyl,
(b) cycloalkyl,
(c) (cycloalkyl)alkyl,
and
(d) benzyl, where the benzyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) —CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) —NR6R6,, where R6 and R6′ are defined above,
(xiv) —SO2NR6R6′, where R6 and R6′ are defined above,
and
(xv) —C(O)NR6R6′, where R6 and R6′ are defined above;
R3 is selected from the group consisting of
(1) and aminoacyl group optionally capped with a carboxyl protecting group,
(2) —N(R6)(CH2)pR7, where p is 0-6, R6 is defined above, and R7 is selected from the group consisting of
(a) hydrogen,
(b) alkyl, where the alkyl can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
(i) oxo,
(ii) thioxo,
(iii) alkoxy,
(iv) —CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) —NR6R6,, where R6 and R6′ are defined above,
(xiv) —SO2NR6R6′, where R6 and R6′ are defined above,
(xv) —C(O)NR6R6′, where R6 and R6′ are defined above,
(xvi) aryl, and
(xvii) hydroxy,
(c) cycloalkyl, where the cycloalkyl can be optionally substituted with 1, 2, or 3 substituents indepdently selected from the group consisting of
(i) alkyl,
(ii) halo,
(iii) oxo, and
(iv) aryl,
(d) aryl, where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) —CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxyaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) —NR6R6,, where R6 and R6′ are defined above,
(xiv) —SO2NR6R6′, where R6 and R6′ are defined above,
(xv) —C(O)NR6R6′, where R6 and R6′ are defined above,
(xvi) aryloxy,
(xvii) arylalkoxy,
(xvi) aryl, and
(xvii) hydroxy,
(e) —CO2R4, where R4 is defined above,
(f) —CONR6R8, where R6 is defined above, and R8 is selected from the group consisting of
(i) hydrogen
(ii) alkyl, and
(iii) aryl,
where (ii) and (iii) can be optionally substituted with one, two, or three groups independently selected from the group consisting of
(1′) alkyl,
(2′) alkanoyl,
(3′) alkoxy,
(4′) —CO2R4, where R4 is defined above,
(5′) alkanoyloxy,
(6′) carboxyaldehyde,
(7′) cycloalkyl,
(8′) cycloalkenyl,
(9′) halo,
(10′) nitro,
(11′) perfluoroalkyl,
(12′) perfluoroalkoxy,
(13′) —NR6R6,, where R6 and R6′ are defined above,
(14′) —SO2NR6N6′, where R6 and R6′ are defined above,
(15′) —C(O)NR6R6′, where R6 and R6′ are defined above,
(16′) aryloxy,
(17′) arylalkoxy,
(18′) aryl, and
(19′) hydroxy,
(g) —NR6R8, where R6 and R8 are defined above, and
(h) —N(R6)SO2R12, where R6 is defined previously, and R12 is selected from the group consisting of
(i) alkyl,
(ii) aryl, and
(iii) arylalkyl,
where (ii) and (iii) can be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of
(1′) alkyl,
(2′) alkanoyl,
(3′) alkoxy,
(4′) —CO2R4, where R4 is defined above,
(5′) alkanoyloxy,
(6′) carboxaldehyde,
(7′) cycloalkyl,
(8′) cycloalkenyl,
(9′) halo,
(10′) nitro,
(11′) perfluoroalkyl,
(12′) perfluoroalkoxy,
(13′) —NR6R6,, where R6 and R6′ are defined above,
(14′) —SO2NR6R6′, where R6 and R6′ are defined above,
(15′) —C(O)NR6R6′, where R6 and R6′ are defined above,
(16′) aryloxy,
(17′) arylalkoxy,
(18′) aryl, and
(19′) hydroxy,
and
(3) —O(CH2)pR7 are defined above;
with the proviso that at least one of R1, R2, or R3 has contained therein an aryl or cycloalkyl group;
X is hydroxyl or sulfhydryl;
and
Y is hydrogen;
or
X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl;
with the proviso that when X is hydroxyl;
Y is hydrogen;
R3 is —N(R6)(CH2)pR7 wherein is hydrogen, p is 0-6, and R7 is alkyl, alkoxycarbonyl, carboxyl, or phenyl;
and R2 is phenyl, m is not 1;
and
with the proviso that when X and Y, together with the carbon atom to which they are attached, are carbonyl;
R3 is —N(R6)(CH2)pR7 wherein R6 is hydrogen, p is 0-6, and R7 is alkyl, alkoxycarbonyl, carboxyl, or phenyl;
and R2 is phenyl, m is not 1.

194 more elements

Facts

Application

09/303,807Filed 30 Apr 1999 · us provisional application

Priority

1 May 1998

Granted

5 Jun 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07D 207/27
With only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms: with substituted…
C07C 235/16
The carbon skeleton being acyclic and saturated: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a…
C07C 237/12
The carbon skeleton being acyclic and saturated: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon…
C07C 237/14
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton being saturated and…