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US 5,554,728 AGranted
Lipid conjugates of therapeutic peptides and protease inhibitors
AssigneeNeXstar Pharmaceuticals, Inc.
InventorsChanna Basava, Karl Y. Hostetler
Life of this patent
Estimating the term…
Abstract
Compounds wherein therapeutic peptides are covalently linked to phospholipids, glycerides or other membrane-targeting and membrane-anchoring species, and their pharmaceutically acceptable salts, together with processes for their preparation. The targeting technology is applicable to HIV protease inhibitors and a variety of other enzyme inhibitors.
Claims8
A peptide-lipid conjugate selected from the group consisting of:
- ##STR7## wherein X represents phosphatidyl-tyrosine;
- phosphatidyl-serine;
- phosphatidyl-threonine;
- phosphatidyl-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-phospho-O-serine;
- 1-O-acyl-sn-glycero-3-phospho-O-serine;
- 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine;
- 1-O-acyl-sn-glycero-3-phospho-O-threonine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-serine;
- 1-O-acyl-sn-glycero-3-diphospho-O-serine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-diphospho-O-threonine;
- 1-O-acyl-sn-glycero-3-diphospho-O-threonine;
- phosphatidyl ethanolamine-Y;
- phosphatidic acid, or phosphatidic acid-Z,
- wherein Y is HOOC--(CH.sub.2).sub.n --COOH;
- Z is HO--(CH.sub.2).sub.n --COOH;
- and n=1 to 12;
- C represents H, OH, OMe, NH.sub.2, NH--R where R represents C.sub.1-12 alkyl, benzyl, substituted benzyl, (CH.sub.2).sub.n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H.sub.2 N--(CH.sub.2).sub.n --COOH, and n=1 to 12.
25 more elements
A peptide-lipid conjugate selected from the group consisting of:
- 5(S)-X-Amino-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-Phe-C;
- 5(S)-X-Amino-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-C;
- 5(S)-X-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(phenylmethyl)hexanoyl-C;
- 5(S)-X-Amino-4(R)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-Phe-C;
- 5(S)-X-Amino-4(R)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-C;
- and
- 5(S)-X-amino-4(R)-hydroxy-6-cyclohexyl-2(R)-(phenylmethyl)hexanoyl-C;
- wherein
- X represents phosphatidyl-tyrosine;
- phosphatidyl-serine;
- phosphatidyl-threonine;
- phosphatidyl-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-phospho-O-serine;
- 1-O-acyl-sn-glycero-3-phospho-O-serine;
- 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine;
- 1-O-acyl-sn-glycero-3-phospho-O-threonine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-serine;
- 1-O-acyl-sn-glycero-3-diphospho-O-serine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-diphospho-O-threonine;
- 1-O-acyl-sn-glycero-3-diphospho-O-threonine;
- phosphatidyl ethanolamine-Y;
- phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH.sub.2).sub.n --COOH and
- Z is HO--(CH.sub.2).sub.n --COOH;
- and n=1 to 12;
- and
- C represents H, OH, OMe, NH.sub.2, NH--R where R represents C.sub.1-12 alkyl, benzyl, substituted benzyl, (CH.sub.2).sub.n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H.sub.2 N--(CH.sub.2).sub.n --COOH, and n=1 to 12.
33 more elements
A peptide-lipid conjugate selected from the group consisting of:
- 5(S)-X-Amino-4(S)-hydroxy-6-cyclcohexyl-2(R)-isopropyl-hexanoyl-Ile-C;
- 5(S)-X-Amino-4(R)-hydroxy-6-cyclcohexyl-2(S)-isopropyl-hexanoyl-Ile-C;
- 5(S)-X-Amino-4(S)-hydroxy-6-phenyl-2(R)-isopropyl-hexanoyl-Ile-C;
- and
- 5(S)-X-Amino-4(R)-hydroxy-6-phenyl-2(S)-isopropyl-hexanoyl-Ile-C;
- wherein
- X represents phosphatidyl-tyrosine;
- phosphatidyl-serine;
- phosphatidyl-threonine;
- phosphatidyl-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-phospho-O-serine;
- 1-O-acyl-sn-glycero-3-phospho-O-serine;
- 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine;
- 1-O-acyl-sn-glycero-3-phospho-O-threonine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-serine;
- 1-O-acyl-sn-glycero-3-diphospho-O-serine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-diphospho-O-threonine;
- 1-O-acyl-sn-glycero-3-diphospho-O-threonine;
- phosphatidyl ethanolamine-Y;
- phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH.sub.2).sub.n --COOH and
- Z is HO--(CH.sub.2).sub.n --COOH;
- and n=1 to 12;
- and
- C represents H, OH, OMe, NH.sub.2, NH--R where R represents C.sub.1-12 alkyl, benzyl, substituted benzyl, (CH.sub.2).sub.n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H.sub.2 N--(CH.sub.2).sub.n --COOH, and n=1 to 12.
31 more elements
A peptide-lipid conjugate selected from the group consisting of:
- (3(S)-X-Asparaginyl)-amino-2(R)-hydroxy-4-phenylbutyl-Pro-C;
- (3(S)-X-Asparaginyl)-amino-2(S)-hydroxy-4-phenylbutyl-Pro-C;
- (3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-Pro-C;
- (3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-Pro-Ile-C;
- (3(S)-X-Leucyl-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-Pro-Ile-C;
- (3(S)-X-Asparaginyl)-amino-2(R)-hydroxy-4-phenylbutyl-N-1,2,3,4-tetrahydro( R,S)isoquinoline carboxyl-C;
- (3(S)-X-Asparaginyl)-amino-2(S)-hydroxy-4-phenylbutyl-N-1,2,3,4-tetrahydro( R,S)isoquinoline carboxyl-C;
- (3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-N-1,2,3,4-tetrahydr o(R,S)isoquinoline carboxyl-C;
- (3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-N-decahydro-3(S)-is oquinoline carboxyl-C;
- (3(S)-X-Asparaginyl)-amino-2(R)-hydroxy-4-phenylbutyl-N-decahydro-3(S)-isoq uinoline carboxyl-C;
- and
- (3(S)-X-Asparaginyl)-amino-2(S)-hydroxy-4-phenylbutyl-N-decahydro-3(S)-isoq uinoline carboxyl-C;
- wherein
- X represents phosphatidyl-tyrosine;
- phosphatidyl-serine;
- phosphatidyl-threonine;
- phosphatidyl-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-phospho-O-serine;
- 1-O-acyl-sn-glycero-3-phospho-O-serine;
- 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine;
- 1-O-acyl-sn-glycero-3-phospho-O-threonine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-serine;
- 1-O-acyl-sn-glycero-3-diphospho-O-serine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-diphospho-O-threonine;
- 1-O-acyl-sn-glycero-3-diphospho-O-threonine;
- phosphatidyl ethanolamine-Y;
- phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH.sub.2).sub.n --COOH and
- Z is HO--(CH.sub.2).sub.n --COOH;
- and n=1 to 12;
- and
- C represents H, OH, OMe, NH.sub.2, NH--R where R represents C.sub.1-12 alkyl, benzyl, substituted benzyl, (CH.sub.2).sub.n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H.sub.2 N--(CH.sub.2).sub.n --COOH, and n=1 to 12.
38 more elements
A peptide-lipid conjugate selected from the group consisting of:
- 4(S)-(X-Alanyl)amino-3(S)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;
- 4(S)-(X-Alanyl-alanyl)amino-3(S)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;
- 4(S)-(X-Seryl-alanyl-alanyl)amino-3(S)-hydroxy-5-phenyl-pentanoyl-Val-Val-C
- 4(S)-(X-Alanyl)amino-3(R)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;
- 4(S)-(X-Alanyl-alanyl)amino-3(R)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;
- and
- 4(S)-(X-Seryl-alanyl-alanyl)amino-3(R)-hydroxy-5-phenyl-pentanoyl-Val-Val-C ;
- wherein
- X represents phosphatidyl-tyrosine;
- phosphatidyl-serine;
- phosphatidyl-threonine;
- phosphatidyl-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-phospho-O-serine;
- 1-O-acyl-sn-glycero-3-phospho-O-serine;
- 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine;
- 1-O-acyl-sn-glycero-3-phospho-O-threonine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-serine;
- 1-O-acyl-sn-glycero-3-diphospho-O-serine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-diphospho-O-threonine;
- 1-O-acyl-sn-glycero-3-diphospho-O-threonine;
- phosphatidyl ethanolamine-Y;
- phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH.sub.2).sub.n --COOH and
- Z is HO--(CH.sub.2).sub.n --COOH;
- and n=1 to 12;
- and
- C represents H, OH, OMe, NH.sub.2, NH--R where R represents C.sub.1-12 alkyl, benzyl, substituted benzyl, (CH.sub.2).sub.n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H.sub.2 N--(CH.sub.2).sub.n --COOH, and n=1 to 12.
33 more elements
A peptide lipid conjugate of the formula
- iBoc-Phe-Pip-Val-DPPE.
- 8.
A peptide-lipid conjugate selected from the group consisting of:
- X-Val-Phe-Nva-(cyclohexylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxoborlan-2-yl) methylamide;
- X-Val-Phe-Nva-(cyclohexylmethyl, dihydroxyboronyl)methylamide;
- X-Val-Phe(L-a-Nal)-Nva-(cyclohexylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxobor lan-2-yl)methylamide;
- X-Val-Phe(L-a-Nal)-Nva-(cyclohexylmethyl, dihydroxyboronyl)methylamide;
- X-Nva(cyclohexylmethyl, dihydroxyboronyl)methylamide;
- and
- X-Val(cyclohexylmethyl, dihydroxyboronyl)methylamide;
- wherein:
- X represents phosphatidyl-tyrosine;
- phosphatidyl-serine;
- phosphatidyl-threonine;
- phosphatidyl-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-phospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-phospho-O-serine;
- 1-O-acyl-sn-glycero-3-phospho-O-serine;
- 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-phospho-O-threonine;
- 1-O-acyl-sn-glycero-3-phospho-O-threonine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-serine;
- 1-O-acyl-sn-glycero-3-diphospho-O-serine;
- 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;
- 1-O-alkyl-sn-glycero-3-diphospho-O-threonine;
- 1-O-acyl-sn-glycero-3-diphospho-O-threonine;
- phosphatidyl ethanolamine-Y;
- phosphatidic acid, or phosphatidic acid-Z,
- wherein Y is HOOC--(CH.sub.2).sub.n --COOH;
- Z is HO--(CH.sub.2).sub.n --COOH;
- and n=1 to 12.
30 more elements
Dependencies are inferred from the claim text.