Renin inhibitors useful for the treatment of aids by inhibition of HIV protease

Claim 2

The use of an inhibitor of renin for the preparation of a medicament useful for the treatment of AIDS, or in the prevention or treatment of infection by HIV.

Claim 3

The use of renin inhibitors having substituent G, for the preparation of a medicament useful for the inhibition of HIV protease, the treatment of AIDS or the prevention or treatment of infection by HIV; wherein R³ is hydrogen; C₁₋₄-alkyl; aryl; aryl C₁₋₄-alkyl; C₁₋₄-alkyl or aryl or aryl C₁₋₄-alkyl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, carboxy, hydroxy, C₁₋₄-alkoxy, and halo; or indolyl; R⁹ is hydrogen; C₁₋₄-alkyl; hydroxy; carboxy; or C₃₋₇-cycloalkyl; R⁶ is C₃₋₆-alkyl; C₃₋₇-cycloalkyl; aryl; or C₃₋₇-cycloalkyl or aryl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, hydroxy, C₁₋₄-­alkoxy, and halo; and wherein X′ is hydroxy, amino, or mono- or di-C₁₋₄-alkyl amino; and W′ is absent; or -CH₂-; or where R⁸ is hydrogen or C₁₋₃-alkyl; where R is hydrogen; C₁₋₄-alkyl; or formyl; or pharmaceutically acceptable salts thereof.

Claim 4

The use of renin inhibitors having substituent G, for the preparation of a medicament useful for the inhibition of HIV protease, the treatment of AIDS or the prevention or treatment of infection by HIV; wherein R³ is hydrogen; C₁₋₄-alkyl; aryl; aryl C₁₋₄-alkyl; C₁₋₄-alkyl or aryl or aryl C₁₋₄-alkyl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, carboxy, hydroxy, C₁₋₄-alkoxy, and halo; or indolyl; R⁹ is hydrogen; C₁₋₄-alkyl; hydroxy; carboxy; or C₃₋₇-cycloalkyl; R⁶ is C₃₋₆-alkyl; C₃₋₇-cycloalkyl; aryl; or C₃₋₇-cycloalkyl or aryl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, hydroxy, C₁₋₄-­alkoxy, and halo; and wherein X′ is hydroxy, amino, or mono- or di-C₁₋₄-alkyl amino; and W′ is absent; or -CH₂-; or where R⁸ is hydrogen or C₁₋₃-alkyl; where R is hydrogen; C₁₋₄-alkyl; or formyl; or pharmaceutically acceptable salts thereof.

Claim 5

The use of compounds of a formula for the preparation of a medicament useful for the treatment of AIDS, the prevention of infection by HIV, the treatment of infection by HIV or the inhibition of HIV protease, said formula defined as wherein: A is hydrogen; or where X is -O-; -S-; -CH-; -NH-CH-; and R² a and R² b may be the same or different and are hydrogen; C₁₋₄-alkyl; aryl; C₃₋₇-cycloalkyl; or C₃₋₇-cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C₁₋₈-alkyl, trifluoromethyl, hydroxy, C₁₋₄-alkoxy, and halo; except that where X is -O-, only one of R² a or R² b is present; B is absent; glycyl; prolyl; sarcosyl; or where R¹ is hydrogen; -COHN²; -COOH C₁₋₄-alkyl; hydroxy C₁₋₄-alkyl; C₁₋₄alkyl substituted with carboxy; aryl; aryl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, and halo; indolyl; imidazolyl; amino C₂₋₄-alkyl; E is absent; or where m is 1 to 4; and R⁵ is (1) hydrogen; (2) C₁₋₄-alkyl; (3) C₁₋₄-alkyl substituted with carboxy; (4) aryl; (5) or aryl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, and halo; (6) R⁵ is indolyl; or (7) imidazolyl; where q is 1 to 4; R⁴ is hydrogen; or where R³ is hydrogen; C₁₋₄-alkyl; aryl; aryl C₁₋₄-alkyl; C₁₋₄-alkyl or aryl or aryl C₁₋₄-alkyl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, carboxy, hydroxy, C₁₋₄-alkoxy, and halo; or indolyl; R⁹ is hydrogen; C₁₋₄-alkyl; hydroxy; carboxy; or C₃₋₇-cycloalkyl; R⁶ is C₃₋₆-alkyl; C₃₋₇-cycloalkyl; aryl; or C₃₋₇-cycloalkyl or aryl substituted with up to three members selected from the group consisting of C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, and halo; and wherein X′ is hydroxy, amino, or mono- or di-C₁₋₄-alkyl amino; and W′ is absent, or -CH₂-; or where R⁸ is hydrogen or C₁₋₃-alkyl; where R is hydrogen; C₁₋₄-alkyl; or formyl; J is absent; or (1) -Y-(CH₂) n -R⁷ where Y is -NH-; n is 0 to 5; and R⁷ is hydrogen; hydroxy; C₁₋₄-alkyl; C₃₋₇-cycloalkyl; carbocyclic, aryl; carbocyclic or aryl substituted with up to five members independently selected from the group consisting of C₁₋₆-alkyl, hydroxy, C₁₋₄-alkoxy, amino, mono- or di-­C₁₋₄-alkylamino, and halo; amino; mono-, di-, or tri-C₁₋₄-­alkylamino; amino substituted with heterocycle; guanidyl; heterocycle; monoalkylamino or heterocycle substituted with up to five members independently selected from the group consisting of C₁₋₆-alkyl, hydroxy, C₁₋₄-alkoxy, halo, amino, and mono- or di-C₁₋₄-alkylamino; where Y is -NH-; q is 1-5; q′ is 0-5; R¹⁰ is hydrogen; hydroxy; N(R′)₂, where R′ may be the same or different and is hydrogen or C₁₋₄-alkyl; guanidyl; or N(R′)₃⊕A⊖, where R′ is as defined above, and A⊖ is a counterion; provided that at least one R¹⁰ is not hydrogen; R¹¹ is C₁₋₄-alkyl; C₃₋₇-cycloalkyl; aryl; aryl substituted with up to three members independently selected from the group consisting of C₁₋₆-alkyl, hydroxy, C₁₋₄-alkoxy, amino, mono- or di-C₁₋₄-alkylamino, amino C₁₋₄-alkyl, mono-, di-, or tri-C₁₋₄-­alkylamino-C₁₋₄-alkyl, carboxy, carboxy ester or amide, carboxy-C₁₋₄-alkyl, carboxy-C₁₋₄-alkyl ester or amide; carboxy, ester or amide; sulfo; heterocycle; or heterocycle substituted with up to five members independently selected from the group consisting of hydroxy, C₁₋₄-alkoxy, halo, amino, and mono- or di-C₁₋₄-alkylamino; R¹² is hydrogen; or carboxy, ester or amide; R¹³ is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C₁₋₄-alkyl, mono-, di-, or tri-C₁₋₄-alkylamino-C₁₋₄-­alkyl, carboxy, carboxy ester or amide, R¹⁴ is carboxy, ester or amide, L is absent; OR˝; NHR˝; or N(R˝)₂, where R˝ may be the same or different and is hydrogen or C₁₋₄-alkyl; or pharmaceutically acceptable salts thereof.

Claim 6

The use of compounds of a formula for the preparation of a medicament useful for the treatment of AIDS, the prevention of infection by HIV, the treatment of infection by HIV or the inhibition of HIV protease, said formula defined as wherein: A is hydrogen; or where X is -O-; -S-; -CH-; -NH-CH-; and R² a and R² b may be the same or different and are hydrogen; C₁₋₄-alkyl; aryl; C₃₋₇-cycloalkyl; or C₃₋₇-cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C₁₋₈-alkyl, trifluoromethyl, hydroxy, C₁₋₄-alkoxy, and halo; except that where X is -O-, only one of R² a or R² b is present; B is absent; glycyl; prolyl; sarcosyl; or where R¹ is hydrogen; -COHN²; -COOH C₁₋₄-alkyl; hydroxy C₁₋₄-alkyl; C₁₋₄alkyl substituted with carboxy; aryl; aryl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, and halo; indolyl; imidazolyl; amino C₂₋₄-alkyl; E is absent; or where m is 1 to 4; and R⁵ is (1) hydrogen; (2) C₁₋₄-alkyl; (3) C₁₋₄-alkyl substituted with carboxy; (4) aryl; (5) or aryl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, and halo; (6) R⁵ is indolyl; or (7) imidazolyl; where q is 1 to 4; R⁴ is hydrogen; or where R³ is hydrogen; C₁₋₄-alkyl; aryl; aryl C₁₋₄-alkyl; C₁₋₄-alkyl or aryl or aryl C₁₋₄-alkyl substituted with up to three members selected from the group consisting of C₁₋₄-alkyl, carboxy, hydroxy, C₁₋₄-alkoxy, and halo; or indolyl; R⁹ is hydrogen; C₁₋₄-alkyl; hydroxy; carboxy; or C₃₋₇-cycloalkyl; R⁶ is C₃₋₆-alkyl; C₃₋₇-cycloalkyl; aryl; or C₃₋₇-cycloalkyl or aryl substituted with up to three members selected from the group consisting of C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, and halo; and wherein X′ is hydroxy, amino, or mono- or di-C₁₋₄-alkyl amino; and W′ is absent, or -CH₂-; or where R⁸ is hydrogen or C₁₋₃-alkyl; where R is hydrogen; C₁₋₄-alkyl; or formyl; J is absent; or (1) -Y-(CH₂) n -R⁷ where Y is -NH-; n is 0 to 5; and R⁷ is hydrogen; hydroxy; C₁₋₄-alkyl; C₃₋₇-cycloalkyl; carbocyclic, aryl; carbocyclic or aryl substituted with up to five members independently selected from the group consisting of C₁₋₆-alkyl, hydroxy, C₁₋₄-alkoxy, amino, mono- or di-­C₁₋₄-alkylamino, and halo; amino; mono-, di-, or tri-C₁₋₄-­alkylamino; amino substituted with heterocycle; guanidyl; heterocycle; monoalkylamino or heterocycle substituted with up to five members independently selected from the group consisting of C₁₋₆-alkyl, hydroxy, C₁₋₄-alkoxy, halo, amino, and mono- or di-C₁₋₄-alkylamino; where Y is -NH-; q is 1-5; q′ is 0-5; R¹⁰ is hydrogen; hydroxy; N(R′)₂, where R′ may be the same or different and is hydrogen or C₁₋₄-alkyl; guanidyl; or N(R′)₃⊕A⊖, where R′ is as defined above, and A⊖ is a counterion; provided that at least one R¹⁰ is not hydrogen; R¹¹ is C₁₋₄-alkyl; C₃₋₇-cycloalkyl; aryl; aryl substituted with up to three members independently selected from the group consisting of C₁₋₆-alkyl, hydroxy, C₁₋₄-alkoxy, amino, mono- or di-C₁₋₄-alkylamino, amino C₁₋₄-alkyl, mono-, di-, or tri-C₁₋₄-­alkylamino-C₁₋₄-alkyl, carboxy, carboxy ester or amide, carboxy-C₁₋₄-alkyl, carboxy-C₁₋₄-alkyl ester or amide; carboxy, ester or amide; sulfo; heterocycle; or heterocycle substituted with up to five members independently selected from the group consisting of hydroxy, C₁₋₄-alkoxy, halo, amino, and mono- or di-C₁₋₄-alkylamino; R¹² is hydrogen; or carboxy, ester or amide; R¹³ is carboxy, ester or amide; sulfo; or aryl substituted with up to three members selected from the group consisting of amino-C₁₋₄-alkyl, mono-, di-, or tri-C₁₋₄-alkylamino-C₁₋₄-­alkyl, carboxy, carboxy ester or amide, R¹⁴ is carboxy, ester or amide, L is absent; OR˝; NHR˝; or N(R˝)₂, where R˝ may be the same or different and is hydrogen or C₁₋₄-alkyl; or pharmaceutically acceptable salts thereof.

Claim 7

The use as claimed in Claim 3, wherein: A is t-butyloxycarbonyl, ethoxycarbonyl, or t-butylacetyl; B is absent; R¹ is C₁₋₄-alkyl, hydroxy C₁₋₄-alkyl, or aryl; R⁵ is C₁₋₄alkyl or aryl. R⁶ is C₃₋₇-cycloalkyl, aryl, or hydroxyaryl. J is defined as in (1) or (2); R⁷ is C₁₋₄-alkyl, aryl, pyridyl, pyridylamino; R⁹ is H; L is NHR˝; and R³ is C₁₋₄-alkyl, aryl, or substituted aryl.

Claim 8

The use as claimed in Claim 3, wherein: A is t-butyloxycarbonyl; R¹ is aryl; R⁵ is aryl; R⁶ is C₃₋₇-cycloalkyl, aryl, or hydroxy aryl; R³ is aryl.

Claim 9

The compound N′-(1,1-Dimethylethoxy­carbonyl)-Phe-Phe-5(S)-Amino-4(S)-Hydroxy-6-Phenyl-­2(R or S)-(Phenylmethyl)-hexanoyl-Leu-Phe-Amide, or pharmaceutically acceptable salts thereof.

Claim 10

The compound N′-(1,1-Dimethylethoxy­carbonyl)-Phe-Phe-5(S)-Amino-4(S)-Hydroxy-6-Phenyl-­2(R or S)-(Phenylmethyl)-hexanoyl-Leu-Phe-Amide, or pharmaceutically acceptable salts thereof.

Claim 11

The compound N′-(1,1-Dimethylethoxy­carbonyl)-Phe-Phe-5(S)-Amino-4(S)-Hydroxy-6-Phenyl-­2(S or R)-(Phenylmethyl)-hexanoyl-Leu-Phe-Amide, or pharmaceutically acceptable salts thereof.

Claim 12

The compound N′-(1,1-Dimethylethoxy­carbonyl)-Phe-Phe-5(S)-Amino-4(S)-Hydroxy-6-Phenyl-­2(S or R)-(Phenylmethyl)-hexanoyl-Leu-Phe-Amide, or pharmaceutically acceptable salts thereof.

Claim 13

The compound N′-Acetyl-Pro-Phe-His-­4(S)-Amino-3(S)-Hydroxy-6-methylheptanoyl-Glu-Phe-­Gly-Amide, or pharmaceutically acceptable salts thereof.

Claim 14

The compound N′-Acetyl-Pro-Phe-His-­4(S)-Amino-3(S)-Hydroxy-6-methylheptanoyl-Glu-Phe-­Gly-Amide, or pharmaceutically acceptable salts thereof.

Claim 15

The compound N′-(1,1-dimethylethoxy carbonyl)-Phe-Phe-5(S)-amino-4(S)-hydroxy-6-phenyl-­2(R)-(phenylmethyl)hexanoyl-N-(phenylmethyl)-leu-­amide, N′-(1,1-Dimethylethoxycarbonyl)-Phe-Phe-5(S)-amino-­4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-­Leu-amide, N′-(1,1-Dimethylethoxycarbonyl)-Asn-5(S)-amino-4(S)-­hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-Phe-­amide, Asn-5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(phenyl­methyl)hexanoyl-Leu-Phe-amide, or N′-(1,1-Dimethylethoxycarbonyl)-Asp-5(S)-amino-4(S)-­hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-N-­phenylmethyl)-Ile-amide, 5(S)-[(1,1-dimethylethoxycarbonyl)-Asp]amine-4(S)-­hydroxy-6-phenyl-2(R)-(phenylmethyl)-N-(cis-2(R)-­hydroxy-1(S)-indanyl)hexanamide, 5(S)-Asp-amino-4(S)-hydroxy-6-phenyl-2(R)-(phenyl­methyl-N-(cis-2(R)-hydroxy-1(S)-indanyl)hexanamide, or pharmaceutically acceptable salt thereof.

Claim 16

The compound N′-(1,1-dimethylethoxy carbonyl)-Phe-Phe-5(S)-amino-4(S)-hydroxy-6-phenyl-­2(R)-(phenylmethyl)hexanoyl-N-(phenylmethyl)-leu-­amide, N′-(1,1-Dimethylethoxycarbonyl)-Phe-Phe-5(S)-amino-­4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-­Leu-amide, N′-(1,1-Dimethylethoxycarbonyl)-Asn-5(S)-amino-4(S)-­hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-Phe-­amide, Asn-5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(phenyl­methyl)hexanoyl-Leu-Phe-amide, or N′-(1,1-Dimethylethoxycarbonyl)-Asp-5(S)-amino-4(S)-­hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-N-­phenylmethyl)-Ile-amide, 5(S)-[(1,1-dimethylethoxycarbonyl)-Asp]amine-4(S)-­hydroxy-6-phenyl-2(R)-(phenylmethyl)-N-(cis-2(R)-­hydroxy-1(S)-indanyl)hexanamide, 5(S)-Asp-amino-4(S)-hydroxy-6-phenyl-2(R)-(phenyl­methyl-N-(cis-2(R)-hydroxy-1(S)-indanyl)hexanamide, or pharmaceutically acceptable salt thereof.

Claim 17

A pharmaceutical composition comprising the compound of Claim 6 and a pharmaceutical carrier.

Claim 18

A pharmaceutical composition comprising the compound of Claim 7 and a pharmaceutical carrier.

Claim 19

A pharmaceutical composition comprising the compound of Claim 8 and a pharmaceutical carrier.

Claim 20

A pharmaceutical composition comprising any compound of Claim 9 and a pharmaceutical carrier.

Claim 21

A compound as defined in any one of claims 1-9 in combination with any of the antivirals, immunomodulators, antibiotics or vaccines of Table 1.

Claim 22

The use of the combination as claimed in Claim 14 for the preparation of a medicament useful for the treatment of AIDS, the prevention of infection by HIV, the treatment of infection by HIV, or the inhibition of HIV protease.

Claim 23

The use of a compound as claimed in any one of Claims 6, 7, 8 or 9 for the preparation of a medicament useful for the treatment of AIDS, the prevention of infection by HIV, the treatment of infection by HIV, or the inhibition of HIV protease.