Retroviral protease binding peptides

Claim 2

A peptide of the formula: A-B-(Q) a -(C) b -(D) c -M-(W) d -(X) e -Y-Z      (I) wherein: A is BocNH, CbzNH, H, R′R˝N, R˝CONR′ or DnsNH, or if a, b and c are 0 and Y is a covalent bond, then A is H, Boc, Cbz, R˝ or R˝CO; B is one or more D or L amino acids, β-Ala or is a covalent bond; C and D are the same or different and are Glx, Asx, Ala, β-Ala, Arg, Gly, Ile, Leu, Lys, Ser, Thr, Val, Met or His; Q is a D or L amino acid and is Ser, Thr, Asp, His, Cys, Arg or Ala; W is Pro or Δ3-dehydro-Pro; X is Ala, Gly, Ile, Leu, Val, Met, Lys, Glx or Asx; Y is one or more D or L amino acids, or is a covalent bond; Z is CO₂R˝˝, CONR′R˝˝, COR′, CH₂OH,CH₂NR′R˝R˝ or H, or if d and e are 0 and Y is a covalent bond, Z is OR˝˝ or NR′R˝˝; a, b, c, d and e are each independently 0 or 1, provided that c and e are not simultaneously 0; M is Cha, Phe(4′R a ) or -NHCHR₁R₂-; wherein: R₁ is independently C₁₋₅Alk, (CH₂) n SC₁₋₅Alk, (CH₂) n OC₁₋₅Alk, (CH₂) n C₃₋₇cycloalkyl or (CH₂) m C₆H₄-R a ; R a is halogen, OR′, NO₂, NH₂ or H; R₂ is (CH₂) n -, CHR₃(CH₂) m CO-, CO(CH₂) m CO-, CHR₃CHR 3′ (CH₂) m CO-, CHR₃CHR 3′ CHR₁(CH₂) m CO-, CHR₃CHR₁CHR′(CH₂) m C0-, CHR₃CHR′CHR₁(CH₂) m CO-, COCR₁CHR′(CH₂) m CO-, COCF₂CR′R˝(CH₂) m CO-, COCF₂(CH₂) m CO-, CH=CR′CHR˝(CH₂) m CO-, COCH=CR′(CH₂) m CO-, CH₂S(O) p CHR′(CH₂) m CO-, CH₂NR′CHR˝(CH₂) m CO-, P=O(OR′)(CH₂) m CO-, R₃ and R 3′ are each independently OH, H or NH₂; R₄ is OH, H, NH₂ or =0; m is independently 0, 1, 2 or 3; n is independently 1 or 2; p is 0, 1 or 2; R′ is H or C₁₋₅Alk; R˝ is H or C₁₋₁₈Alk; R˝˝ is H, C₁₋₅Alk, C₃₋₆cycloalkyl, (CH₂) n C₆H₅, (CH₂) n C₅H₄N, (CH₂) n OH, (CH₂) n NH₂, or(CH₂) n NHC(NH)NH₂; and pharmaceutically acceptable salts thereof.

Claim 3

A compound according to claim 1 in which B is one or two D or L amino acids chosen from the group consisting of Ala, β-Ala, Gly, Val, Ile, Leu, Met, His, Lys, Arg, Glx, Asx, Cys, Ser and Thr, or is a covalent bond, and Y is one to three D or L amino acids chosen from the group consisting of Ala, Gly, Ile, Leu, Met, Val, Arg, Lys, Thr, Ser, Cys, Glx and Asx, or is a covalent bond.

Claim 4

A compound according to claim 1 or 2 in which Q is a D or L amino acid chosen from the group consisting of Ser, Thr, Asp and His, and D is chosen from the group consisting of Glx, Asx, Ser, Ala, β-Ala, Ile, Leu, Val and Met.

Claim 5

A compound according to any one of claims 1 to 3 in which d is 0 and M is -NHCHR₁R₂.

Claim 6

A compound according to any one of claims 1 to 4 in which R₁ is CH₂C₆H₄-R a , CH₂C₆H₁₁ or C₁₋₅Alk, and R₂ is CHR₃CHR 3′ (CH₂) m CO-, CHR₃CHR 3′ CHR₁CO-, CHR₃CHR₁CHR′C0-, CHR₃(CH₂) m CO-, CO(CH₂) m CO-,COCR₁CHR′(CH₂) m CO-, CHR₃CF₂(CH₂) m CO-, -COCF₂(CH₂) m CO-, -P=O(OR′)(CH₂) m CO-,

Claim 7

A compound according to any one of claims 1 to 5 in which Y is one amino acid chosen from the group consisting of Ala, Gly, Ile, Met, Asx, Arg and Val, or is a covalent bond and C and D are chosen from the group consisting of Gln, Asn and Ala.

Claim 8

A compound according to any one of claims 1 to 6 in which R₂ is CH(OH)CH₂CH₂CO-.

Claim 9

A compound according to any one of claims 1 to 7 in which B is a covalent bond and a is 0.

Claim 10

A compound according to claim 8 in which b is 0.

Claim 11

A compound according to claim 1 which is: 2-(acetyl-serylglutaminylasparaginyl)amino-3-­phenylpropyl-prolylvalyl valinamide; 2-(serylglutaminylasparaginyl)amino-3-phenylpropyl­prolylvalyl valinamide; 4-(acetyl-serylglutaminylasparaginyl)amino-3-hydroxy-1-­oxo-5-phenylpentylprolylvalyl valinamide; 4-(acetyl-serylglutaminylasparaginyl)amino-3-hydroxy-1-­oxo-5-phenylpentylvalyl valinamide; 4-(seryl glutaminylasparaginyl)amino-3(S)-hydroxy-1-oxo-­5-phenyl pentylvalyl valinamide; 5-(carbobenzyloxy-alanylalanyl)amino-6-phenyl-4-hydroxy­(1-oxo)hexyl-valyl valinol; carbobenzyloxy-alanyl-(3-hydroxy-5-amino-6-­phenyl)hexanoyl-valyl-(4-aminomethyl)pyridine; or 5-(carbobenzyloxyalanylalanyl)amino-4-hydroxy-6-phenyl­(1-oxo)hexyl-valine isobutylamide; and pharmaceutically acceptable salts thereof.

Claim 12

A compound according to claim 1 which is: 2-((2-(tert-butoxycarbonyl-serylalanylalanyl)amino-1-oxo-­3-phenylpropyl)cyclopentylcarbonylvalyl valine methyl ester; 2-(2-(serylalanylalanyl)amino-1-oxo-3-phenylpropyl)cyclo­pentylcarbonylvalylvaline methyl ester; 2-(2-(tert-butoxycarbonyl-serylalanylalanyl)amino-1-­hydroxy-3-phenylpropyl)cyclopentylcarbonylvalyl valine methyl ester; 2-(-1-hydroxy-3-phenyl-2-(serylalanylalanyl)amino­propyl)cyclopentylcarbonylvalylvaline methyl ester; 2-((1-methoxy-1-(2-phenyl-1-(tert-butyloxycarbonyl­serylalanylalanyl)amino)ethyl)phosphinyl)cyclopentyl­carbonyl-valylvaline methyl ester; 2-((1-hydroxy-1-(2-phenyl-1-(serylalanylalanyl)amino) ethyl)phosphinyl)cyclopentylcarbonyl-valyl valine methyl ester; 5-(tert-butoxycarbonyl-serylalanylalanyl)amino-4-hydroxy-­1-oxo-6-phenylhexyl-valyl valine methyl ester; 5-(tert-butoxycarbonyl-serylalanylalanyl)amino-4-hydroxy-­1-oxo-6-(4-hydroxy-phenyl)hexyl-valyl valine methyl ester; 4-(tert-butoxycarbonyl-serylalanylalanyl)amino-2,2-­difluoro-3-hydroxy-1-oxo-5-phenylpentyl-valyl valine methyl ester; 4-(serylalanylalanyl)amino-2,2-difluoro-3-hydroxy-1-oxo-­5-phenylpentyl-valyl valine methyl ester; 4-(serylalanylalanyl)amino-2,2-difluoro-1,3-dioxo-5-­phenylpentyl-valyl valine methyl ester; 5-(t-butyloxycarbonylserylalanylalanyl)amino-4-hydroxy-­6-(4-hydroxy)phenyl-1-oxo-hexyl-valyl amide 5-((carbobenzyloxy-D-seryl)alanylalanyl)amino-4-hydroxy-­1-oxo-6-phenylhexyl-valyl valine methyl ester; 5-((D-seryl)alanylalanyl)amino-4-hydroxy-1-oxo-6-­phenylhexyl-valyl valine methyl ester; 5-(t-butyloxycarbonylserylalanylalanyl)amino-6-(4-­hydroxy)phenyl-4-hydroxy-1-oxo-hexyl-valyl valine; 5-(serylalanylalanyl)amino-6-(4-hydroxy)phenyl-4-­hydroxy-1-oxo-hexyl-valyl valine; 2-((1-hydroxy-2-(serylalanylalanyl)amino-3-cyclohexyl)­propyl)cyclopentanecarbonyl-valyl valine methyl ester; (4S,5S) 5-(carbobenzyloxyalanyl)amino-4-hydroxy-1-oxo-6-­phenylhexyl-valyl valine methyl ester; (4S,5S) 5-(alanyl)amino-4-hydroxy-1-oxo-6-phenylhexyl­valyl valine methyl ester; (4S,5S) 5-(tert-butyloxycarbonylalanyl)amino-4-hydroxy-­1-oxo-6-(4-hydroxyphenyl)hexyl-valyl valine methyl ester; (4S,5S)-5-alanylamino-4-hydroxy-1-oxo-6-(4-­hydroxyphenyl)-hexyl-valyl valine methyl ester; (4S,5S) 5-(alanylalanyl)amino-4-hydroxy-1-oxo-6-(4-­hydroxyphenyl)hexyl-valyl valine methyl ester; (4S,5S) 5-[(carbobenzyloxy-β-alanyl)alanyl]amino-4-­hydroxy-1-oxo-6-(4-hydroxyphenyl)hexyl-valyl valine methyl ester; (4S,5S) 5-[(β-alanyl)alanyl]amino-4-hydroxy-1-oxo-6-(4-­hydroxyphenyl)hexyl-valyl valine methyl ester; (4S,5S) 5-(alanylalanyl)amino-4-hydroxy-1-oxo-6-­cyclohexyl-hexyl-valyl valine methyl ester; (4S,5S) 5-(carbobenzyloxyalanylalanyl)amino-4-hydroxy-1-­oxo-6-phenylhexyl-valyl valine methyl ester; (4S,5S) 5-(alanylalanyl)amino-4-hydroxy-1-oxo-6-­phenylhexyl-valyl valine methyl ester; (4RS,5S) 5-amino-6-(4-hydroxy)phenyl-4-hydroxy-1-oxo-­hexyl-valyl valine benzyl ester; (1R,2R)-2-(((1S,2S)-1-hydroxy-2-amino-3-cyclohexyl)­propyl)cyclopentanecarbonyl-valyl valine methyl ester; (4S,5S) 5-amino-4-hydroxy-1-oxo-6-phenylhexyl-valyl valine methyl ester; (4S,5S)-5-(tert-butyloxycarbonyl)amino-4-hydroxy-1-oxo-­6-phenylhexyl-valyl valine methyl ester; (4S,5S) 5-(methoxycarbonyl-alanylalanyl)amino-6-phenyl-­4-hydroxy-(1-oxo)hexyl-valyl valine; or (4RS,5S) 5-((tert-butyloxycarbonyl)isoleucyl)amino-7-­methyl-4-hydroxy-1-oxo-octyl-leucyl-aspartic acid methyl ester; or the carboxamides thereof; and pharmaceutically acceptable salts thereof.

Claim 13

A compound according to any one of claims 4-11 for use in a medicament.

Claim 14

A pharmaceutical composition which comprises a compound according to any one of claims 4-11 and a pharmaceutically acceptable carrier.

Claim 15

A pharmaceutical composition which comprises a compound according to any one of claims 4-11 , azidothymidine and a pharmaceutically acceptable carrier.

Claim 16

An intermediate compound of the formula: wherein: R₁ is independently C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, -(CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R a is halogen, NO₂, OH, OC₁₋₅Alk, NH₂, or H; R₂ is (CH₂) n -X, (CH₂) n CO-X, CHR₃CHR₁CHR′(CH₂) m C0-, COCR₁CHR′(CH₂) m CO-, CHR₃CF₂(CH₂) m CO-X, COCF₂CR′R˝(CH₂) m CO-X, CHR₃(CH₂) m CO-X, CO(CH₂) m CO-X, COCR₁CHR′(CH2) m CO-X, R₃ is H, NH₂ or OH; R₄ is H, NH₂, OH, or =O; R₅ is H; R₆ is CH₃CO, C₁₋₅Alk, Dns, Cbz or Boc, or taken together R₅ and R₆ are phthalimido; X is H, halogen, OH, OC₁₋₅Alk, NHR′R˝ or OCOC₁₋₅Alk; R′ and R˝ are H or C₁₋₅Alk; m is independently 0, 1, 2 or 3; and n is independently 1 or 2; provided that R₂ is not CHR₃CH₂CO-X, COCH₂CO-X, COCF₂CO-X or CHR₃CF₂CO-X when R₁ is phenylmethylene, isobutyl or cyclohexylmethylene, and R₂ is not CH(OH)CH₂CH₂CO-X or COCH₂CH₂CO-X, when R₁ is isobutyl.

Claim 17

An intermediate compound of the formula: wherein: R₁ is independently C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, -(CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R a is halogen, NO₂, OH, OC₁₋₅Alk, NH₂, or H; R₂ is (CH₂) n -X, (CH₂) n CO-X, CHR₃CHR₁CHR′(CH₂) m C0-, COCR₁CHR′(CH₂) m CO-, CHR₃CF₂(CH₂) m CO-X, COCF₂CR′R˝(CH₂) m CO-X, CHR₃(CH₂) m CO-X, CO(CH₂) m CO-X, COCR₁CHR′(CH2) m CO-X, R₃ is H, NH₂ or OH; R₄ is H, NH₂, OH, or =O; R₅ is H; R₆ is CH₃CO, C₁₋₅Alk, Dns, Cbz or Boc, or taken together R₅ and R₆ are phthalimido; X is H, halogen, OH, OC₁₋₅Alk, NHR′R˝ or OCOC₁₋₅Alk; R′ and R˝ are H or C₁₋₅Alk; m is independently 0, 1, 2 or 3; and n is independently 1 or 2; provided that R₂ is not CHR₃CH₂CO-X, COCH₂CO-X, COCF₂CO-X or CHR₃CF₂CO-X when R₁ is phenylmethylene, isobutyl or cyclohexylmethylene, and R₂ is not CH(OH)CH₂CH₂CO-X or COCH₂CH₂CO-X, when R₁ is isobutyl.

Claim 18

A compound according to claim 15 which is: wherein: R₁ is C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, (CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R a is halogen, NO₂, OH, OC₁₋₅Alk, NH₂ or H; m is 0, 1, 2 or 3; n is 1 or 2; R₅ is H; R₆ is CH₃CO, C₁₋₅Alk, Dns, Cbz or Boc, or taken together R₅ and R₆ are phthalimido; X is H, halogen, OH, OC₁₋₅Alk, NHR′R˝ or OCOC₁₋₅Alk; and R′ and R˝ are H or C₁₋₅Alk.

Claim 19

A compound according to claim 15 which is: wherein: R is C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, (CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R 1′ is H, C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, (CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R₄ is OH, NH₂, H or =O; R a is halogen, NO₂, OH, OC₁₋₅Alk, NH₂ or H; m is independently 0, 1, 2 or 3; n is independently 1 or 2; R₅ is H; R₆ is CH₃CO, C₁₋₅Alk, Dns, Cbz or Boc, or taken together R₅ and R₆ are phthalimido; X is H, halogen, OH, OC₁₋₅Alk, NHR′R˝ or OCOC₁₋₅Alk; and R′ and R˝ are H or C₁₋₅Alk; provided that R₁ is not isobutyl when R 1′ is H.

Claim 20

A compound according to claim 17 in which R 1′ is H, R₁.is CH₂C₆H₄-R a and R₄ is OH or =O.

Claim 21

A compound according to claim 15 which is: wherein: R₁ is C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, (CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R a is halogen, NO₂, OH, OC₁₋₅Alk, NH₂ or H; R₄ is H, NH₂, OH, or =O; m is 0, 1, 2 or 3; n is 1 or 2; R₅ is H; R₆ is CH₃CO, C₁₋₅Alk, Dns, Cbz or Boc, or taken together R₅ and R₆ are phthalimido; X is H, halogen, OH, OC₁₋₅Alk, NHR′R˝ or OCOC₁₋₅Alk; and R′ and R˝ are H or C₁₋₅Alk.

Claim 22

A compound according to claim 15 which is: wherein: R₁ is C₁₋₅Alk, -(CH₂) n SC₁₋₅Alk, -(CH₂) n OC₁₋₅Alk, (CH₂) n C₃₋₇cycloalkyl or -(CH₂) m C₆H₄-R a ; R a is halogen, NO₂, OH, OC₁₋₅Alk, NH₂ or H; m is 0, 1, 2 or 3; n is 1 or 2; R₅ is H; R₆ is CH₃CO, C₁₋₅Alk, Dns, Cbz or Boc, or taken together R₅ and R₆ are phthalimido; X is H, halogen, OH, OC₁₋₅Alk, NHR′R˝ or OCOC₁₋₅Alk; and R′ and R˝ are H or C₁₋₅Alk.