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US 6,632,830 B1Granted
ACE-2 inhibiting compounds and methods of use thereof
AssigneeMillennium Pharmaceuticals, Inc.
InventorsSusan L. Acton, Timothy D. Ocain, Alexandra E. Gould, Natalie A. Dales, Bing Guan, James A. Brown
Life of this patent
Estimating the term…
Abstract
ACE-2 inhibiting compounds are disclosed. These compounds include compounds of formula (IV): wherein the variables are as described in the specification. Pharmaceutical compositions containing the compounds are also discussed. The pharmaceutical compositions may contain an effective amount of a compound of the invention to treat ACE-2 associated disorders such as a blood pressure related disease or disorder, cell proliferation disorder, kidney disorder, kinetensin associated disorder, inflammation associated disorder, or an allergic disorder.
Claims145
An ACE-2 inhibiting compound, wherein said compound is of the formula:
- wherein
- Q is CH2, O, NH, or NR3, wherein R3 is substituted or unsubstituted C1-C5 branched or straight chain alkyl, C2-C5 branched or straight chain alkenyl, substituted or unsubstituted acyl, aryl, or a C3-C8 ring;
- R6 is hydroxyl or a protecting prodrug moiety;
- R7 is a hydrogen atom, carboxylic acid, ether, alkoxy, an amide, a protecting prodrug moiety, hydroxyl, thiol, heterocyclic, alkyl, or an amine;
- G is a covalent bond, C1-C5 alkyl, alkenyl, alkynyl, ether, thioether, amine, or carbonyl;
- M is heteroaryl, wherein M is substituted with at least one subanchor moiety, linked to M through a sublinking moiety, wherein said subanchor moiety is substituted or unsubstituted phenyl;
- J is selected from the group consisting of a bond, a substituted or unsubstituted alkyl, alkenyl, or alkynyl moiety;
- and
- D is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, optionally linked to G or M to form a ring, and pharmaceutically acceptable salts thereof.
6 more elements
An ACE-2 inhibiting compound, wherein said compound is of the formula:
- wherein
- Q is CH2, O, NH, or NR3, wherein R3 is substituted or unsubstituted C1-C5 branched or straight chain alkyl, C2-C5 branched or straight chain alkenyl, substituted or unsubstituted acyl, aryl, or a C3-C8 ring;
- R6 is hydroxyl or a protecting prodrug moiety;
- R7 is a hydrogen atom, carboxylic acid, an amide, a protecting prodrug moiety, hydroxyl, thiol, heterocyclic, alkyl, or an amine;
- G is a covalent bond, C1-C5 alkyl, alkenyl, alkynyl, ether, thioether, amine, or carbonyl;
- M is heteroaryl, and is substituted with at least one subanchor moiety, linked to M through a sublinking moiety, wherein said sublinking moiety is CH2 and said subanchor moiety is selected from the group consisting of 4-chlorophenyl, biphenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 3,5-dimethylphenyl, 3-CF3-phenyl, 2,5-dichlorophenyl, m-fluorophenyl, m-iodophenyl, methylenedioxyphenyl, m-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethoxyphenyl, p-fluorophenyl, p-nitrophenyl, p-t-butylphenyl, p-isopropyl phenyl, p-trifluoromethoxyphenyl, 3,4-dimethylphenyl, 3,4-chlorophenyl, 4-methylphenyl, 4-cyanophenyl, cycloalkyl, or 4-trifluoromethylphenyl;
- J is selected from the group consisting of a bond, a substituted or unsubstituted alkyl, alkenyl, or alkynyl moiety;
- and
- D is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, optionally linked to G or M to form a ring, and pharmaceutically acceptable salts thereof.
6 more elements
A compound of the formula:
- and pharmaceutically acceptable salts thereof.
A compound that is:
- 2-{1-Carboxy-2-[3-(3-nitro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[2-(3-Benzyl-3H-imidazol-4-yl)-1-carboxy-ethylamino]-hexanoic acid;
- 2-[2-(3-Benzyl-3H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(3-Benzyloxymethyl-3H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(1-Benzyl-1H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[1-(4-chloro-benzyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[2-(1-Benzyl-1H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[1-(2,4-dinitro-phenyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[2-(1-Benzyl-1H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[1-(4-methoxy-benzyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[1-(4-trifluoromethyl-benzyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[1-(4-methoxy-benzyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-(1-Carboxy-2-[1-(4-trifluoromethyl-benzyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-trifluoromethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-chloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(2-phenyl-thiazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(1-Benzyl-1H-benzoimidazol-2-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3,4-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-cyano-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-chloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3,5-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-methyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{2-[3-(4-Butyl-benzyl)-3H-imidazol-4-yl]-1-carboxy-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3,4-dimethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[2-(2-Benzylamino-thiazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-methyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3,5-dimethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-isopropyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-methyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{2-[3-(4-tert-Butyl-benzyl)-3H-imidazol-4-yl]-1-carboxy-ethylamino}-4-methyl-pentanoic acid;
- 2-{2-[3-(2-Benzenesulfonylmethyl-benzyl)-3H-imidazol-4-yl]-1-carboxy-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-nitro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[2-(3-Biphenyl-2-ylmethyl-3H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{2-[3-(3,5-Bis-trifluoromethyl-benzyl)-3H-imidazol-4-yl]-1-carboxy-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(4-fluoro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(2-phenyl-thiazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(1-Benzyl-1H-pyrazol-3-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,3-dimethoxy-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-methyl-biphenyl-3-ylmethyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,3-difluoro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[1-(2,3-difluoro-benzyl)-1H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,3-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-trifluoromethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,5-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,6-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 4-Methyl-2-[1-methylcarbamoyl-2-(3-phenylamino-3H-imidazol-4-yl)-ethylamino]-pentanoic acid;
- 2-[2-(4-Benzyl-furan-3-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(3-phenyl-3H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(3-phenethyl-3H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(pyridin-3-yloxy)-3H-imidazo}-4-yl]-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-[3-(4-nitro-phenoxy)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(3-phenoxy-3H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-nitro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-nitro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-trifluoromethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-trifluoromethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-methyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-methyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-chloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-chloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-hydroxy-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-hydroxy-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2-fluoro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[2-(3-Benzyl-3H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(3-phenylamino-3H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-{[2,3-Dioxo-1-(3-phenylamino-3H-imidazol-4-ylmethyl)-butyl]-methyl-amino}-4-methyl-pentanoic acid;
- 2-{[2,3-Dioxo-1-(4-phenylamino-furan-3-ylmethyl)-butyl]-methyl-amino}-4-methyl-pentanoic acid;
- 2-[2,3-Dioxo-1-(4-phenylamino-furan-3-ylmethyl)-butylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(4-phenylamino-furan-3-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(2-o-tolyl-2H-isoindol-1-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(2-Benzyl-2H-isoindol-1-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(2-phenyl-2H-isoindol-1-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[2-(3-nitro-phenyl)-2H-isoindol-1-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[2-(4-nitro-phenyl)-2H-isoindol-1-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[2-(4-nitro-benzyl)-2H-isoindol-1-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{-Carboxy-2-[3-(3-trifluoromethyl-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,5-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(2,6-dichloro-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(3-phenethyl-3H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-{1-Carboxy-2-[3-(3-iodo-benzyl)-3H-imidazol-4-yl]-ethylamino}-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-[3-(3-fluoro-benzyl)-3H-imidazol-4-yl]-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(2-phenylethynyl-1H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(1-methyl-2-phenylethynyl-1H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(2-phenethyl-1H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-3-(3-phenyl-3H-imidazol-4-yl)-propylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-2-(3-phenyl-3H-imidazol-4-yl)-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(3-Benzyl-2,5-dimethyl-3H-imidazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[1-Carboxy-4-(3-phenyl-3H-imidazol-4-yl)-butylamino]-4-methyl-pentanoic acid;
- 2-[2-(2-Benzyl-thiazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- 2-[2-(5-Benzyl-2-methyl-thiazol-4-yl)-1-carboxy-ethylamino]-4-methyl-pentanoic acid;
- or pharmaceutically acceptable salts thereof.
89 more elements
A compound that is:
- or pharmaceutically acceptable salts thereof.
A compound that is:
- or pharmaceutically acceptable salts thereof.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound that is:
- or pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.