JPH03275623A - New blood platelet agglutination inhibitor - Google Patents

Abstract

PURPOSE:To obtain a blood platelet agglutination inhibitor containing a forskolin derivative or salt thereof as an active ingredient. CONSTITUTION:The objective substance, containing 0. 1-100wt.% forskolin deriva tive expressed by the formula [R<1> is group expressed by -CO-(CH2)n-NR<3>R<4> (R<3> and R<4> are H, lower alkyl or both together are linked to form lower alkylene which may have O or N; n is 1-5); R<2> is 2-3C hydrocarbon; Ac is acetyl] or salt thereof as an active ingredient and obtained by, as necessary, mixing an excipient or carrier therewith and preparing a formulation according to a conventional method. The aforementioned derivative can be formulated as the form of injection, granule, fine granule, powder, capsule, suppository, eye drop, application agent, ointment, spray, etc. The dose thereof is 0.001-30mg/kg/ day for parenteral administration and 0.003-300mg/kg/day for oral administra tion.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a platelet aggregation inhibitor.

[Conventional technology]

Conventionally, anticoagulant therapy, thrombolytic therapy, and antiplatelet therapy have been performed as antithrombotic therapy.

Heparin and warfarin are known as anticoagulant therapeutic agents, urokinase is known as a thrombolytic therapeutic agent, and ticlopidine and aspirin are known as antiplatelet therapeutic agents.

[Problem to be solved by the invention]

Heparin, warfarin, and urokinase are effective in preventing coagulation and dissolving thrombi in secondary thrombus formation, but are almost ineffective against primary thrombus caused by platelet aggregation. Most arterial thromboses such as myocardial infarction and cerebral thrombosis are primary thrombi caused by platelet aggregation. Currently, ticlopidine and aspirin are used as antiplatelet therapeutic agents, but these are not satisfactory, and new antithrombotic therapeutic agents are desired.

[Means to solve the problem]

The present invention provides a group represented by the general formula (I) [wherein R1 is the formula -COmoCH2)nNR'', R' (where RR and R4 are hydrogen or a lower alkyl group, or R3 and R4 are bonded together). A lower alkylene group which may contain an oxygen atom or a nitrogen atom in its bonded chain, n
is an integer of 1 to 5), R2 is a hydrocarbon group having 2 to 3 carbon atoms,
The present invention relates to a platelet aggregation inhibitor containing a forskolin derivative represented by the formula [Ac represents an acetyl group] or a physiologically acceptable salt thereof as an active ingredient.

In the above general formula, the formula of R1 -COmoCH2)N<W
n*, R4 in, for example, hydrogen, methyl,
Examples of C1-C4 lower alkyl groups such as ethyl, propyl, butyl, and lower alkylene groups in which R3 and R4 are bonded and which may contain an oxygen or nitrogen atom in the bonded chain include pyrrolidine, piperidine, and morpholine. can be given.

Specific examples of R1 include dimethylaminoacetyl group, dimethylaminopropionyl group, dimethylaminobutyryl group, dimethylaminopentanoyl group, dimethylaminohexanoyl group, aminopropionyl group, aminobutyryl group, aminopentanoyl group, and aminohexanoyl group. group, pyrrolidinoacetyl group, piperidinopropionyl group,
Examples include morpholinoacetyl group.

Examples of R2 include vinyl group, ethyl group, and cyclopropyl group.

Specifically, for example, 6-(3-dimethylaminopropionyl)forskolin, 6-(4-dimethylaminobutyryl)forskolin, 6-(5-dimethylaminopentanoyl)forskolin, 6-(6-dimethylaminopropionyl)forskolin, Methylaminohexanoyl) forskolin, 6-(3-aminopropionyl) forskolin, 6-(4-aminophthyryl) forskolin, 6-(5-aminopentanoyl) forskolin, 6-(6-aminohexanoyl) Forskolin, 14.15-dihydro-6-(3-dimethylaminopropionyl)forskolin, 14.15-dihydro-6(4-dimethylaminobutyryl)forskolin, etc., and also JP-A-63- 10783
Examples include the compounds described in the publication.

When the compound of general formula (I) is used as a platelet aggregation inhibitor, it can be used alone or mixed with excipients or carriers to form injections, granules, fine granules, powders, capsules, molds, eye drops, etc. It is administered orally or parenterally in preparations such as patches, ointments, and sprays. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the route and method of administration.

For example, water, alcohol, animal or vegetable oils such as soybean oil, peanut oil, sesame oil, mineral oil, or synthetic oils are used as liquid carriers. Saccharides such as maltose and sucrose, amino acids, cellulose derivatives such as hydroxypropyl cellulose, and organic acid salts such as magnesium stearate are used as solid carriers. In the case of injections, physiological saline, various buffer solutions, saccharide solutions such as glucose, inositol, mannitol, and xylitol, and glycols such as ethylene glycol and polyethylene glycol are generally preferred.

It is made into a lyophilized preparation together with sugars such as mataculcose, inositol, mannitol, xylitol, maltose, and sucrose, and excipients such as phenylalanine, and then administered in a suitable solvent for injection, such as sterile water, physiological saline, glucose solution, etc. It can also be administered by dissolving it in a liquid for intravenous administration, such as an electrolyte solution or an amino acid.

The content of the compound of general formula (I) in a preparation varies depending on the preparation, but is usually 0.1 to 100% by weight.

For example, in the case of an injection solution, it is usually preferable to contain 0.1 to 5% by weight of the present compound (I).

When administered orally, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with the solid carrier or liquid carrier. capsules, tablets,
In the case of granules and powders, the content of the present compound fI) is generally about 0.
The amount is 1 to 100% by weight, and the remainder is carrier.

The dose is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dose is generally administered parenterally.
1-30■/kg/day, oral administration 0003-300■
/kg/day.

[For production]

The action of the platelet aggregation inhibitor of the present invention will be illustrated in the following experimental example using 6(3-dimethylaminopropionyl) forskolin hydrochloride (hereinafter, this compound will be referred to as NKH477).

Experimental Example 1゜Co1Co11a-induced aggregation and A of rabbit blood platelets
, investigated using DP-induced aggregation.

Experimental method Male Japanese white rabbits (Tokyo Experimental Animals, body weight 2.4-2.
8 kg) were used in each group of 5 birds. The animals were anesthetized with ether, and blood was collected from the carotid artery. Add 3.8% sodium citrate solution (final concentration: 0.38%) to this and mix at 1000 rpm for 15 minutes.
Platelet rich plasma (RRP) was obtained by centrifugation at room temperature for minutes. Furthermore, the remaining blood was centrifuged at 300 Orpm for 15 minutes to obtain platelet-poor plasma (PPP). First, the transmittance of PRP and PPP was measured using an Alibometer (Rika Denki Kogyo, H
MA-31), 0% and 100%, respectively.
It was set to %. Separately, 250 μl of PRP was placed in a cuvette and prewarmed at 37° C. for 2 minutes, and then 20 μl of the sample was added and stirred for 2 minutes for incubation. This was followed by ADP (Sigma, final concentration 3X10'M) or collagen (Hormon-Chemie
, final concentration 10 μg/ml) was added, the transmittance was measured, and the maximum transmittance at this time was taken as the maximum aggregation rate.

The recording was done using an ink writing recorder (Rika Denki Kogyo, B-3).
81L).

NKH-477 (Nippon Kayaku) is dissolved in physiological saline and 1
A final concentration of 0-8 to 10''M was prepared.

Additionally, forskolin dissolved in ethanol was used as a control.

Results The results are shown in Table 1. In addition, it was confirmed that ethanol itself lacks any platelet aggregation inhibitory effect.

Table 1 (Data are average values, n-5) As is clear from this table, NKH477 has a platelet aggregation inhibitory effect that is 10 times or more stronger than forskolin.

Experimental Example 2 A lyophilized NKH477 preparation was dissolved in physiological saline and administered intravenously to four healthy adults at a rate of 08 μg/kg/min for 1 hour. Measure ADP-induced aggregation, epinephrine-induced aggregation, and collagen-induced aggregation at the end of administration,
The values were compared with those before administration. (The numbers are the average values of 4 cases) [Efficacy] As shown by these results, NKH477 showed excellent platelet aggregation inhibiting effects even in clinical cases. However, the compound of general formula (I) is expected to act as a platelet aggregation inhibitor.

〔Example〕

Formulation Example 1 30 parts by weight of NK) 1477 was dissolved in purified water to make a total of 2000 parts, and filtered through a Millipore filter.
Disinfect using GS type.

2 g of this F solution was placed in a 10 ml vial and lyophilized to obtain a lyophilized injection containing 30 ml of NKH477 per vial.

Formulation Example 2: 50 parts by weight of granules NKH477, 600 parts of lactose, 250 parts of crystalline cellulose and 100 parts of low-substituted hydroxypropyl cellulose were mixed using a roll compactor. compress,
The mixture was crushed and sieved to obtain between 16 mesh and 60 mesh to obtain granules containing 50 μm of NKH477 per gram.

Formulation Example 3 10 parts by weight of NKH477 tablets, 30 parts of white starch, 150 parts of crystalline lactose, 108 parts of crystalline cellulose and 2 parts of magnesium stearate were mixed in a ■-type mixer, and each tablet was compressed into 60 parts, Each tablet contained 2 μ of NKH477.

License applicant: Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is the formula -CO■CH_2■_nNR^3,
A group represented by R^4 (where R^3 and R^4 are hydrogen or lower alkyl groups, or even if R^3 and R^4 are bonded and the bonded chain contains an oxygen or nitrogen atom) a good lower alkylene group, n is an integer of 1 to 5), R^2 has 2 carbon atoms
~3 hydrocarbon group, Ac represents an acetyl group] or a physiologically acceptable salt thereof, as an active ingredient, a platelet aggregation inhibitor.