Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-07-20
1998-07-21
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, A61K 3829, C07K 14635
Patent
active
057835586
DESCRIPTION:
BRIEF SUMMARY
The invention concerns new parathyroid hormone (PTH) fragments, as well as their pharmacologically compatible derivatives, the preparation of these fragments and of their derivatives by chemical ways and medicaments containing these.
Parathyroid hormone (PTH), a hormone of the adrenal glands, is an important regulator inter alia for the maintenance of the calcium level in the body. PTH can stimulate the bone formation or bone resorption. It thereby acts as regulatory hormone on a series of enzymes, inter alia ornithine decarboxylase and adenylate cyclase (cAMP synthesis). In the case of calcium deficiency, PTH mobilises calcium from the bones, reduces the calcium excretion of the kidneys and simultaneously improves the resorption of calcium from the intestine by means of an increased synthesis of 1,25-(OH).sub.2 D.sub.3. Due to the action on these target organs, a normalisation of the calcium level is achieved. On the other hand, in the case of increased calcium level, the incorporation of calcium into the bones is stimulated. Furthermore, PTH shows a mitogenic effect. especially a stimulation of osteoblasts and chondrocytes.
Furthermore, from DE-OS 37 25 319, it is known that the above-mentioned effect is brought about by a special region of the PTH and that it is possible to achieve the same action by administration of PTH fragments which correspond to this region (see also Somjen et al., Biochem. J. (1990) 272, 781-785; Shurtz-Swirski et al., Acts Endocrinol. (1990) 122, 217-226 and Potts et al, Advances in Protein chemistry (1982) 35, 323-396). From this literature, it is also to be found how such PTH fragments can be prepared and varied, whereby not only a cleavage of the naturally-occurring PTH but also chemically synthetic or gene-technological processes are possible. A chemically synthetic process for the preparation of hPTH (1-37) is described in the International Application WO 91/06564. However, this known solid phase and liquid phase synthesis has the disadvantage that the yields in the case of the preparation are relatively low.
PTH fragments are especially interesting for the treatment of osteoporosis. However, it has been found that the fragments are of differing effectiveness and that in some cases, e.g. in the case of the use of hPTH(1-34), the action is positive in the case of some patients but in others an impairment of the calcium retention occurred and the total bone mass diminished during the treatment.
Therefore, it is the task of the invention to make available new PTH fragments which have an improved therapeutic action, especially in the case of the regulation of the calcium level in the body and in the case of the incorporation of calcium into the bones. Furthermore, these fragments are to be preparable with a relatively small expense in good yield.
This task is solved with PTH fragments which include the amino acid sequences of bPHT(3-35), pPTH(3-35) or hPTH(3-35), whereby the C-terminal end of these sequences can be extended by one amino acid or the N-terminal end by one or two amino acids. In particular, in the meaning of the invention, there come into question the PTH fragments (1-35) and (1-36). In the sequence protocol, there are contained the amino acid sequences of the following fragments:
Furthermore, the subject of the invention is a process for the preparation of these fragments in that one prepares the said fragments or part fragments thereof by means of liquid phase synthesis from protected amino acids which are coupled with one another in the sequence so that the desired amino acid sequence of the particular fragment results. The subject of the invention are also medicaments which contain a PTH fragment according to the invention as active material, besides usual adjuvant and additive materials.
The amino acid sequences of hPTH, bPTH and pPTH (h=human, b=bovine, p=porcine) are known from Potts et al., Adv. in Protein Chem. (1982), 323-396; e.g. hPTH(1-34).
The PTH fragments according to the invention with the amino acid region of PTH(3-35) which, starting from the am
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Kikuchi et al, Endocrinology, vol. 128, No. 3, pp. 1229-1237 (1991).
Somjen et al. Stimulation by defined parathyroid hormone fragments . . . Biochem. J. 1990, vol. 272, pp. 781-785.
Copy of specification of U.S. application serial No. 70/225,344 (Jul. 28, 1988).
Duvos Christian
Mayer Hubert
Mueller-Beckmann Bernd
Strein Klaus
Wingender Edgar
Boehringer Mannheim GmbH
Russel Jeffrey E.
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