Peptide derivatives

An insulin derivative having the sequence shown in Formula I:

• 4 Formula I A-Chain S S | 7 | Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser- (SEQ ID No. 1) 1 2 3 4 5 6 | 8 9 10 11 12 S | B-Chain S | Xaa-Val-Xaa-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val- (SEQ ID No. 2) 1 2 3 4 5 6 7 8 9 10 11 12 20 Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Xaa 13 14 15 16 17 18 19 | 21 S | S | Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe- 13 14 15 16 17 18 19 20 21 22 23 24 Phe-Tyr-Thr-Xaa-Xaa-Xaa 25 26 27 28 29 30
• wherein
• Xaa at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys;
• Xaa at position B1 is (a) Phe, which is optionally substituted in the amino group with a substituent of the formula —CO—W—COOH wherein W is a divalent long chain hydrocarbon group having from 12 to 22 carbon atoms;
• or (b) deleted, in which case the amino group of Val at position B2 is either free or has a substituent of the formula —CO—W—COOH as defined above;
• Xaa at position B28 is (a) Pro, in which case Xaa at position B29 is Lys which optionally, in its ε-amino group, has a substituent of the formula —CO—W—COOH as defined above;
• (b) Asp or Ser, in any of which cases Xaa at position B29 is Lys which optionally, in its ε-amino group, has a substituent of the formula —CO—W—COOH as defined above;
• or (c) Lys which optionally, in its ε-amino group, has a substituent of the formula —CO—W—COOH as defined above, in which case, whether the ε-amino group of the Lys has the optional substituent or not, Xaa at position B29 is Pro;
• Xaa at position B30 is (a) Thr;
• (b) Ala;
• or (c) deleted;
• and any zinc complexes thereof, provided that the insulin derivative of formula I has at least one lipophilic substituent of the formula —CO—W—COOH.