Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2001-05-14
2004-02-03
Saoud, Christine J. (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S243000, C435S320100, C435S325000, C514S003100, C514S866000, C530S303000
Reexamination Certificate
active
06686177
ABSTRACT:
This application is the National Stage of International Application No. PCT/EP99/03490, filed May 21, 1999, which claims priority to German Application No. 198 25 447.4, filed Jun. 6, 1998.
The present invention relates to insulin analogs which have an increased zinc binding ability, and to stable zinc complexes thereof which, in comparison with human insulin, have a delayed profile of action, to a process for their preparation and to their use, in particular in pharmaceutical preparations for the therapy of diabetes mellitus of type I and also type II.
Worldwide, approximately 120 million people suffer from diabetes mellitus. Among these, approximately 12 million are type I diabetics, for whom the substitution of the lacking endocrine insulin secretion is the only possible therapy at present. Those affected are prescribed insulin injections, as a rule several times daily, for life. Unlike type I diabetes, in type II diabetes there is not fundamentally a lack of insulin, but in a large number of cases, especially in the advanced stage, treatment with insulin, if appropriate in combination with an oral antidiabetic, is regarded as the most favorable form of therapy.
In healthy people, the release of insulin by the pancreas is strictly coupled to the concentration of the blood glucose. Increased blood glucose levels, such as occur after meals, are rapidly compensated by a corresponding increase in insulin secretion. In the fasting state, the plasma insulin level drops to a basal value which is sufficient to guarantee a continuous supply of insulin-sensitive organs and tissues with glucose and to keep the hepatic glucose production low during the night. The replacement of the endogenous insulin secretion by exogenous, mostly subcutaneous, administration of insulin as a rule does not nearly achieve the quality of the physiological regulation of the blood glucose described above. Frequently, there are losses of control of the blood glucose upward or downward, which in their most severe forms can be life-threatening. In addition, blood glucose levels which have been raised for years without initial symptoms, however, also represent a considerable risk to health. The large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N, Engl. J. Med. 329, 977-986) clearly demonstrated that chronically raised blood glucose levels are largely responsible for the development of diabetic late damage. Diabetic late damage is micro- and macrovascular damage which is manifested, under certain circumstances, as retinopathy, nephropathy, or neuropathy and leads to blindness, kidney failure and the loss of extremities and is moreover accompanied by a high risk of cardiovascular diseases. It can be derived from this that an improved therapy of diabetes must primarily aim to keep the blood glucose as closely as possible in the physiological range. According to the concept of intensified insulin therapy, this should be achieved by a number of daily injections of rapid- and slow-acting insulin preparations. Rapid-acting formulations are given at mealtimes in order to level out the post-prandial increase in blood glucose. Slow-acting basal insulins should ensure the basic supply of insulin, in particular during the night, without leading to hypoglycemia.
The basal insulins available at present fulfill this requirement only inadequately. The frequently used NPH insulins especially have a too strongly pronounced maximum action and have too short an overall action. In the case of administration in the evening, this involves the risk of nightly hypoglycemia and morning hyperglycemia.
EP 0 821 006 discloses insulin analogs having increased zinc binding ability, which in combination with zinc have a delayed profile of action compared with human insulin. These analogs differ from human insulin essentially by variation of the amino acid in position A21 of the A chain and by addition of a histidine residue or of a peptide having 2 to 35 amino acid residues, which contains 1 to 5 histidine residues, in position B30 of the B chain.
It is the object of the present invention to provide further insulin analogs (analogs of human or animal insulin) which have an increased zinc binding ability, form a stable complex comprising a hexamer of the insulin analog and zinc, and, in a suitable preparation, make possible an improved therapy of diabetes mellitus of type I and of type II on subcutaneous injection as a result of the profile of action, which is delayed in comparison with human insulin.
Insulin analogs are derived from naturally occurring insulins, namely human insulin (see SEQ ID NO: 1: A chain of human insulin and SEQ ID NO: 2: B chain of human insulin) or animal insulins by substitution or absence of at least one naturally occurring amino acid residue and/or addition of at least one amino acid residue to the A and/or B chain of the naturally occurring insulin.
1. An insulin analog or a physiologically tolerable salt thereof of the formula I
in which
(A1-A5) are the amino acid residues in the positions A1 to A5 of the A chain of human insulin (cf. SEQ ID NO: 1) or animal insulin,
(A15-A19) are the amino acid residues in the positions A15 to A19 of the A chain of human insulin (cf. SEQ ID NO: 1) or animal insulin,
(B8-B18) are the amino acid residues in the positions B8 to B18 of the B chain of human insulin (cf. SEQ ID NO: 2) or animal insulin,
(B20-B29) are the amino acid residues in the positions B20 to B29 of the B chain of human insulin (cf. SEQ ID NO: 2) or animal insulin,
R8 is Thr or Ala,
R9 is Ser or Gly,
R10 is lle or Val,
R14 is Tyr, His, Asp or Glu,
R21 is Asn, Asp, Gly, Ser, Thr, Ala, Glu or Gln,
R1 is any desired genetically encodable amino acid residue, absent or a hydrogen atom,
R2 is Val, Ala or Gly,
R3 is Asn, His, Glu or Asp,
R4 is Ala, Ser, Thr, Asn, Asp, Gln, Gly or Glu,
R30 is any desired genetically encodable amino acid residue or —OH,
Z is a hydrogen atom or a peptide residue having 1 to 4 genetically encodable amino acid residues, comprising 1 to 4 histidine residues (His),
with the proviso that at least one of the following is true: (1) when Z is a hydrogen atom, R1 or R3 is chosen from His, Glu, and Asp; (2) when R1 is a neutral or negatively charged amino acid residue, R3 is His; or (3) when Z is a hydrogen atom, R14 is chosen from His, Asp and Glu; and with the further proviso that when in formula I R3, R3 in combination with R21, or R3 in combination with R4 differs from human insulin, the insulin analog or the physiologically tolerable salt thereof of the formula I contains at least one additional variation from human insulin. (cf. SEQ ID NO: 1 and SEQ ID NO: 2).
Preferably, the insulin analog or the physiologically tolerable salt thereof is one wherein
2. R8 is Thr, R9 is Ser and R10 is lle,
3. R1 is Phe, His, Asn, Asp or Gly,
4. R30 is Thr, Ala or Ser or
5. wherein R21 is Asn and R1 is Phe.
6. A preferred embodiment of the present invention is an insulin analog or a physiologically tolerable salt thereof of the formula 1, wherein R2 is Val, R3 is Asn and R4 is Gln.
An insulin analog or a physiologically tolerable salt thereof of the formula I is furthermore preferred which is distinguished in that R14 is
7. Tyr,
8. His,
9. Asp or
10. Glu.
An insulin analog or a physiologically tolerable salt thereof of the formula I is furthermore preferred which is distinguished in that R30 is
11. Thr,
12. Ala,
13. Ser or
14. —OH.
An insulin analog or a physiologically tolerable salt thereof of the formula I is furthermore preferred which is distinguished in that Z is
15. His,
16. His-Ala- or
17. His-Ala-Ala-.
Examples of insulin analogs according to the present invention are
18. an insulin analog or a physiologically tolerable salt thereof of the formula I, which is distinguished in that the B chain has the sequence
His Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys
(SEQ ID NO: 3), for example His(B0), des(B30) human insulin,
19. an insulin analog or a physiologically tolerable salt thereo
Ertl Johann
Geisen Karl
Habermann Paul
Seipke Gerhard
Wollmer Axel
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Saoud Christine J.
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