GLP-1 derivatives II

Abstract

The present invention relates to a derivative of GLP-1(7-C), wherein C is 35 or 36 which derivative has just one lipophilic substituent which is attached to the C-terminal amino acid residue.

1 - 91 . (canceled) 
     
     
         92 . A derivative of an analogue of exendin-4 where said analogue has an amino acid sequence that differs from the amino acid sequence of exendin-4 by the substitution of up to ten amino acid residues with any α-amino acid residue, and wherein said derivative has one lipophilic substituent attached, optionally via a spacer, to an amino acid residue of said analogue which is not the N-terminal or C-terminal amino acid residue of said analogue. 
     
     
         93 . The derivative of  claim 92 , wherein said analogue has an amino acid sequence that differs from the amino acid sequence of exendin-4 by the substitution of up to six amino acid residues with any α-amino acid residue 
     
     
         94 . The derivative of  claim 92 , wherein the lipophilic substituent has 4 to 40 carbon atoms. 
     
     
         95 . The derivative of  claim 94 , wherein the lipophilic substituent has 8 to 25 carbon atoms. 
     
     
         96 . The derivative of  claim 94 , wherein the lipophilic substituent is attached by means of a spacer. 
     
     
         97 . The derivative of  claim 96 , wherein the spacer is an unbranched alkane α,ω-dicarboxylic acid group having from 1 to 7 methylene groups. 
     
     
         98 . The derivative of  claim 97 , wherein the spacer is an unbranched alkane α,ω-dicarboxylic acid group having two methylene groups. 
     
     
         99 . The derivative of  claim 96 , wherein the spacer is an amino acid residue except cys, or a dipeptide such as gly-lys. 
     
     
         100 . The derivative of  claim 94 , wherein the lipophilic substituent is a partially or completely hydrogenated cyclopentanophenathrene skeleton. 
     
     
         101 . The derivative of  claim 94 , wherein the lipophilic substituent is a straight-chain or branched alkyl group. 
     
     
         102 . The derivative of  claim 94 , wherein the lipophilic substituent is a straight-chain or branched acyl group. 
     
     
         103 . The derivative of  claim 102 , wherein the acyl group is of the formula CH 3 (CH 2 ) n CO—, wherein n is 4 to 38. 
     
     
         104 . The derivative of  claim 103 , wherein the acyl group is CH 3 (CH 2 ) 6 CO—, CH 3 (CH 2 ) 8 CO—, CH 3 (CH 2 ) 10 CO—, CH 3 (CH 2 ) 12 CO—, CH 3 (CH 2 ) 14 CO—, CH 3 (CH 2 ) 16 CO—, CH 3 (CH 2 ) 18 CO—, CH 3 (CH 2 ) 20 CO— or CH 3 (CH 2 ) 22 CO—. 
     
     
         105 . The derivative of  claim 94 , wherein the lipophilic substituent is an acyl group of a straight-chain or branched alkane α,ω-dicarboxylic acid. 
     
     
         106 . The derivative of  claim 105 , wherein the acyl group is of the formula HOOC(CH 2 ) m CO—, wherein m is from 4 to 38. 
     
     
         107 . The derivative of  claim 106 , wherein the acyl group is HOOC(CH 2 ) 14 CO—, HOOC(CH 2 ) 16 CO—, HOOC(CH 2 ) 18 CO—, HOOC(CH 2 ) 20 CO— or HOOC(CH 2 ) 22 CO—. 
     
     
         108 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula CH 3 (CH 2 ) p ((CH 2 ) q COOH)CHNH—CO(CH 2 ) 2 CO—, wherein p and q are integers and p+q is an integer of from 8 to 33. 
     
     
         109 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula CH 3 (CH 2 ) r CO—NHCH(COOH)(CH 2 ) 2 CO—, wherein r is an integer of from 10 to 24. 
     
     
         110 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula CH 3 (CH 2 ) s CO—NHCH((CH 2 ) 2 COOH)CO—, wherein s is an integer of from 8 to 24. 
     
     
         111 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula —NHCH(COOH)(CH 2 ) 4 NH—CO(CH 2 ) u CH 3 , wherein u is an integer of from 8 to 18. 
     
     
         112 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula —NHCH(COOH)(CH 2 ) 4 NH—COCH((CH 2 ) 2 COOH)NH—CO(CH 2 ) w CH 3 , wherein w is an integer of from 10 to 16. 
     
     
         113 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula —NHCH(COOH)(CH 2 ) 4 NH—CO(CH 2 ) 2 CH(COOH)NH—CO(CH 2 ) x CH 3 , wherein x is an integer of from 10 to 16. 
     
     
         114 . The derivative of  claim 94 , wherein the lipophilic substituent is a group of the formula —NHCH(COOH)(CH 2 ) 4 NH—CO(CH 2 ) 2 CH(COOH)NH—CO(CH 2 ) y CH 3 , wherein y is zero or an integer of from 1 to 22. 
     
     
         115 . The derivative of  claim 95 , having an amino acid sequence of HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGX, wherein X=P or Y, or a fragment or an analogue thereof. 
     
     
         116 . The derivative of  claim 95 , having an amino acid sequence of HX1X2GTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS, wherein X1X2=SD or GE, or a fragment or an analogue thereof. 
     
     
         117 . The derivative of  claim 95 , having an amino acid sequence of DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS, or a fragment or an analogue thereof. 
     
     
         118 . The derivative of  claim 92 , which is Arg 18 , Leu 20 , Gln 34 , Lys 33  (N ε -(γ-aminobutyroyl(N α -hexadecanoyl))) Exendin-4-(7-45)-NH 2 . 
     
     
         119 . The derivative of  claim 92 , which is Arg 33 , Leu 20 , Gln 34 , Lys 18  (N ε -(γ-aminobutyroyl(N α -hexadecanoyl))) Exendin-4-(7-45)-NH 2 . 
     
     
         120 . A pharmaceutical composition comprising a derivative of  claim 92  and a pharmaceutically acceptable vehicle or carrier. 
     
     
         121 . A method of treating insulin dependent or non-insulin dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a derivative of  claim 92  and a pharmaceutically acceptable carrier.