Insulin derivative

An insulin derivative having a formula

• wherein Ins is a parent insulin and X1—X2—X3—Q—Z is a substituent and where the Ins is attached to the substituent via an amide bond between the α-amino group of the N-terminal amino acid residue of the B chain of Ins or an e-amino group of a Lys residue present in the A or B chain of Ins and a CO-group in X1, X2 or X3 of the substituent;
• X1 is:
• —CO—(CH2)n where n is 1, 2, 3, 4, 5 or 6;
• —CO—((CR6R7)q—NR—CO)1-4—, where R6 and R7 independently of each other and independently for each value of q can be hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, —(CH2)1-6—COOH;
• —(CH2)1-6—CONH2, —(CH2)1-6—SO3H;
• —(CH2)1-6—PO3H2;
• —(CH2)1-6—O—SO3H2;
• —(CH2)1-6—O—POSH, q is 1-6 and R is hydrogen, —(CH2)1-6—COOH;
• —(CH2)1-6—CONH2;
• —(CH2)1-6—SO3H;
• —(CH2)1-6—PO3H2;
• —(CH2)1-6—O—SO3H2;
• —(CH2)1-6—O—PO3H2;
• C1-6-alkyl, C2-6-alkenyl;
• C2-6-alkynyl or aryl or CH2-aryl, in which the aryl group may be substituted with 1 or 2 groups selected from group consisting of —COOH, —CH3, —SO3H, —(CH2)1-6—SO3H, —PO3H2, —(CH2)1-6—O—PO3H2, tetrazol-5-lyl or CONH2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, hydrogen, halogen, —CN, —CF3, —OCF3, —S(O)2CF3, —SCF3, —NO2, —OR2, —SR2, —NR2S(O)2R3, —S(O)2NR2R3, —S(O)NR2R3, —S(O)R2, —S(O)2R2, —C(O)NR2R3, —OC(O)NR2R3, —NR2C(O)R3, —CH2C(O)NR2R3, —OCH2C(O)NR2R3, —OC(O)R2, —OCH2C(O)R2, —C(O)R2 or —C(O)OR2 or —OCH2C(O)OR2, where R2 and R3 independently are hydrogen, C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl;
• an amino acid amide residue of an amino acid with carboxylic acid in the side chain, or an amino acid with an uncharged side chain, or an amino acid with negatively charged side chain, which residue forms, with its carboxylic acid group, an amide bond together with the a-amino group of the N-terminal amino acid residue of the B chain of Ins or together with the e-amino group of a Lys residue present in the A or B chain of Ins;
• a chain composed of two, three or four residues linked together via amide bonds in which the residues are chosen from the group consisting of:
• a-amino acid amide residues and amino acid residues as specified above, in which the chain—via an amide bond—is linked to the a-amino group of the N-terminal amino acid residue of the B chain of Ins or to the e-amino group of a Lys residue present in the A or B chain of Ins;
• or
• a bond;
• X2 is:
• —CO—;
• —COCH(R8)—;
• —COCH2N(CH2R8)—;
• —COCH2N(CH2RS)COCH2N(CH2R8)—;
• —COCH2CH2N(CH2CH2R8)—;
• —COCH2CH2N(CH2CH2RS)—COCH2CH2N(CH2CH2R8)—;
• —COCH2N(CH2CH2RS)—;
• —COCH2CH2N(CH2RS)— where R8 can be COOH or CONH2;
• —CO—((CH2)2-6—NH—CO)1-4—;
• —(CO—(CH2)2-6—CO—NH)1-4—;
• —(CO—(CR9R10)1-6—CO—NH))1-4—, where R9 can be H, —COOH, —(CH2)1-6COOH, CH3, —(CH2)1-6CH3 or CONH2 and R10 can be H, —(CH2)1-6COOH, CH3 or —(CH2)1-6CH3;
• or
• a bond;
• provided that if an amine in X1 or X2 forms a bond with the rest of the substituent, the amine must be bound to the rest of the substituent via a carbonyl group;
• X3 is —C═O, provided that X3 is only present if X1 and X2 are bonds;
• Q is
• a chain of the formula —(CH2)s1-Q1-(CH2)s2-Q2-(CH2)s3-Q3-(CH2)s4-Q4-(CH2)s5—;
• wherein Q1, Q2 and Q3 are all bonds, Q4 is C6H4, S2, S3 and s4 are all one, S1 is 5, 6, 7 or 8 and s5 is 0, 1 or 2;
• and
• Z is:
• —COOH;
• —CO-Asp;
• —CO-Glu;
• —CO-Gly;
• —CO-Sar;
• —CH(COOH)2;
• —N(CH2COOH)2;
• —SO3H;
• —PO3H2;
• O—SO3H;
• O—PO3H2;
• or
• tetrazo-5-lyl;
• and any Zn2+ complex thereof.