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US 2003/0195159 A1Published application
HIV protease inhibitors based on amino acid derivatives
AssigneePharmacor Inc.
InventorsBrent Richard Stranix, Gilles Sauve, Abderrahim Bouzide, Alexandre Cote, Gervais Berube, Patrick Soucy, Yongsen Zhao, Jocelyn Yelle
Life of this patent
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Abstract
A compound selected from the group consisting of a compound of formula I 1 a compound of formula II 2 and when the compound of formula I and II comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein R1, R2, Cx, n, R3, R4, R5, Y are as defined in the specification.
Claims56
A compound selected from the group consisting of a compound of formula I
- 28
- a compound of formula II
- 29
- and when the compound of formula I and II comprises an amino group pharmaceutically acceptable ammonium salts thereof,
- wherein n is 3 or 4
- wherein Y is O, S or N—CN
- wherein Cx is selected from the group consisting of —COOM, COOR6, —CHO, —CH2OR7, —CH2OCOR8, —CONHR9 and —CONR10R11, wherein M is an alkali metal or alkaline earth metal,
- wherein R1 is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R2 is selected from the group consisting of a benzenesulfonyl group of formula III,
- 30
- and a thiophenesulfonyl group of formula IV,
- 31
- wherein R3 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 6 carbon atoms, a phenyl or a benzyl group
- wherein R4 is selected from the group consisting of H, a group of formula formula IIIa
- 32
- a group of formula IVa
- 33
- C6H11—, C5H10N—CH2CH2—, OC4H8N—CH2CH2—, C6H3CH2CH2—, 2,3-(CH3O)2C6H3CH2—, C6H5—, 2-C5H4N, 3-C5H4N, 4-C5H4N, 3-quinolyl, C6H5CS—, 2-naphthyl-SO2— and a group of formula R4C—CO—, R4C being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkylpart thereof, CF3, 1-pyrrolidinyl, 4-morpholinyl, tetrahydro-3-furanyloxy, 4-CH3OC6H4NH—, CH3NH—, HOCH2CH2NH—, 9-fluorenyl-CH2O—, tert-butylO-, iso-butylO-, C6H5CH2O—, CH3O—, unsubstituted C6H5—, C6H5— substituted by one or more members selected from the group consisting of F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —SR10, —COOR10, —COR10 and —CH2OH, unsubstituted C6H5CH2—, C6H5CH2— substituted by one or more members selected from the group consisting of F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —SR10, —COOR10, —COR10 and —CH2OH, unsubstituted C6H5CH2CH2—, and C6H5CH2CH2-substituted by one or more members selected from the group consisting of F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —SR10, —COOR10, —COR10 and —CH2OH,
- wherein R5 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 8 carbon atoms, HOCH2—,
- C6H5CH2OCH2—, benzyl-OCH(CH3), HO2CCH2—, HO2CCH2CH2—, NC—CH2—, H2NC(O)CH2—, H2NC(O)CH2CH2—, 4-CH3C6H4CH2SCH2—, CH3SCH2CH2—, H2NCH2CH2CH2CH2—, C6H5—, C6H5CH2—, C6H5CH(OH)—, C6H5CH(CN)—, C6F5CH2—, 4-(9-fluorenylmethoxycarbonyl)-NHCH2—C6H4CH2—, C5H4N-2-CH2—, C5H4N-3-CH2—, C5H4N-4-CH2—, 2-thiophene-CH2—, indole-3-CH2—, 2-benzothiophene-CH2—, Nε-benzyl-imidazole-4-CH2—, imidazole-4-CH2—, thiazole-4-CH2— and benzyl substituted by a group selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10—COR10 and —CH2OH,
- wherein Ra represents a member selected from the group consisting of
- 34
- wherein Met is a methylene linked to the α′ nitrogen
- wherein R6 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms and glycyl
- wherein R7 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms
- wherein R8 is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R9 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, —OH, —NH2 and —CH2CH2OH
- wherein R10 and R11, are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms
- wherein m is 0 or 1
- wherein o is 0 or 1
- wherein R12 and R13 are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR1,o —COR10 and —CH2OH, R10 and R11 being as defined above.
28 more elements
A compound of formula IA
- 35
- and when the compound of formula IA comprises an amino group pharmaceutically acceptable ammonium salts thereof,
- wherein n is 3 or 4
- wherein Y is O, S or N—CN
- wherein Cx is selected from the group consisting of —COOM, COOR6, —CHO, —CH2OR7, —CH2OCOR8, —CONHR9 and —CONR10R11, wherein M is an alkali metal or alkaline earth metal,
- wherein R1 is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R2 is selected from the group consisting of a benzenesulfonyl group of formula III,
- 36
- and a thiophenesulfonyl group of formula IV,
- 37
- wherein R3 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 6 carbon atoms, a phenyl or a benzyl group
- wherein R4 is selected from the group consisting of H, C6H11—, C5H10N—CH2CH2—, OC4H8N—CH2CH2—, C6H5CH2CH2—, 2,3-(CH3O)2C6H3CH2—, C6H5—, 2-C5H4N, 3-C5H4N, 4-C5H4N, 3-quinolyl, CH3CO—, CF3CO, C6H5CO—, C6H5CS—, 4-CH3OC6H4CH2CO—, C6H5CH2CH2CO—, iso-butyl-CO—, iso-propyl-CO—, tert-butyl-CO—, tert-butyl-CH2CO—, 1-pyrrolidine-CO—, 4-morpholine-CO—, carbotetrahydro-3-furanyloxy, 4-CH3OC6H4NHCO—, CH3NHCO—, HOCH2CH2NHCO—, 9-fluorenylmethoxycarbonyl, tert-butylO-CO—, iso-butylO-CO—, C6H5CH2O—CO—, CH3O—CO—, C6H5SO2—, 4-CH3C6H4SO2—, 4-CF3C6H4SO2—, 4-NO2C6H4SO2—, 4-NH2C6H4SO2—, 4-AcNHC6H4SO2—, 4-FC6H4SO2—, 4-ClC6H4SO2—, 4-BrC6H4SO2—, 4-CH3OC6H4SO2—, 2-thiophene-SO2— and 2-naphthyl-SO2—
- wherein R5 is selected from the group consisting of H, CH3—, CH3CH2CH2—,CH3CH2CH2CH2—, iso-C4H9CH2—, C6H11CH2—, HOCH2—, C6H5CH2OCH2—, benzyl-OCH(CH3), HO2CCH2—, HO2CCH2CH2—, NC—CH2—, H2NC(O)CH2—, H2NC(O)CH2CH2—, 4-CH3C6H4CH2SCH2—, CH3SCH2CH2—, 2HNCH2CH2CH2CH2—, C6H5—, C6H5CH2—, C6F5CH2—, 4-tert-butyl-C6H4CH2—, 4-HOC6H4CH2—, 4-benzyl-O—C6H4CH2—, 4-NO2C6H4CH2—, 4-(9-fluorenylmethoxycarbonyl)NHCH2—C6H4CH2—, 2-FC6H4CH2—, 3-FC6H4CH2—, 4-FC6H4CH2—, C5H4N-2-CH2—, C5H4N-3-CH2—, C5H4N-4-CH2—, 2-thiophene-CH2— indole-3-CH2—, 2-benzothiophene-CH2—, N-benzyl-imidazole-4-CH2— and thiazole-4-CH2—
- wherein R6 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms and glycyl
- wherein R7 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms
- wherein R8 is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R9 is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, —OH, —NH2 and —CH2CH2OH
- wherein R10 and R11 are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms
- wherein m is 0 or 1
- wherein o is 0 or 1
- wherein R12 and R13 are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10,—COR10 and —CH2OH, R10 and R11, being as defined above.
18 more elements
A compound of formula
- 39
- and K, Na and Cs salts thereof.
A compound of formula
- 40
- and K, Na and Cs salts thereof.
A compound of formula
- 41
- and K, Na and Cs salts thereof.
A compound of formula
- 42
- pharmaceutically acceptable ammonium salts thereof and K, Na and Cs salts thereof.
A compound of formula
- 43
- pharmaceutically acceptable ammonium salts thereof and K, Na and Cs salts thereof.
A compound of formula
- 44
- and K, Na and Cs salts thereof.
A compound of formula
- 45
- and K, Na and Cs salts thereof.
A compound of formula
- 46
- pharmaceutically acceptable ammonium salts thereof and K, Na and Cs salts thereof.
A compound of formula
- 47
- pharmaceutically acceptable ammonium salts thereof and K, Na and Cs salts thereof.
A compound of formula
- 48
- and K, Na and Cs salts thereof.
A compound of formula
- 49
- and K, Na and Cs salts thereof.
A compound of formula
- 50
- and K, Na and Cs salts thereof.
A compound of formula
- 51
- and K, Na and Cs salts thereof.
A compound of formula
- 52
- and K, Na and Cs salts thereof.
A compound of formula
- 53
- pharmaceutically acceptable ammonium salts thereof and K, Na and Cs salts thereof.
A compound of formula
- 54
A compound of formula
- 55
A compound of formula
- 56
A compound of formula
- 57
- and K, Na and Cs salts thereof.
A compound of formula
- 58
- and K, Na and Cs salts thereof.
A compound of formula
- 59
A compound of formula
- 60
- pharmaceutically acceptable ammonium salts thereof and K, Na and Cs salts thereof.
A compound of formula
- 61
- and K, Na and Cs salts thereof.
A compound of formula
- 62
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 63
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 64
- and K, Na and Cs salts thereof.
A compound of formula
- 65
A compound of formula
- 66
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 67
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 68
A compound of formula
- 69
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 70
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 71
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 72
A compound of formula
- 73
A compound of formula
- 74
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 75
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 76
- and pharmaceutically acceptable ammonium salts thereof.
A compound of formula
- 77
A compound of formula
- 78
A compound selected from the group consisting of a compound of formula Ia
- 79
- and when the compound of formula Ia comprises an amino group pharmaceutically acceptable ammonium salts thereof,
- wherein Cx is selected from the group consisting of —COOM and —CH2OH, M being an alkali metal or alkaline earth metal,
- wherein R1A is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R2A and R4A are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11,—NHCOR10, —OR10, —OCH2C6H5, —SR10—COOR10-COR10 and —CH2OH,
- wherein R5A is selected from the group consisting of H, a straight or branched alkyl group of 1 to 8 carbon atoms, HOCH2—, C6H5CH2OCH2—, benzyl-OCH(CH3), HO2CCH2—, HO2CCH2CH2—, NC—CH2—, H2NC(O)CH2—, H2NC(O)CH2CH2—, 4-CH3C6H4CH2SCH2—, CH3SCH2CH2—H2NCH2CH2CH2CH2—, C6H5—, C6H5CH2—, C6H5CH(OH)—, C6H5CH(CN)—, C6F5CH2—,4-(9-fluorenylmethoxycarbonyl)-NHCH2—C6H4CH2—, C5H4N-2-CH2—, C5H4N-3-CH2—, C5H4N-4-CH2—, 2-thiophene-CH2—, indole-3-CH2—, 2-benzothiophene-CH2—, N-benzyl-imidazole-4-CH2—, imidazole-4-CH2-, thiazole-4-CH2— and benzyl substituted by a group selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10,—OCH2C6H5, —SR10, —COOR10, —COR10 and —CH2OH,
- and wherein R10 and R11, are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms.
4 more elements
A compound selected from the group consisting of a compound of formula Ib
- 80
- and when the compound of formula Ib comprises an amino group pharmaceutically acceptable ammonium salts thereof,
- wherein Cx is selected from the group consisting of —COOM, and —CH2OH, M being an alkali metal or alkaline earth metal, wherein R1A is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R2A and R4B are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10—COOR10, —COR10 and —CH2OH,
- wherein R5A is selected from the group consisting of H, a straight or branched alkyl group of 1 to 8 carbon atoms, HOCH2—, C6H5CH2OCH2—, benzyl-OCH(CH3), HO2CCH2—, HO2CCH2CH2—, NC—CH2—, H2NC(O)CH2—, H2NC(O)CH2CH2—, 4-CH3C6H4CH2SCH2—, CH3SCH2CH2—, H2NCH2CH2CH2CH2—, C6H5—, C6H5CH2—, C6H5CH(OH)—, C6H5CH(CN)—, C6F5CH2—, 4-(9-fluorenylmethoxycarbonyl)-NHCH2—C6H4CH2—, C5H4N-2-CH2—, C5H4N-3-CH2—, C5H4N-4-CH2—, 2-thiophene-CH2— indole-3-CH2—, 2-benzothiophene-CH2—, NT-benzyl-imidazole-4-CH2—, imidazole-4-CH2-, thiazole-4-CH2— and benzyl substituted by a group selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10, —COR10 and —CH2OH, and wherein R10 and R11 are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms.
2 more elements
A compound of selected from the group consisting of a compound of formula Ic
- 81
- and when the compound of formula Ic comprises an amino group pharmaceutically acceptable ammonium salts thereof,
- wherein Cx is selected from the group consisting of —COOM and —CH2OH, M being an alkali metal or alkaline earth metal,
- wherein R1A is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
- wherein R2B and R4B are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10, —COR10 and —CH2OH, wherein R5A is selected from the group consisting of H, a straight or branched alkyl group of 1 to 8 carbon atoms, HOCH2—, C6H5CH2OCH2—, benzyl-OCH(CH3), HO2CCH2—, HO2CCH2CH2—, NC—CH2—, H2NC(O)CH2—, H2NC(O)CH2CH2—, 4-CH3C6H4CH2SCH2—, CH3SCH2CH2—, H2NCH2CH2CH2CH2—, C6H5—, C6H5CH2—, C6H5CH(OH)—, C6H5CH(CN)—, C6F5CH2—, 4-(9-fluorenylmethoxycarbonyl)-NHCH2—C6H4CH2—, C5H4N-2-CH2—, C5H4N-3-CH2—, C5H4N-4-CH2—, 2-thiophene-CH2—, indole-3-CH2—, 2-benzothiophene-CH2—, Nτ-benzyl-imidazole-4-CH2—, imidazole-4-CH2—, thiazole-4-CH2— and benzyl substituted by a group selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10, —COR10 and —CH2OH, and wherein R10 and R11 are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms.
2 more elements
A compound of selected from the group consisting of a compound of formula
- 82
- and when the compound of formula Id comprises an amino group pharmaceutically acceptable ammonium salts thereof,
- wherein Cx is selected from the group consisting of —COOM and —CH2OH, M being an alkali metal or alkaline earth metal,
- wherein R1A is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, wherein R4A is selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11-NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10, —COR10 and —CH2OH,
- wherein R4 is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, CF3, pyrrolidine, 4-morpholine, tetrahydro-3-furanyloxy, 4-CH3OC6H4NH—, CH3NH—, HOCH2CH2NH—, 9-fluorenyl-CH2O—, tert-butylO-, iso-butylO-, C6H5CH2O—, CH3O—, unsubstituted C6H5—, C6H5— substituted by one or more members selected from the group consisting of F, Cl, Br, I, —CF3, —NO2, —NR10R11-NHCOR10-OR10, —SR10, —COOR10, —COR10 and —CH2OH, unsubstituted C6H5CH2—, C6H5CH2— substituted by one or more members selected from the group consisting of F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —SR , —COOR10, —COR10 and —CH2OH, unsubstituted C6H5CH2CH2—, and C6H5CH2CH2-substituted by one or more members selected from the group consisting of F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —SR10, —COOR10, —COR10 and —CH2OH,
- wherein R5A is selected from the group consisting of H, a straight or branched alkyl group of 1 to 8 carbon atoms, HOCH2—, C6H5CH2OCH2—, benzyl-OCH(CH3), HO2CCH2—, HO2CCH2CH2—, NC—CH2—, H2NC(O)CH2—, H2NC(O)CH2CH2—, 4-CH3C6H4CH2SCH2—, CH3SCH2CH2—H2NCH2CH2CH2CH2—, C6H5-, C6H5CH2—, C6H5CH(OH)—, C6H5CH(CN)—, C6F5CH2—, 4-(9-fluorenylmethoxycarbonyl)-NHCH2—C6H4CH2—, C5H4N-2-CH2—, C5H4N-3-CH2—, C5H4N-4-CH2—, 2-thiophene-CH2— indole-3-CH2—, 2-benzothiophene-CH2—, Nτ-benzyl-imidazole-4-CH2-imidazole-4-CH2—, thiazole-4-CH2—, and benzyl substituted by a group selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms, F, Cl, Br, I, —CF3, —NO2, —NR10R11, —NHCOR10, —OR10, —OCH2C6H5, —SR10, —COOR10, —COR10 and —CH2OH,
- and wherein R10 and R11 are independently selected from the group consisting of H, a straight or branched alkyl group of 1 to 4 carbon atoms.
4 more elements
Dependencies are inferred from the claim text.