Non-natural amino acids

Patent metadata

Field	Value
Publication number	US-9359291-B2
Application number	US-201313784212-A
Country	US
Kind code	B2
Filing date	Mar 4, 2013
Priority date	Jun 17, 2004
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

This invention relates in one aspect to non-natural desamino alkyl amino acid compounds, methods of making these compounds, and peptides containing these compounds. In one embodiment, the peptide is neurotensin (8-13) in which the N-terminus is an alpha-desamino, alpha-methyl-N,N-dimethyl-homolysine residue of the invention.

First claim

What is claimed is:

1. A non-natural desamino, alkyl amino acid compound of Formula I is:

wherein
n is 3, 4, or 5;
m is 0 or 1;
R is a straight or branched chain C 1 -C 6 alkyl group;
R 1 , R 2 , and R 3 are independently selected from the group consisting of: H; branched or straight chain C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkenyl; a protecting group that is removable by a chemical method that does not also cause cleavage of other groups; a C 6 -C 18 aromatic group, wherein the aromatic group is optionally substituted with one or two substituents independently selected from the group consisting of halogen, alkyloxy, carboxy, amide and alkyl; and a C 4 -C 18 heteroaromatic group and one or two heteroatoms independently selected from the group consisting of oxygen and sulfur, wherein the heteroaromatic group is optionally substituted with one or two substituents independently selected from the group consisting of halogen, alkyloxy, carboxy, amide and alkyl,
with the proviso that a maximum of two of R 1 , R 2 , and R 3 are aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic group; and
Cα is a carbon atom and the stereochemistry at C is either R or S;
or an ester, amide, alkyl amide or metal cation or ammonium salt of the carboxylic acid group thereof, or an organic or inorganic acid salt of the amine group thereof, or any combination thereof.

2. The compound of claim 1 , wherein the stereochemistry at Cα is S.

3. The compound of claim 1 , wherein R 1 , R 2 , and R 3 are independently H or methyl.

4. The compound of claim 1 , wherein R is methyl.

5. The compound of claim 1 , wherein the compound is selected from the group consisting of compounds 22-24:

6. The compound of claim 1 , wherein the protecting group is BOC (t-butoxy carbonyl), FMOC (fluorenylmethoxycarbonyl), Alloc (allyloxycarbonyl), CBZ (benzyloxycarbonyl), Pbf (2,2,4,6,7- pentamethyl-dihydrobenzofuran-5-sulfonyl), NO 2 (nitro), Pmc (2,2,5,7,8-pentamethylchroman-6-sulfonyl), Mtr (4-methoxy-2,3,6-trimethylbenzenesulfonyl), or Tos (tosyl).

7. A peptide comprising a residue of Formula (I), wherein the residue of Formula (I) is the N-terminus residue of the peptide:

wherein:
n is 3, 4, or 5;
m is 0 or 1;
R is a straight or branched chain C 1 -C 6 alkyl group;
R 1 , R 2 , and R 3 are independently selected from the group consisting of: H;
branched or straight chain C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; a protecting group that is removable by a chemical method that does not also cause cleavage of other groups; a C 6 -C 18 aromatic group, wherein the aromatic group is optionally substituted with one or two substituents independently selected from the group consisting of halogen, alkyloxy, carboxy, amide and alkyl; and a C 4 -C 18 heteroaromatic group and one or two heteroatoms independently selected from the group consisting of oxygen and sulfur, wherein the heteroaromatic group is optionally substituted with one or two substituents independently selected from the group consisting of halogen, alkyloxy, carboxy, amide and alkyl,
with the proviso that a maximum of two of R 1 , R 2 , and R 3 are aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic group; and
Cα is a carbon atom and the stereochemistry at C is either R or S; wherein the carboxylic acid (COOH) group of the residue of Formula (I) is covalently coupled within the peptide through an amide bond.

8. The peptide of claim 7 wherein the residue is covalently coupled through an amide bond to the N-terminus amine group of a given peptide, or the residue is a substitute for a natural amino acid moiety at the N-terminus of a given peptide,
wherein the given peptide is selected from the group consisting of a transcription factor, a ligand for a cellular receptor, a hormone and an extracellular binding peptide.

9. The peptide of claim 8 , wherein the given peptide is neurotensin(8-13) and wherein the residue is a substitute for a natural amino acid moiety at the N-terminus of neurotensin(8-13).

10. The peptide of claim 9 , wherein the peptide comprises ABS201 (SEQ ID NO:3).

11. The peptide of claim 8 , wherein the given peptide is enkephalin, LHRH, a neuropeptide, a glycoincretin, integrin, a glucagon, a glucagon-like peptide, an antithrombotic peptide, a cytokine, an interleukin, a transferrin, an interferon, an endothelin, a natriuretic hormone, an extracellular kinase ligand, an angiotensin enzyme inhibitor, a peptide antiviral compound, thrombin, substance P, substance G, somatotropin, somatostatin, GnRH, secretin, bradykinin, vasopressin, insulin, neurotensin, proinsulin, or a growth factor.

12. The peptide of claim 8 , wherein the peptide has an extended half-life in vivo or in vitro, as compared to the given peptide.

13. The peptide of claim 8 , wherein the peptide has an increased ability to cross a biological barrier in a patient, as compared to the given peptide.

14. A pharmaceutical composition comprising a pharmaceutical carrier and a peptide comprising a residue of Formula (I), wherein the residue of Formula (I) is the N-terminus residue of the peptide:

wherein:
n is 3, 4, or 5;
m is 0 or 1;
R is a straight or branched chain C I -C 6— alkyl group;
R 1 , R 2 , and R 3 are independently selected from the group consisting of: H; branched or straight chain C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; a protecting group that is removable by a chemical method that does not also cause cleavage of other groups; a C 6 -C 18 aromatic group, wherein the aromatic group is optionally substituted with one or two substituents independently selected from the group consisting of halogen, alkyloxy, carboxy, amide and alkyl; and a C 4 -C 18 heteroaromatic group and one or two heteroatoms independently selected from the group consisting of oxygen and sulfur, wherein the heteroaromatic group is optionally substituted with one or two substituents independently selected from the group consisting of halogen, alkyloxy, carboxy, amide and alkyl,
with the proviso that a maximum of two of R 1 , R 2 , and R 3 are aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic group; and
Cα is a carbon atom and the stereochemistry at C is either R or S; wherein the carboxylic acid (COOH) group of the residue of Formula (I) is covalently coupled within the peptide through an amide bond.

15. The composition of claim 14 , wherein the peptide is present in unit dosage form.

16. A cosmetic formulation comprising a cosmetic base formulation and a compound of Formula I:

wherein:
n is 3, 4, or 5;
m is 0 or 1;
R is a straight or branched chain C 1 -C 6 alkyl group;
R 1 , R 2 , and R 3 are independently selected from the group consisting of: H; branched or straight chain C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; a protecting group that is removable by a chemical method that does not also cause cleavage of other groups; a C 6 -C 18 aromatic group, wherein the aromatic group is optionally substituted with one or two substi

Assignees

• Musc Found For Res Dev

Inventors

• Dix Thomas A

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P5/02

  of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title