AGENTS FOR PROPHYLAXIS AND TREATMENT OF THROMBOPENIA

Abstract: Agents for prophylaxis and treatment of thrombopenia, which contain as an effective ingredient a muramyldipep­ tide derivative represented by general formula (I) (wherein X represents a residue of an amino acid selected from among L-alanine, L-serine and L-valine, Y represents (II), R₁ represents a carboxyl group, n represents an integer of 1 to 6, A rep­ resents a saturated, optionally branched aliphatic hydrocarbyl residue containing 7 to 29 carbon atoms, and Acyl represen­ ts an acyl group containing 2 to 6 carbon atoms). The agents show an excellent effect for prophylaxis and treatment of thrombopenia.

Description: This invention relates to the use of a muramyldipeptide derivative represented by the formula (I): wherein X represents an amino acid residue selected from L-alanine, L-serine and L-valine, Y represents wherein R₁ represents a carboxyl group, n represents an integer of 1 to 6, A represents a saturated aliphatic hydrocarbon group having 7 to 29 carbon atoms which may have branched chains, and Acyl represents an acyl group having 2 to 6 carbon atoms, for preparing a pharmaceutical composition for preventing and treating thrombocytopenia. Multipotential stem cells, which can differentiate to granulocytes, monocytes (macrophages), red blood cells, platelets, lymphocytes, exist in the bone marrow of higher animals such as human and mouse. The stem cells differentiate to precursor cells and these cells differentiate to the above blood cells. On the differentiation to these blood cells, several specific growth factors have been known to function to each blood cell's differentiation. For example, Interleukin-3 functions to the multipotential stem cells to induce the differentiation thereof to precursory granulocytes, and the granulocyte growth factors such as granulocyte-colony stimulating factor (G-CSF) function to the precursor cells to induce the differentiation thereof and to mature into granulocytes. With respect to the platelets, precursor cells such as megakaryocytes and platelet growth factor (MK-CSF) participate in the platelets. However, the details thereof have not been clarified. Of various cells which are considered to have maturation function, platelets have a significant role to maintain the health independently or in cooperation with other blood cells. Therefore, when the differentiation to platelets is inhibited, some diseases caused by reduction of platelet numbers appear. Examples of such diseases include symptomatic thrombocytopenia or idiopathic thrombocytopenia caused by medical agents (an anticancer agent, e.g.), radiation, or blood diseases. More specific symptoms thereof include bleeding and coagulation defect. Conventionally, as the treating method for such various thrombocytopenia, only platelets transfusion which is complicated and expensive, has been used. Thus, there was no agent for the prevention and treatment of such symptoms. The compounds of the present invention are disclosed in EP-A-21 367 (Japanese Patent Publication No. 62-27079) as having an excellent adjuvant activity and/or preventing and treating effects on infection by microorganisms. However, it has been unknown that the compounds of the formula (I) are effective for the prevention and treatment of thrombocytopenia. As a result of extensive studies on the compounds of formula (I) above, the present inventors found that the compounds exhibit excellent effects on prevention and treatment of thrombocytopenia. That is, the present invention relates to the use of a compound of the formula (I) for preparing a pharmaceutical composition for preventing and treating thrombocytopenia. Pharmaceutical preparations for administering the compound of the formula (I) include tablets, capsules, powders, granules, injections, suppositories, sprays and dermal preparations. These preparations can be prepared by known pharmaceutical techniques using appropriate additives such as excipients, e.g., corn starch, lactose, and mannitol, binders, e.g., hydroxypropyl cellulose, and polyvinyl pyrrolidone, disintegrators, e.g., low substituted hydroxypropyl cellulose crystalline cellulose, and lubricants, e.g., talc, or magnesium stearate. If desired, the preparation of the present invention can be a slow release preparation which can be prepared using known pharmaceutical techniques. The pharmaceutical agent of the present invention thus prepared can be administered orally or parenterally. The dose level usually ranges from 100 to 400 µg/day for adult in case of subcutaneous administration. The therapeutic effect of the agent according to the present invention is expected to be further enhanced by combining with whole blood transfusion or platelets transfusion which is a typical conventional therapeutic method for the treatment of thrombocytopenia. The compounds of the present invention are of low toxicity. For example, LD₅₀ of Compound A described below, which is a typical compound, was found to be 600 to 1,000 mg/kg in rats by subcutaneous injection. The present invention is hereinafter described with reference to the following examples. Example 1 According to the above furmulation, a lyophilized injection containing 200 µg was prepared using known pharmaceutical techniques. This preparation is used by dissolving in the additive solution just before use. Example 2 Compound A (200 µg) was administered subcutaneously to 20 patients with malignant lymphoma in a single daily dose for 10 consecutive days from 3 to 5 days after the starting day of chemotherapy for the above disease. Blood test was carried out on the 7, 10, 14, 17, 21 and 24th days after the starting day of the chemotherapy. The number of platelets was compared with that in the same patients of non-medication by the cross over method. The results are shown in Table 1 below as mean ± standard error. *Compound A : An anomeric mixture of N²-[(N-acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N⁶-stearoyl-L-lysine As it is apparent from the results in Table 1 above, the increase in the platelet numbers was observed by administration of Compund A, and a tendency to suppress the reduction in the platelet numbers caused by the anticancer agent and to restore the platelet numbers was observed. The compound of formula (I) exhibits excellent prevention and treatment effects of thrombocytopenia and, therefore, is excellent as an agent for preventing and treating the thrombocytopenia.

Claims: The use of a muramyldipeptide derivative of the formula: wherein X represents an amino acid residue selected from L-alanine, L-serine and L-valine, Y represents wherein R₁ represents a carboxyl group, n represents an integer of 1 to 6, A represents a saturated aliphatic hydrocarbon group having 7 to 29 carbon atoms which may have branched chains, and Acyl represents an acyl group having 2 to 6 carbon atoms, for preparing a pharmaceutical composition for preventing and treating thrombocytopenia. The use according to claim 1 wherein the muramyldipeptide is N²-[(N-acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N⁶-stearoyl-L-lysine.

Inventors: INOUE, ATSUO DAIICHI SEIYAKU CO., LTD., MASAOKA, TORU, MASUO, KEN DAIICHI SEIYAKU CO., LTD., NAKAYASU, TOSHIRO DAIICHI SEIYAKU CO., LTD., TAKAYANAGI, T. DAIICHI SEIYAKU RESEARCH INSTITUTE, TSUBURA, EIRO
Applicants: DAIICHI PHARMACEUTICAL CO., LTD.
Application year: 1988
Main classification: A61K37
IPC codes: C07K9