Glucagon-like peptide and insulinotropin derivates

Claim 2

A derivative of a polypeptide according to claim 1 comprising the primary structure H 2 N-W-(X) m -(Y) n -Z and the pharmaceutically-acceptable salts thereof wherein m is zero or one; n is zero or one; X is a basic or neutral L-amino acid residue; Y is a basic or neutral L-amino acid residue and Z is CO 2 R 1 or CONR 2 R 3 wherein R 1 is H or (C 1 -C 6 ) straight or branched-chain alkyl when (a) m is one, n is zero and X is a basic L-amino acid residue, or (b) m is zero, n is one and Y is a basic L-amino acid residue, or (c) m and n are both one and one or both of X and Y are a basic L-amino acid residue; R 1 is (C 1 -C 6 )straight or branched-chain alkyl when (a) m and n are both zero, or (b) m is one, n is zero and X is a neutral L-amino acid residue, or (c) m is zero, n is one and Y is a neutral L-amino acid residue, or (d) m and n are both one and both X and Y are a neutral L-amino acid residue; and R 2 and R 3 are each, independently, H or (C 1 -C 6 )straight or branched-chain alkyl.

Claim 3

A derivative of a polypeptide comprising the primary structure H 2 N-R-COOH wherein R is an amino acid sequence selected from the group consisting of His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2), Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO: 3), His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly (SEQUENCE ID NO: 4) and His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys (SEQUENCE ID NO: 5); and the pharmaceutically-acceptable salts thereof wherein the derivative has a pl of about 4.0 or less, or a pl of about 7.0 or greater and having inculinotropic activity, provided that said derivative is not a C-terminal (C 1 -C 6 )straight or branched-chain alkyl ester and provided further that said derivative is not a C-terminal carboxamide of the formula CONR 2 R 3 wherein R 2 and R 3 are each, independently, H or (C 1 -C 6 )straight or branched-chain alkyl.

Claim 4

A derivative of a polypeptide according to claim 3 comprising the primary structure. H 2 N-R-X-(Y) n -Z and the pharmaceutically-acceptable salts thereof wherein n is zero or one; X is a basic or neural L-amino acid residue; Y is a basic or neutral L-amino acid residue; and Z is CO 2 R 1 or CONR 2 R 3 wherein R 1 is H or (C 1 -C 6 ) straight or branched-chain alkyl when (a) n is zero and X is a basic L-amino acid residue, or (b) n is one and one or both of X and Y are basic L-amino acid residue; R 1 is (C 1 -C 6 )straight or branched-chain alkyl when (a) n is zero and X is a neutral L-amino acid residue, or (b) n is one and both X and Y are a neutral L-amino acid residue; and R 2 and R 3 are each, independently, H or (C 1 -C 6 )straight or branched-chain alkyl.

Claim 5

A derivative of a polypeptide according to claim 4 and the pharmaceutically-acceptable salts thereof wherein R is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2).

Claim 6

A derivative of a polypeptide according to claim 5 and the pharmaceutically-acceptable salts thereof wherein n is zero and X is Arg.

Claim 7

A derivative of a polypeptide according to claim 6 and the pharmaceutically-acceptable salts thereof wherein Z is CO 2 R 1 and R 1 is H.

Claim 8

A derivative of a polypeptide according to claim 6 and the pharmaceutically-acceptable salts thereof wherein Z is CONR 2 R 3 and R 2 and R 3 are each H.

Claim 9

A derivative of a polypeptide according to claim 5 and the pharmaceutically-acceptable salts thereof wherein n is one and X and Y are each Arg.

Claim 10

A derivative of a polypeptide according to claim 9 and the pharmaceutically-acceptable salts thereof wherein Z is CO 2 R 1 and R 1 is H.

Claim 11

A derivative of a polypeptide according to claim 9 and the pharmaceutically-acceptable salts thereof wherein Z is CONR 2 R 3 and R 2 and R 3 are each H.

Claim 12

A pharmaceutical composition comprising a derivative of a polypeptide according to any preceding claim.

Claim 13

A derivative according to any of claims 1 to 11 or a pharmaceutical composition according to claim 12, for use in medicine.

Claim 14

The use of a derivative according to any of claims 1 to 11 or a pharmaceutical composition according to claim 12 in the preparation of a medicament for treating type II diabetes.

Claim 15

The use according to claim 14 wherein the medicament is for use in iontophoretic transdermal administration.

Claim 16

A process for preparing a derivative of a polypeptide comprising the primary structure H 2 N-W-COOH wherein W is an amino acid sequence selected from the group consisting of His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 1) and His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO: 6); and the pharmaceutically-acceptable salts thereof wherein the derivative has a pl of about 4.0 or less, or a pl of about 7.0 or greater and which derivative when processed in a mammal results in polypeptide derivative having an insulinotropic activity, which process comprises preparing a derivative of said primary structure by methods known per se and, optionally, converting said derivative to a pharmaceutically-acceptable salt Thereof by methods known per se .

Claim 17

A process for preparing a derivative of a polypeptide according to claim 16 comprising the primary structure H 2 N-W-(X) m -(Y) n -Z and the pharmaceutically-acceptable salts thereof wherein m is zero or one; n is zero or one; X is a basic or neutral L-amino acid residue: Y is a basic or neutral L-amino acid residue; and Z is CO 2 R 1 or CONR 2 R 3 wherein R 1 is H or (C 1 -C 6 ) straight or branched-chain alkyl when (a) m is one, n is zero and X is a basic L-amino acid residue, or (b) m is zero, n is one and Y is a basic L-amino acid residue, or (c) m and n are both one and one or both of X and Y are a basic L-amino acid residue; R 1 is (C 1 -C 6 )straight or branched-chain alkyl when (a) m and n are both zero, or (b) m is one, n is zero and X is a neutral L-amino acid residue, or (c) m is zero, n is one and Y is a neutral L-amino acid residue, or (d) m and n are both one and both X and Y are a neutral L-amino acid residue; and R 2 and R 3 are each, independently, H or (C 1 -C 6 )straight or branched-chain alkyl, which process comprises preparing a derivative of said primary structure by methods known per se and, optionally, converting said derivative to a pharmaceutically-acceptable salt thereof by methods known per se .

Claim 18

A process for preparing a derivative of a polypeptide comprising the primary structure H 2 N-R-COOH wherein R is an amino acid sequence selected from the group consisting of His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2), His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO: 3) His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly (SEQUENCE ID NO: 4) and His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys (SEQUENCE ID NO: 5); and the pharmaceutically-acceptable salts thereof wherein the derivative has a pl of about 4.0 or less, or a pl of about 7.0 or greater and having insulinotropic activity, provided that said derivative is not a C-terminal (C 1 -C 6 )straight or branched-chain alkyl ester and provided further that said derivative is not a C-terminal carboxamide of the formula, CONR 2 R 3 wherein R 2 and R 3 are each, independently, H or (C 1 -C 6 or branched-chain alkyl, which process comprises preparing a derivative of said primary structure by methods known per se and, optionally, converting said derivative to a pharmaceutically-acceptable salt thereof by methods known per se .

Claim 19

A process for preparing a derivative of a polypeptide according to claim 18 comprising the primary structure H 2 N-R-X-(Y) n -Z and the pharmaceutically-acceptable salts thereof wherein n is zero or one; X is a basic or neutral L-amino acid residue; Y is a basic or neutral L-amino acid residue; and Z is CO 2 R 1 or CONR 2 R 3 wherein R 1 is H or (C 1 -C 6 ) straight or branched-chain alkyl when (a) n is zero and X is a basic L-amino acid residue, or (b) n is one and one or both of X and Y are a basic L-amino acid residue; R 1 is (C 1 -C 6 )straight or branched-chain alkyl when (a) n is zero and X is a neutral L-amino acid residue, or (b) n is one and both X and Y are a neutral L-amino acid residue; end R 2 and R 3 are each, independently, H or (C 1 -C 6 ) straight or branched-chain alkyl, which process comprises preparing a derivative of said primary structure by methods known per se and, optionally, converting said derivative to a pharmaceutically-acceptable salt thereof by methods known per se .

Claim 20

A process according to claim 19 wherein R is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2).

Claim 21

A process according to claim 20 wherein n is zero and X is Arg.

Claim 22

A process according to claim 21 wherein Z is CO 2 R 1 and R 1 is H, or Z is CONR 2 R 3 and R 2 and R 3 are each H.

Claim 23

A process according to claim 20 wherein n is one and X and Y are each Arg.

Claim 24

A Process according to claim 23 wherein Z is CO 2 R 1 and R 1 is H, or Z is CONR 2 R 3 and R 2 and R 3 are each H.

Claim 25

A process according to any one of claims 16-24 wherein said derivative if formed by one or more of the following: (a) reacting the primary structure with a (C 1 -C 6 )alkanol in the presence of a catalytic acid to produce a C -terminal (C 1 -C 6 ) alkyl ester thereof; (b) reacting the primary structure with a(C 1 -C 6 ) alkanol in the presence of a catalytic acid to produce a (C 1 -C 6 ) alkyl ester of the Asp and/or Glu residues thereof; (c) synthesizing a carboxamide derivative of the primary structure by solid phase peptide synthesis; (d) deamidating the gln residue thereof; (e) alkylating or amidating the free amino group at the N-terminus and/or at the epsilon group of one or more Lys residues of the primary structure, or a combination thereof; (f) reading the primary structure with a cyclic annhydride; (g) replacing a basic amino acid residue of the primary structure with an acidic or neutral amino acid residue; and (h) replacing a neutral amino acid residue with an acidic amino acid residue.