IP Library › Patent Application 14366531

Patent Application

App. No. 14/366,531

N-ACYLPEPTIDE DERIVATIVES AND THEIR USES

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Patent No.: US None
App. No.: 14/366,531

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Abstract

N-acylpeptide derivatives are described. Compositions comprising N-acylpeptide derivatives are therapeutically effective for topical or systemic administration to alleviate or improve conditions, disorders, diseases, symptoms or syndromes associated with tumors or cancers, immune, nervous, vascular, musculoskeletal, cutaneous system, or other tissues or systems in a subject.

Claims (59)

1 . A peptide derivative having the following generic Formula (I):

R 1 -AAB-(AAA) n -AAC-R 2 Formula (I)

or an isomer, free acid, base, salt, lactone, amide, hydroxylamide, hydrazide, or ester thereof, wherein R 1 is an acyl radical having up to 19 carbon atoms; AAB is an amino-terminal amino acid residue; (AAA) n is a peptide having n amino acid residues, each of the amino acid residues is independently selected from any amino acid; n is an integer from 3-18; AAC is a carboxyl-terminal amino acid residue; R 2 is OR 3 , NHR 4 or NHNHR 5 ; R 3 is H, an alkyl, aralkyl or aryl radical having up to 19 carbon atoms; R 4 or R 5 is independently H, OH, an alkyl, aralkyl, aryl or acyl radical having up to 19 carbon atoms; a side chain of each of the AAB, AAA and AAC optionally and independently has an extra functional radical selected from the group consisting of OH, SH, NHCONH 2 , NHC(═NH)NH 2 , NH 2 , COOH, CONH 2 , imidazolyl, pyrrolidinyl, and indolyl; and the H or OH of the extra functional radical is optionally substituted by NH 2 , an acyl, alkyl, aralkyl, or aryl radical having up to 19 carbon atoms.

2 . The peptide derivative of claim 1 , wherein the peptide derivative is present as an amide form.

3 . The peptide derivative of claim 1 , wherein n=3 such that the peptide derivative is an N-acylpentapeptide derivative selected from the group consisting of:

N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Ac-Gly-Ile-Arg-Val-Ala-OH, N-Ac-Gly-Ile-Arg-Val-Ala-OEt, N-Ac-Gly-Ile-Arg-Val-Ala-NH 2 , N-Ac-Gly-Ile-Arg-Val-Ala-NHAc, N-Ac-Gly-Ile-Arg-Val-Ala-NHNH 2 , N-Ac-Gly-Ile-Arg-Val-Ala-NHNHAc, N-Ac-Gly-Ile-Arg-Val-Ala-NHOH, N-Ac-Ala-Leu-Lys-His-Arg-OH, N-Ac-Ala-Leu-Lys-His-Arg-OEt, N-Ac-Ala-Leu-Lys-His-Arg-NH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHNHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHOH, N-Pr-Ala-Leu-Lys-His-Arg-OH, N-Pr-Ala-Leu-Lys-His-Arg-OEt, N-Pr-Ala-Leu-Lys-His-Arg-NH 2 , N-Pr-Ala-Leu-Lys-His-Arg-NHPr, N-Pr-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Pr-Ala-Leu-Lys-His-Arg-NHNHPr, N-Pr-Ala-Leu-Lys-His-Arg-NHOH, N-Bz-Ala-Leu-Lys-His-Arg-OH, N-Bz-Ala-Leu-Lys-His-Arg-OEt, N-Bz-Ala-Leu-Lys-His-Arg-NH 2 , N-Bz-Ala-Leu-Lys-His-Arg-NHBz, N-Bz-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Bz-Ala-Leu-Lys-His-Arg-NHNHPr, and N-Bz-Ala-Leu-Lys-His-Arg-NHOH (SEQ ID NOs: 28-69, respectively).

4 . The peptide derivative of claim 1 , wherein n=13 such that the peptide derivative is an N-acylpentadecapeptide derivative selected from the group consisting of:

N-Ac-(EASPEAVAGVGFESK)-OH, N-Ac-(EASPEAVAGVGFESK)-OEt, N-Ac-(EASPEAVAGVGFESK)-NH 2 , N-Ac-(EASPEAVAGVGFESK)-NHAc, N-Ac-(EASPEAVAGVGFESK)-NHNH 2 , N-Ac-(EASPEAVAGVGFESK)-NHNHAc, N-Ac-(EASPEAVAGVGFESK)-NHOH, N-Pr-(EASPEAVAGVGFESK)-OH, N-Pr-(EASPEAVAGVGFESK)-OEt, N-Pr-(EASPEAVAGVGFESK)-NH 2 , N-Pr-(EASPEAVAGVGFESK)-NHPr, N-Pr-(EASPEAVAGVGFESK)-NHNH 2 , N-Pr-(EASPEAVAGVGFESK)-NHNHPr, N-Pr-(EASPEAVAGVGFESK)-NHOH, N-Bz-(EASPEAVAGVGFESK)-OH, N-Bz-(EASPEAVAGVGFESK)-OEt, N-Bz-(EASPEAVAGVGFESK)-NH 2 , N-Bz-(EASPEAVAGVGFESK)-NHBz, N-Bz-(EASPEAVAGVGFESK)-NHNH 2 , N-Bz-(EASPEAVAGVGFESK)-NHNHBz, and N-Bz-(EASPEAVAGVGFESK)-NHOH (SEQ ID NOs: 103-123, respectively).

5 . The peptide derivative of claim 1 , wherein n=14 such that the peptide derivative is an N-acylhexadecapeptide derivative selected from the group consisting of:

N-Ac-(EEASPEAVAGVGFESK)-OH, N-Ac-(EEASPEAVAGVGFESK)-OEt, N-Ac-(EEASPEAVAGVGFESK)-NH 2 , N-Ac-(EEASPEAVAGVGFESK)-NHAc, N-Ac-(EEASPEAVAGVGFESK)-NHNH 2 , N-Ac-(EEASPEAVAGVGFESK)-NHNHAc, N-Ac-(EEASPEAVAGVGFESK)-NHOH, N-Pr-(EEASPEAVAGVGFESK)-OH, N-Pr-(EEASPEAVAGVGFESK)-OEt, N-Pr-(EEASPEAVAGVGFESK)-NH 2 , N-Pr-(EEASPEAVAGVGFESK)-NHPr, N-Pr-(EEASPEAVAGVGFESK)-NHNH 2 , N-Pr-(EEASPEAVAGVGFESK)-NHNHPr, N-Pr-(EEASPEAVAGVGFESK)-NHOH, N-Bz-(EEASPEAVAGVGFESK)-OH, N-Bz-(EEASPEAVAGVGFESK)-OEt, N-Bz-(EEASPEAVAGVGFESK)-NH 2 , N-Bz-(EEASPEAVAGVGFESK)-NHBz, N-Bz-(EEASPEAVAGVGFESK)-NHNH 2 , N-Bz-(EEASPEAVAGVGFESK)-NHNHBz, N-Bz-(EEASPEAVAGVGFESK)-NHOH, N-Ac-(EEASPEAVAGVGBESK)-NH 2 , and N-Ac-(EEASPEAVAGVGBESK)-NHNH 2 (SEQ ID NOs: 124-146, respectively).

6 . The peptide derivative of claim 1 , wherein n=17 such that the peptide derivative is an N-acylnonadecapeptide derivative selected from the group consisting of:

N-Ac-(CKKEEASPEAVAGVGFESK)-OH, N-Ac-(CKKEEASPEAVAGVGFESK)-OEt, N-Ac-(CKKEEASPEAVAGVGFESK)-NH 2 , N-Ac-(CKKEEASPEAVAGVGFESK)-NHAc, N-Ac-(CKKEEASPEAVAGVGFESK)-NHNH 2 , N-Ac-(CKKEEASPEAVAGVGFESK)-NHNHAc, and N-Ac-(CKKEEASPEAVAGVGFESK)-NHOH (SEQ ID NOs: 147-153, respectively).

7 . The peptide derivative of claim 1 , wherein n=18 such that the peptide derivative is an N-acyleicosapeptide derivative selected from the group consisting of:

N-Ac-(FCTGIRVAHLALKHRQGKNH)-OH, N-Ac-(FCTGIRVAHLALKHRQGKNH)-OEt, N-Ac-(FCTGIRVAHLALKHRQGKNH)-NH 2 , N-Ac-(FCTGIRVAHLALKHRQGKNH)-NHAc, N-Ac-(FCTGIRVAHLALKHRQGKNH)-NHNH 2 , N-Ac-(FCTGIRVAHLALKHRQGKNH)-NHNHAc, N-Ac-(FCTGIRVAHLALKHRQGKNH)-NHOH, N-Pr-(FCTGIRVAHLALKHRQGKNH)-OH, N-Pr-(FCTGIRVAHLALKHRQGKNH)-OEt, N-Pr-(FCTGIRVAHLALKHRQGKNH)-NH 2 , N-Pr-(FCTGIRVAHLALKHRQGKNH)-NHPr, N-Pr-(FCTGIRVAHLALKHRQGKNH)-NHNH 2 , N-Pr-(FCTGIRVAHLALKHRQGKNH)-NHNHPr, N-Pr-(FCTGIRVAHLALKHRQGKNH)-NHOH, N-Bz-(FCTGIRVAHLALKHRQGKNH)-OH, N-Bz-(FCTGIRVAHLALKHRQGKNH)-OEt, N-Bz-(FCTGIRVAHLALKHRQGKNH)-NH 2 , N-Bz-(FCTGIRVAHLALKHRQGKNH)-NHBz, N-Bz-(FCTGIRVAHLALKHRQGKNH)-NHNH 2 , N-Bz-(FCTGIRVAHLALKHRQGKNH)-NHNHBz, and N-Bz-(FCTGIRVAHLALKHRQGKNH)-NHOH (SEQ ID NOs: 154-174, respectively).

8 . A composition for topical or systemic administration to a mammal comprising a pharmaceutically or cosmetically acceptable carrier and a therapeutically effective amount of a peptide derivative having the following generic Formula (I):

R 1 -AAB-(AAA) n -AAC-R 2 Formula (I)

or an isomer, free acid, base, salt, lactone, amide, hydroxylamide, hydrazide, or ester thereof, wherein R 1 is an acyl radical having up to 19 carbon atoms; AAB is an amino-terminal amino acid residue; (AAA) n is a peptide having n amino acid residues, each of the amino acid residues is independently selected from any amino acid; n is an integer from 1-18; AAC is a carboxyl-terminal amino acid residue; R 2 is OR 3 , NHR 4 or NHNHR 5 ; R 3 is H, an alkyl, aralkyl or aryl radical having up to 19 carbon atoms; R 4 or R 5 is independently H, OH, an alkyl, aralkyl, aryl or acyl radical having up to 19 carbon atoms; a side chain of each of the AAB, AAA and AAC optionally and independently has an extra functional radical selected from the group consisting of OH, SH, NHCONH 2 , NHC(═NH)NH 2 , NH 2 , COOH, CONH 2 , imidazolyl, pyrrolidinyl, and indolyl; and the H or OH of the extra functional radical is optionally substituted by NH 2 , an acyl, alkyl, aralkyl, or aryl radical having up to 19 carbon atoms.

9 . The composition of claim 8 , wherein the peptide derivative is selected from the group consisting of: N-Ac-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-NHNHAc and N-Ac-Tyr-Tyr-Tyr-NHOH.

10 . The composition of claim 8 , wherein the peptide derivative is selected from the group consisting of: N-Ac-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-NHOH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Ac-Ala-Leu-Lys-His-Arg-OH, N-Ac-Ala-Leu-Lys-His-Arg-OEt, N-Ac-Ala-Leu-Lys-His-Arg-NH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHNHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHOH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-(EEASPEAVAGVGFESK)-OH, N-Ac-(EEASPEAVAGVGFESK)-OEt, N-Ac-(EEASPEAVAGVGFESK)-NH 2 , N-Ac-(EEASPEAVAGVGFESK)-NHAc, N-Ac-(EEASPEAVAGVGFESK)-NHNH 2 , N-Ac-(EEASPEAVAGVGFESK)-NHNHAc, N-Ac-(EEASPEAVAGVGFESK)-NHOH, N-Ac-(EEASPEAVAGVGBESK)-NH 2 , and N-Ac-(EEASPEAVAGVGBESK)-NHNH 2 (SEQ ID NOs: 7, 8, 9, 10, 11, 12, 13, 28, 29, 30, 31, 32, 33, 34, 49, 50, 51, 52, 53, 54, 55, 70, 71, 72, 124, 125, 126, 127, 128, 129, 130, 145, and 146, respectively).

11 . The composition of claim 8 , wherein the peptide derivative is selected from the group consisting of: N-Ac-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Ala-Leu-Lys-His-Arg-OH, N-Ac-Ala-Leu-Lys-His-Arg-OEt, N-Ac-Ala-Leu-Lys-His-Arg-NH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-(EEASPEAVAGVGFESK)-OH, N-Ac-(EEASPEAVAGVGFESK)-OEt, N-Ac-(EEASPEAVAGVGFESK)-NH 2 , N-Ac-(EEASPEAVAGVGFESK)-NHAc, N-Ac-(EEASPEAVAGVGFESK)-NHNH 2 , N-Ac-(EEASPEAVAGVGFESK)-NHNHAc, N-Ac-(EEASPEAVAGVGFESK)-NHOH, N-Ac-(EEASPEAVAGVGBESK)-NH 2 , and N-Ac-(EEASPEAVAGVGBESK)-NHNH 2 (SEQ ID NOs: 9, 10, 30, 31, 49, 50, 51, 52, 72, 124, 125, 126, 127, 128, 129, 130, 145, and 146, respectively).

12 . The composition of claim 8 , wherein the peptide derivative is selected from the group consisting of: N-Ac-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-NH 2 (SEQ ID NO: 9), N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 (SEQ ID NO: 30), N-Ac-Ala-Leu-Lys-His-Arg-OH (SEQ ID NO: 49), N-Ac-Ala-Leu-Lys-His-Arg-OEt (SEQ ID NO: 50), N-Ac-Ala-Leu-Lys-His-Arg-NH 2 (SEQ ID NO: 51), N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 (SEQ ID NO: 72), N-Ac-(EEASPEAVAGVGFESK)-OH (SEQ ID NO: 124), N-Ac-(EEASPEAVAGVGFESK)-Oet (SEQ ID NO: 125), N-Ac-(EEASPEAVAGVGFESK)-NH 2 (SEQ ID NO: 126), and N-Ac-(EEASPEAVAGVGBESK)-NH 2 (SEQ ID NO: 145), N-Pr-L-Ala-L-Leu-L-Lys-L-His-L-Arg-NH2 (SEQ ID NO: 58), N-Bz-L-Ala-L-Leu-L-Lys-L-His-L-Arg-NH2 (SEQ ID NO: 65), N-Ac-(EASPEAVAGVGFESK)-NH2 (SEQ ID NO: 105), and N-Ac-(CKKEEASPEAVAGVGFESK)-NH2 (SEQ ID NO: 149).

13 . The composition of claim 8 , wherein n=1 such that the peptide derivative is an N-acyltripeptide derivative selected from the group consisting of:

N-Ac-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Cys-Cys-Tyr-NH 2 , N-Ac-Cys-Tyr-Tyr-NH 2 , N-Ac-Val-Val-Tyr-NH 2 , N-Ac-Val-Tyr-Tyr-NH 2 , N-Ac-Cys-Dopa-Tyr-NH 2 , N-Ac-Dopa-Dopa-Tyr-NH 2 , N-Ac-Dopa-Cys-Tyr-NH 2 , N-Ac-Dopa-Dopa-Cys-NH 2 , N-Ac-Tyr-Val-Ala-NH 2 , N-Ac-Val-Ala-Tyr-NH 2 , N-Ac-Glu-Cys-Ala-NH 2 , N-Ac-Glu-Cys-Gly-NH 2 , N-Ac-Asp-Cys-Gly-NH 2 , N-Ac-Asp-Cys-Ala-NH 2 , N-Ac-Tyr-Tyr-Tyr-NHOH, N-Ac-Val-Val-Ala-NHOH, N-Ac-Dopa-Dopa-Tyr-NHOH, N-Ac-Cys-Dopa-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-NHAc, N-Pr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-NHNHAc, N-Pr-Cys-Cys-Tyr-NH 2 , N-Pr-Dopa-Tyr-Tyr-NH 2 , N-Pr-Dopa-Dopa-Tyr-NH 2 , N-Pr-Cys-Dopa-Tyr-NH 2 , N-Pr-Cys-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-NHOH, N-Pr-Val-Val-Ala-NHOH, N-Pr-Dopa-Dopa-Tyr-NHOH, N-Pr-Cys-Dopa-Tyr-NHOH, N-Bz-Tyr-Tyr-Tyr-NH 2 , N-Bz-Tyr-Tyr-Tyr-NHNH 2 , N-Bz-Tyr-Tyr-Tyr-NHNHAc, N-Bz-Cys-Cys-Tyr-NH 2 , N-Bz-Dopa-Tyr-Tyr-NH 2 , N-Bz-Dopa-Dopa-Tyr-NH 2 , N-Bz-Cys-Dopa-Tyr-NH 2 , N-Bz-Cys-Tyr-Tyr-NH 2 , N-Bz-Tyr-Tyr-Tyr-NHOH, N-Bz-Val-Val-Ala-NHOH, N-Bz-Dopa-Dopa-Tyr-NHOH, and N-Bz-Cys-Dopa-Tyr-NHOH.

14 . The composition of claim 8 , wherein n=2 such that the peptide derivative is an N-acyltetrapeptide derivative selected from the group consisting of:

N-Ac-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-NHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-NHNHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Bz-Tyr-Tyr-Tyr-Tyr-OH, N-Bz-Tyr-Tyr-Tyr-Tyr-OEt, N-Bz-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Bz-Tyr-Tyr-Tyr-Tyr-NHBz, N-Bz-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Bz-Tyr-Tyr-Tyr-Tyr-NHNHBz, and N-Bz-Tyr-Tyr-Tyr-Tyr-NHOH (SEQ ID NOs: 7-27, respectively).

15 . The composition of claim 8 , wherein n=3 such that the peptide derivative is an N-acylpentapeptide derivative selected from the group consisting of:

N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Ac-Gly-Ile-Arg-Val-Ala-OH, N-Ac-Gly-Ile-Arg-Val-Ala-OEt, N-Ac-Gly-Ile-Arg-Val-Ala-NH 2 , N-Ac-Gly-Ile-Arg-Val-Ala-NHAc, N-Ac-Gly-Ile-Arg-Val-Ala-NHNH 2 , N-Ac-Gly-Ile-Arg-Val-Ala-NHNHAc, N-Ac-Gly-Ile-Arg-Val-Ala-NHOH, N-Ac-Ala-Leu-Lys-His-Arg-OH, N-Ac-Ala-Leu-Lys-His-Arg-OEt, N-Ac-Ala-Leu-Lys-His-Arg-NH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHNHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHOH, N-Pr-Ala-Leu-Lys-His-Arg-OH, N-Pr-Ala-Leu-Lys-His-Arg-OEt, N-Pr-Ala-Leu-Lys-His-Arg-NH 2 , N-Pr-Ala-Leu-Lys-His-Arg-NHPr, N-Pr-Ala-Leu-Lys-His-Arg-NHNH 2 , and N-Pr-Ala-Leu-Lys-His-Arg-NHNHPr, N-Pr-Ala-Leu-Lys-His-Arg-NHOH, N-Bz-Ala-Leu-Lys-His-Arg-OH, N-Bz-Ala-Leu-Lys-His-Arg-OEt, N-Bz-Ala-Leu-Lys-His-Arg-NH 2 , N-Bz-Ala-Leu-Lys-His-Arg-NHBz, N-Bz-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Bz-Ala-Leu-Lys-His-Arg-NHNHPr, and N-Bz-Ala-Leu-Lys-His-Arg-NHOH (SEQ ID NOs:28-69, respectively).

16 . The composition of claim 8 , wherein n=4 such that the peptide derivative is an N-acylhexapeptide derivative selected from the group consisting of:

N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHBz, N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHBz, N-Bz-Tyr-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Ac-Cys-Ser-Val-Thr-Cys-Gly-OH, N-Ac-Cys-Ser-Val-Thr-Cys-Gly-OEt, N-Ac-Cys-Ser-Val-Thr-Cys-Gly-NH 2 , N-Ac-Cys-Ser-Val-Thr-Cys-Gly-NHAc, N-Ac-Cys-Ser-Val-Thr-Cys-Gly-NHNH 2 , N-Ac-Cys-Ser-Val-Thr-Cys-Gly-NHNHAc, N-Pr-Cys-Ser-Val-Thr-Cys-Gly-OH, N-Pr-Cys-Ser-Val-Thr-Cys-Gly-OEt, N-Pr-Cys-Ser-Val-Thr-Cys-Gly-NH 2 , N-Pr-Cys-Ser-Val-Thr-Cys-Gly-NHPr, N-Pr-Cys-Ser-Val-Thr-Cys-Gly-NHNH 2 , and N-Pr-Cys-Ser-Val-Thr-Cys-Gly-NHNHPr (SEQ ID NOs:70-102, respectively).

17 . The composition of claim 8 , wherein n=13 such that the peptide derivative is an N-acylpentadecapeptide derivative selected from the group consisting of:

18 . The composition of claim 8 , wherein n=14 such that the peptide derivative is an N-acylhexadecapeptide derivative selected from the group consisting of:

19 . The composition of claim 8 , wherein n=17 such that the peptide derivative is an N-acylnonadecapeptide derivative selected from the group consisting of:

20 . The composition of claim 8 , wherein n=18 such that the peptide derivative is an N-acyleicosapeptide derivative selected from the group consisting of:

21 . A method of treating a disorder, disease, symptom or syndrome associated with a tumor, cancer, immune, nervous, vascular, musculoskeletal or cutaneous system, or other tissues or systems in a subject, comprising systemically or topically administering to the subject a composition comprising a pharmaceutically or cosmetically acceptable carrier and a therapeutically effective amount of a peptide derivative having the following generic Formula (I):

R 1 -AAB-(AAA) n -AAC-R 2 Formula (I)

or an isomer, free acid, base, salt, lactone, amide, hydroxylamide, hydrazide, or ester thereof, wherein R 1 is an acyl radical having up to 19 carbon atoms; AAB is an amino-terminal amino acid residue; (AAA) n is a peptide having n amino acid residues, each of the amino acid residues is independently selected from any amino acid; n is an integer from 1-18; AAC is a carboxyl-terminal amino acid residue; R 2 is OR 3 , NHR 4 or NHNHR 5 ; R 3 is H, an alkyl, aralkyl or aryl radical having up to 19 carbon atoms; R 4 or R 5 is independently H, OH, an alkyl, aralkyl, aryl or acyl radical having up to 19 carbon atoms; a side chain of each of the AAB, AAA and AAC optionally and independently has an extra functional radical selected from the group consisting of OH, SH, NHCONH 2 , NHC(═NH)NH 2 , NH 2 , COOH, CONH 2 , imidazolyl, pyrrolidinyl, and indolyl; and the H or OH of the extra functional radical is optionally substituted by NH 2 , an acyl, alkyl, aralkyl, or aryl radical having up to 19 carbon atoms.

22 . The method of claim 21 , wherein the immune disorder, tumor or cancer is selected from the group consisting of lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Graves' disease, Addison's disease, cirrhosis, hepatitis A, hepatitis B, hepatitis C, psoriasis, inflammation, dermatitis, eczema, psoriasis, dermatoses, painful joints, arthritis, Type 1 diabetes, inflammatory bowel disease, allergic food reactions, nephritis, vasculitis, vitiligo, multiple sclerosis, HIV, AIDS, actinic keratosis, adrenal cancer, basal cell carcinoma, bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, esophagus cancer, head and neck cancer, Hodgkin disease, Kaposi's sarcoma, larynx cancer, leukemia, lung carcinoma, liver cancer, melanoma, multiple myeloma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, rectal cancer, stomach cancer, squamous cell carcinoma, thyroid cancer, testicular cancer, thyroid cancer, and uterine cancer.

23 . The method of claim 21 , wherein the nervous, vascular or musculoskeletal disorder is selected from the group consisting of nervousness, hypertension, dementia, Alzheimer's disease, carpal tunnel syndrome, encephalitis, headache, migraine, meningitis, neuralgia, nerve pain, peripheral neuropathy, sciatica, shingles, trigeminal neuralgia, Parkinson's disease, amnesia, Bell's palsy, epilepsy, multiple sclerosis, dermatitis, dermatosis, drug eruptions, inflammation, eczema, erythema, lupus erythematosus, mycosis fungoides, photoallergy, photosensitivity, pityriasis rosea, pityriasis rubra pilaris, rosacea, sclerosis, telangiectasia, urticarial, osteoporosis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, bursitis, tendinitis, gout, pain; inflammation and arthritis of neck, shoulder, elbow, wrist, lower back, hip, knee and ankle.

24 . The method of claim 21 , wherein the cutaneous disorder is selected from the group consisting of disturbed keratinization; aging related skin changes; dry skin; dryness or looseness of skin, nail and hair; xerosis; ichthyosis; calluses; keratoses; acne; rosacea; blemished skin; dandruff; uneven skin tone; uneven and rough surface of skin; abnormal skin texture and pores; flakiness and redness; and to improve or make skin soft, smooth, fresh, balanced, visibly clear; fine lines; wrinkles; age spots; blotches; cellulite; elastosis; lentigine; mottled skin; photoaging and photodamage; stretch marks; thinning of skin, nail plate and hair; warts; wrinkles; breakdown, defective synthesis or repair of dermal components; abnormal or diminished synthesis of collagen, glycosaminoglycans, proteoglycans and elastin, as well as diminished levels of such components in the dermis; loss or reduction of skin, nail and hair resiliency, elasticity and recoilability; laxity; lack of skin, nail and hair lubricants and luster; fragility and splitting of nail and hair; yellowing skin; and dull and older-looking skin, nail and hair, even-toned and brighter; to increase skin fullness and plumpness, and to reduce or prevent underarm perspiration.

25 . The method of claim 21 , wherein the other tissue or system disorder is selected from the group consisting of tremor or shaking, vision disorders of eyes, vocal dysfunctions, gum and periodontal diseases, hearing loss, sexual dysfunctions, desired augmentation of breast and penis; to control, reduce or lose body weight or appetite for food; and to increase body strength.

26 . The method of claim 21 , wherein n=1 such that the peptide derivative is an N-acyltripeptide derivative selected from the group consisting of: N-Ac-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Cys-Cys-Tyr-NH 2 , N-Ac-Cys-Tyr-Tyr-NH 2 , N-Ac-Val-Val-Tyr-NH 2 , N-Ac-Val-Tyr-Tyr-NH 2 , N-Ac-Cys-Dopa-Tyr-NH 2 , N-Ac-Dopa-Dopa-Tyr-NH 2 , N-Ac-Dopa-Cys-Tyr-NH 2 , N-Ac-Dopa-Dopa-Cys-NH 2 , N-Ac-Tyr-Val-Ala-NH 2 , N-Ac-Val-Ala-Tyr-NH 2 , N-Ac-Glu-Cys-Ala-NH 2 , N-Ac-Glu-Cys-Gly-NH 2 , N-Ac-Asp-Cys-Gly-NH 2 , N-Ac-Asp-Cys-Ala-NH 2 , N-Ac-Tyr-Tyr-Tyr-NHOH, N-Ac-Val-Val-Ala-NHOH, N-Ac-Dopa-Dopa-Tyr-NHOH, N-Ac-Cys-Dopa-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-NHAc, N-Pr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-NHNHAc, N-Pr-Cys-Cys-Tyr-NH 2 , N-Pr-Dopa-Tyr-Tyr-NH 2 , N-Pr-Dopa-Dopa-Tyr-NH 2 , N-Pr-Cys-Dopa-Tyr-NH 2 , N-Pr-Cys-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-NHOH, N-Pr-Val-Val-Ala-NHOH, N-Pr-Dopa-Dopa-Tyr-NHOH, N-Pr-Cys-Dopa-Tyr-NHOH, N-Bz-Tyr-Tyr-Tyr-NH 2 , N-Bz-Tyr-Tyr-Tyr-NHNH 2 , N-Bz-Tyr-Tyr-Tyr-NHNHAc, N-Bz-Cys-Cys-Tyr-NH 2 , N-Bz-Dopa-Tyr-Tyr-NH 2 , N-Bz-Dopa-Dopa-Tyr-NH 2 , N-Bz-Cys-Dopa-Tyr-NH 2 , N-Bz-Cys-Tyr-Tyr-NH 2 , N-Bz-Tyr-Tyr-Tyr-NHOH, N-Bz-Val-Val-Ala-NHOH, N-Bz-Dopa-Dopa-Tyr-NHOH, and N-Bz-Cys-Dopa-Tyr-NHOH.

27 . The method of claim 21 , wherein n=2 such that the peptide derivative is an N-acyltetrapeptide derivative selected from the group consisting of:

28 . The method of claim 21 , wherein n=3 such that the peptide derivative is an N-acylpentapeptide derivative selected from the group consisting of:

N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHNHPr, N-Pr-Tyr-Tyr-Tyr-Tyr-Tyr-NHOH, N-Ac-Gly-Ile-Arg-Val-Ala-OH, N-Ac-Gly-Ile-Arg-Val-Ala-OEt, N-Ac-Gly-Ile-Arg-Val-Ala-NH 2 , N-Ac-Gly-Ile-Arg-Val-Ala-NHAc, N-Ac-Gly-Ile-Arg-Val-Ala-NHNH 2 , N-Ac-Gly-Ile-Arg-Val-Ala-NHNHAc, N-Ac-Gly-Ile-Arg-Val-Ala-NHOH, N-Ac-Ala-Leu-Lys-His-Arg-OH, N-Ac-Ala-Leu-Lys-His-Arg-OEt, N-Ac-Ala-Leu-Lys-His-Arg-NH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Ac-Ala-Leu-Lys-His-Arg-NHNHAc, N-Ac-Ala-Leu-Lys-His-Arg-NHOH, N-Pr-Ala-Leu-Lys-His-Arg-OH, N-Pr-Ala-Leu-Lys-His-Arg-OEt, N-Pr-Ala-Leu-Lys-His-Arg-NH 2 , N-Pr-Ala-Leu-Lys-His-Arg-NHPr, N-Pr-Ala-Leu-Lys-His-Arg-NHNH 2 , and N-Pr-Ala-Leu-Lys-His-Arg-NHNHPr, N-Pr-Ala-Leu-Lys-His-Arg-NHOH, N-Bz-Ala-Leu-Lys-His-Arg-OH, N-Bz-Ala-Leu-Lys-His-Arg-OEt, N-Bz-Ala-Leu-Lys-His-Arg-NH 2 , N-Bz-Ala-Leu-Lys-His-Arg-NHBz, N-Bz-Ala-Leu-Lys-His-Arg-NHNH 2 , N-Bz-Ala-Leu-Lys-His-Arg-NHNHPr, and N-Bz-Ala-Leu-Lys-His-Arg-NHOH (SEQ ID NO: 28-69, respectively).

29 . The method of claim 21 , wherein n=4 such that the peptide derivative is an N-acylhexapeptide derivative selected from the group consisting of:

30 . The method of claim 21 , wherein n=13 such that the peptide derivative is an N-acylpentadecapeptide derivative selected from the group consisting of:

31 . The method of claim 21 , wherein n=14 such that the peptide derivative is an N-acylhexadecapeptide derivative selected from the group consisting of:

32 . The method of claim 21 , wherein n=17 such that the peptide derivative is an N-acylnonadecapeptide derivative selected from the group consisting of:

33 . The method of claim 21 , wherein n=18 such that the peptide derivative is an N-acyleicosapeptide derivative selected from the group consisting of:

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 21, 2017

From: YU, RUEY J., PHD; VAN SCOTT, EUGENE J.

To: NEOSTRATA COMPANY, INC.

Reel/Frame 041319/0625 →