HIV protease inhibitors containing derived amino acids

Claim 2

A compound as recited in claim 1 wherein X is as defined in claim 1; A is Ala, Abu, Val, Nva, Leu, Ile, Nle or Tbg; B is NHCH(R²)-Q wherein R² is lower alkyl, (lower cycloalkyl)methyl, benzyl, (4-hydroxyphenyl)methyl or (4-methoxyphenyl)methyl and Q is CH(OH)CH₂C(O) or CH₂NHCH(R³)C(O) wherein R³ is lower alkyl, (lower cycloalkyl)methyl or phenyl; C' is NHCH(R⁴)C(W) wherein R⁴ is cyclopropylmethyl, CH₂CH₂C(O)OH, CH₂CH(CH₃)C(O)OH, CH(C₂H₅)CH₂C(O)OH, CH₂CH₂C(O)OCH₃, CH₂CH(CH₃)C(O)OCH₃, CH(CH₃)CH(CH₃)C(O)OCH₃, CH₂CH₂CH₂C(O)OH or CH₂CH₂CH₂C(O)OCH₃ and W is oxo or thioxo; and Y is OR¹¹ wherein R¹¹ is (i) (1-10C)alkyl, (ii) cyclopropyl, cyclopentyl or cyclohexyl, (iii) (lower cycloalkyl)methyl, (lower cycloalkyl)ethyl or (lower cycloalkyl)propyl, (iv) phenyl(lower alkyl) or phenyl(lower alkyl) substituted at position 4 of the phenyl with hydroxy, lower alkoxy, fluoro, chloro or lower alkylthio; or Y is NR¹³R¹⁴ wherein R¹³ is hydrogen or methyl and R¹⁴ has the same meaning as defined in this claim for R¹¹; or a therapeutically acceptable salt thereof.

Claim 3

A compound as recited in claim 1 wherein X is acetyl, 1-oxopropyl, 1-oxobutyl, 3-methyl-1-oxobutyl, 3,3-dimethyl-1-oxobutyl, 2-ethyl-1-oxobutyl, 2-hydroxy-1-oxopropyl, 3-hydroxy-1-oxopropyl or 2,3-dihydroxy-1-oxopropyl; A is Val, Nva, Leu, Ile, Nle or Tbg; B is NHCH(R²)CH(OH)CH₂C(O) wherein R² is 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, (4-hydroxyphenyl)methyl or (4-methoxyphenyl)methyl, or B is NHCH(R²)CH₂NHCH(R³)C(O) wherein R² is as defined in the last instance and R³ is 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2,2-dimethylpropyl, cyclopropylmethyl, cyclohexylmethyl or phenyl; C' is Cpa, Glu, Glu(OMe), Adp or Adp(OMe); and Y is methoxy, ethoxy, hexyloxy, octyloxy, cyclopropyloxy, 3-cyclopropylpropoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy, 2-phenylethoxy, 2-(4-fluorophenyl)ethoxy, 2-[4-(methylthio)phenyl]ethoxy, 3-phenylpropoxy, 3-(4-hydroxyphenyl)propoxy, 3-(4-propoxyphenyl)propoxy, 3-(4-fluorophenyl)propoxy, 3-(4-chlorophenyl)propoxy, 3-[4-(methylthio)phenyl]propoxy, methylamino, 3-cyclopropylpropylamino, 2-cyclohexylethylamino, 3-cyclohexylpropylamino, 2-phenylethylamino, 2-(4-fluorophenyl)ethylamino, 2-[4-(methylthio)phenyl]ethylamino, 3-phenylpropylamino, 3-(4-hydroxyphenyl)propylamino, 3-(4-methoxyphenyl)propylamino, 3-(4-propoxyphenyl)propylamino, 3-(4-fluorophenyl)propylamino, 3-(4-chlorophenyl)propylamino or 3-[4(methylthio)phenyl]propylamino; or a therapeutically acceptable salt thereof.

Claim 4

A compound as recited in claim 1 wherein X is acetyl, 1-oxopropyl, 3,3-dimethyl-1-oxobutyl, 2-ethyl-1-oxobutyl, 2(S)-hydroxy-1-oxopropyl or 2(S)-3-dihydroxy-1-oxopropyl; A is Val or Tbg, B either is NHCH(R²)CH(OH)CH₂C(O) wherein R² is 1-methylpropyl, 2-methylpropyl, butyl, cyclopropylmethyl or cyclohexylmethyl, or B is NHCH(R²)CH₂NHCH(R³)C(O) wherein R² is benzyl and R³ is 2-methylpropyl or cyclopropylmethyl, the two asymmetric centers of the last said radical having the (S) chiral configuration; C' is Cpa, Glu or Glu(OMe) and Y is 2-phenylethoxy, 3-phenylpropoxy, 2-phenylethylamino, 2-(4-fluorophenyl)ethylamino, 2-[4-(methylthio)phenyl]ethylamino, 3-phenylpropylamino, 3-(4-hydroxyphenyl)propylamino, 3-(4-propoxyphenyl)propylamino or 3-[4-(methylthio)phenyl]propylamino; or a therapeutically acceptable salt thereof.

Claim 5

A compound as recited in claim 1 selected from the group consisting of Ac-Val-ACHPA-Glu-NHCH₂CH₂Ph, Ac-Val-ACHPA-Glu(OMe)-NHCH₂CH₂Ph, Ac-Tbg-ACHPA-Glu-NHCH₂CH₂Ph, Ac-Tbg-ACHPA-Glu(OMe)-NHCH₂CH₂Ph, (S)-HOCH₂CH(OH)C(O)-Tbg-ACHPA-Glu-CH₂CH₂Ph, (S)-HOCH₂CH(OH)C(O)-Tbg-ACHPA-Glu(OMe)-NHCH₂CH₂Ph, CH₃CH₂C(O)-Tbg-ACHPA-Glu-NHCH₂CH₂Ph, (CH₃)₃CCH₂C(O)-g-ACHPA-Glu-NHCH₂CH₂Ph, Ac-Tbg-ACHPA-Cpa-NHCH₂CH₂Ph, (C₂H₅)₂CHC(O)-Val-ACHPA-Cpa-NHCH₂CH₂CH₂Ph and Ac-Val-PheΨ[CH₂NH]Leu-Glu-NHCH₂CH₂Ph.

Claim 6

A pharmaceutical composition comprising a compound as recited in claim 1, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Claim 7

The use of a compound as recited in anyone of claims 1 to 5, or a therapeutically acceptable salt thereof, for the manufacture of a medicament for treating HIV infections in a human.

Claim 8

The use of a compound as recited in anyone of claims 1 to 5, or a therapeutically acceptable salt thereof, for the manufacture of a medicament for protecting human cells against HIV pathogenesis.

Claim 9

A process for preparing a compound of formula 1 as recited in claim 1 comprising: coupling the acid of formula X-OH wherein x is as defined in claim 1 with an intermediate of formula H-A-B-C''-Y wherein A, B and Y are as defined in claim 1 and C'' has the same meaning as defined for C'' in claim 1 except that a side chain carboxy or ester group is replaced by a protected carboxy to obtain: a) when the intermediate does not bear a protected carboxy, the corresponding compound of formula 1; or b) when the intermediate bears a protected carboxy, the corresponding intermediate of formula X-A-B-C''-Y and subjecting the last said intermediate to carboxy deprotection, or carboxy deprotection and esterification, to obtain the corresponding compound of formula 1; and, if desired transforming the compound of formula 1 into a therapeutically acceptable salt.