A preparation method of salmon calcitonin, its combined preparation and the application of the combined preparation in medicine for osteoporosis

Abstract

The invention discloses a preparation method for salmon calcitonin, a preparation of the salmon calcitonin and use of the preparation in drugs for osteoporosis. According to the preparation method, when amino acids of 22 and 23 positions of a fragment of the salmon calcitonin prepared by an Fmoc-policy solid-phase method are condensed, a condensation agent system DFIH / EEDQ is employed, and thus, generation of an impurity E and an impurity C of the salmon calcitonin can be lowered; and when amino acids of 17 and 18 positions of a fragment of the salmon calcitonin prepared by the Fmoc-policy solid-phase method are condensed, DMSO is used as a condensation agent, a weight ratio of the DMSO to Fmoc-His-OH is (10 to 15): 1, and thus, generation of an impurity F of the salmon calcitonin can be lowered. The calcitonin prepared by the preparation method is good in stability and few in impurities; and the calcitonin biological vector conjugated preparation disclosed by the invention has new usein treatment of osteoporosis of the male.

Description

Technical field[0001]The invention relates to the field of medicine, in particular to a preparation method and preparation of salmon calcitonin and its use in osteoporosis medicine.Background technique[0002]Calcitonin is one of the hormones that regulate calcium metabolism and inhibit parathyroid hormone. It can significantly reduce the loss of bone calcium in high turnover bone diseases. It can inhibit osteoclast activity and stimulate osteoblast formation. Calcitonin can also inhibit osteolysis, thereby reducing the pathologically elevated blood calcium concentration and increasing urinary calcium, phosphorus and sodium excretion by reducing renal tubular reabsorption. Salmon calcitonin has a high affinity to its receptor binding site, has a very good clinical effect and has a longer duration of action than synthetic mammalian (including human) calcitonin.[0003]The synthesis method of salmon calcitonin used in patent CN1865283B is Fmoc strategy solid-phase method, the main synthes...

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Problems solved by technology

[0004] However, in the synthesis method reported by these two patents, there are relatively large impurities in salmon calcitonin, especially 22-position tyrosine, and tert-butyl (-tBu) is used to protect the hydroxyl group, which is prone to incomplete protection and generates a large amount of impurity E; and Under the above condensation conditions, the 22-position tyrosine cannot be condensed completely with the proline of the 23-position four-membered ring, and it is easy to generate salmon calcitonin impurity C that loses the 22-position tyrosine; in addition, the 17-position histidine (His) Racemization is prone to occur, especially when the protection group such as trityl (Trt) or p-toluenesulfonyl (Tos) is introduced into the amino protecting agent, or when a condensing agent is used to react, the condensation with adjacent amino acids is more likely to cause racemization, forming Impurity F

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