JPH04342526A - Peripheral circulation improver of extremity and inhibitor of blood vessel contracture - Google Patents

Abstract

PURPOSE:To obtain a medicinal composition capable of increasing an amount of blood flow of arteria femoralis, reducing peripheral blood vessel resistance of extremity and remitting blood vessel contracture, comprising a forskolin derivative as an active ingredient. CONSTITUTION:A medicinal composition comprising a compound shown by formula I [R<1> is group shown by formula II (R<3> and R<4> are H, lower alkyl or mutually condensed to form lower alkylene which may contain O of N in the condensed chain); R<2> is 2-3C hydrocarbon group; AC is acetyl@{9147-28} known to have positive inotropic action, antihypertensive action and activating action on adenylate cyclase or a pharmaceutically active salt thereof such as 6-(3-dimethylamino)forskolin as an active ingredient. The compound is useful for treating diseases (e.g. Burger diseases or congelation) caused by disorders of peripheral blood circulation in extremity, preventing exacerbation of symptoms and relapse and other diseases (e.g. Raynaud's diseases and acrocyanosis) caused by blood vessel contracture.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to an agent for improving peripheral circulation in the extremities or an agent for suppressing vasospasm.

0002

[Prior Art] A forskolin derivative represented by the following general formula (I) having positive inotropic action, hypotensive action and adenylate cyclase activating action is disclosed in Japanese Patent Application Laid-open No. 1078-1078.
It is known from Publication No. 3.

[0003] β-stimulants and phosphodiesterase inhibitors are conventionally known as drugs that increase cAMP in vascular smooth muscles and exhibit vasodilation. Also, for vasospasm,
Prostaglandins are known to have preventive and therapeutic effects.

0004

[Problems to be Solved by the Invention] There is a desire for a drug that exhibits a vasodilatory effect with an unprecedented new mechanism of action that is also effective against pathological conditions that are resistant to the above-mentioned drugs.

[0005]

[Means for Solving the Problems] The present invention provides general formula (I)

[0006]

[C3]

[In the formula, R1 is hydrogen or the formula -CO-(-C
H2-)n-NR3R4 (where R
3, R4 is hydrogen or a lower alkyl group, or R3 and R4
is bonded to a lower alkylene group which may contain an oxygen atom or a nitrogen atom in the bonded chain, n is an integer of 1 to 5)
, R2 is a hydrocarbon group having 2 to 3 carbon atoms, Ac is an acetyl group] A forskolin derivative or a physiologically acceptable salt thereof as an active ingredient. Regarding.

In the above general formula (I), R1 has the formula -CO
-(-CH2-)n-R3,R in NR3R4
4 is, for example, hydrogen, a C1 to C4 lower alkyl group such as methyl, ethyl, propyl, butyl, or R3 and R
Examples of the lower alkylene group to which 4 is bonded and which may contain an oxygen atom or a nitrogen atom in the bonded chain include pyrrolidine, piperidine, and morpholine.

Specific examples of R1 include dimethylaminoacetyl group, dimethylaminopropionyl group, dimethylaminobutyryl group, dimethylaminopentanoyl group,
Examples include dimethylaminohexanoyl group, aminopropionyl group, aminobutyryl group, aminopentanoyl group, aminohexanoyl group, pyrrolidinoacetyl group, piperidinopropionyl group, and morpholinoacetyl group. Examples of R2 include vinyl group, ethyl group, and cyclopropyl group.

Specifically, for example, 6-(3-dimethylaminoperopionyl) forskolin, 6-(4-dimethylaminobutyryl) forskolin, 6-(5-dimethylaminopentanoyl) forskolin, 6 -(6-dimethylaminohexanoyl)forskolin, 6-(3
-aminopropionyl) forskolin, 6-(4-aminobutyryl) forskolin, 6-(5-aminopentanoyl) forskolin, 6-(6-aminohexanoyl) forskolin, 14, 15-dihydro-6-
(3-dimethylaminopropionyl)forskolin,
Examples include 14,15-dihydro-6-(4-dimethylaminobutyryl)forskolin, and further examples include compounds described in JP-A-63-10783.

When the compound of general formula (I) is used as an agent for improving peripheral circulation in the extremities and as an agent for suppressing vasospasm, it can be used alone or in combination with excipients or carriers to form injections, granules,
The preparations include fine granules, powders, capsules, suppositories, eye drops, patches, ointments, and sprays, and are administered orally or parenterally. 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 the liquid carrier. As solid carriers, sugars such as maltose and sucrose, amino acids, cellulose derivatives such as hydroxypropylcellulose, and organic acid salts such as magnesium stearate are used. In the case of injections, generally physiological saline, various buffer solutions, sugar solutions such as glucose, inositol, mannitol, and xylitol, and glycols such as ethylene glycol and polyethylene glycol are preferable. . In addition, it is made into a lyophilized preparation together with saccharides such as glycose, inositol, mannitol, xylitol, maltose, and sucrose, and excipients such as phenylalanine. It can also be administered by being dissolved in a liquid for intravenous administration, such as sterile water, physiological saline, glucose solution, electrolyte solution, or amino acid sugar.

The content of the compound of general formula (I) in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight.
It is. 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, sugars, etc. together with the solid carrier or liquid carrier. In the case of capsules, tablets, granules, and powders, the content of the present compound (I) is generally about 0.1 to
100% by weight, the remainder being carrier.

[0014] The dosage is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dosage is generally 0.001 to 30 mg/kg/day for parenteral administration and 0.0 mg/kg/day for oral administration.
03 to 3000 mg/kg/day.

[0015]

[Action] The action of the present invention is expressed by 6-(3-dimethylaminopropionyl)forskolin hydrochloride (hereinafter referred to as this compound)
This is shown in the following experimental example using KH477).

Experimental example 1. The effect on femoral artery blood flow in anesthetized dogs was investigated. Experimental method A non-invasive electromagnetic blood flow probe (Nihon Kohden, FF-030T) was attached to the left femoral artery of a dog anesthetized with pentobarbital, and femoral artery blood flow was measured using an electromagnetic flowmeter (Nihon Kohden, MFV-2100). and recorded on an ink writing recorder (Nihon Kohden, WI-681G). NKH477 was dissolved in physiological saline before use and administered via a Neraton tube inserted into the right cephalic vein. Results The results are shown in Table 1.

[0017]

[Table 1]

As is clear from Table 1, NKH477 is 1
Intravenous administration of ~10 μg/kg increased femoral artery blood flow in a dose-dependent manner.

Experimental example 2. The effect on total peripheral vascular resistance in anesthetized dogs was investigated. Experimental method A pressure transducer (
Century Technology Company, CP-01) strain pressure amplifier (Nihon Kohden, AP-620G)
) and a dilution cardiac output calculator (
Cardiac output was measured by thermodilution using Nihon Kohden MLC-4200). Total peripheral vascular resistance was calculated by dividing mean blood pressure by cardiac output.

[0020] NKH477 was dissolved in physiological saline at the time of use, at doses of 0.15, 0.3 and 0.6 μg/kg/min.
A continuous infusion pump (Harvard, Model 975C) was used from the right cephalic vein at a dosing rate of (flow rate 0.2 ml/min).
) was used for continuous infusion for 2 hours. Similarly, physiological saline was continuously injected at 0.2 ml/min to form a control group. Results Table 2 shows the changes in total peripheral vascular resistance over time in the NKH477 administration group and the control group.

[0021]

[Table 2]

As is clear from Table 2, after the start of NKH477 injection, the total peripheral vascular resistance gradually decreased. This effect was dose-dependent, showing a maximum response 30 minutes to 1 hour after the start of the infusion, and was maintained until the end of the infusion. Moreover, this effect almost recovered 2 hours after the end of the injection.

Experimental Example 3 The spasm alleviation effect on isolated canine coronary and basilar arteries was investigated. Experimental Method The coronary artery and basilar artery of a dog anesthetized with pentobarbital were removed, and ring specimens with a width of 3 mm were prepared. The specimen was a 10 m tube filled with Krebs-Henseleit solution.
1.5 g (crown) and 1.5 g (crown) in 1 organ bath.
The animal was suspended under a resting tension of 0 g (basilar). Nutrient liquid is 37
It was maintained at 0.degree. C. and vented with 95% O2-5% CO2. The isometric tension of the muscle was measured using an FD pickup (Nihon Kohden, TB-6).
11T) and a pressure strain meter (Nihon Kohden, AP-621G) on a recorder (Tokai Irika, TI-104).

After approximately 2 hours of equilibration time, 30mM (crown)
and 35 mM (basilar) KCl to induce contraction, and after the contraction stabilized, NKH477 was cumulatively administered. still,
The contraction-alleviating effect was expressed as an inhibition rate as 100% of the maximum response obtained with paparin hydrochloride (10-4M). Results The results are shown in Table 3.

[0025]

[Table 3]

As is clear from Table 3, NKH477 exhibited a concentration-dependent inhibitory effect on KCl contraction in coronary and basilar arteries. Its IC50 value was 6.73 ± 1.45 × 10-8 M (n = 6) for coronary and basilar arteries, respectively.
and 1.02±0.26×10 −7 M (n=3).

Experimental Example 4 A lyophilized NKH477 preparation was dissolved in physiological saline and administered continuously intravenously to four healthy adults at a rate of 0.4 μg/kg/min for 1 hour. Based on the cardiac output and mean blood pressure calculated from the echocardiogram, the percentage decrease in total peripheral vascular resistance 40 minutes after the start of administration compared to before administration was calculated for each patient, and the average was 19.7%. Ta. On the other hand, the reduction rate of total peripheral vascular resistance was similarly calculated for each of five healthy adults who received continuous intravenous administration of physiological saline alone for one hour, and the average was only 1.7%.

[0028]

[Results] As is clear from the above, the compound of general formula (I) increases femoral artery blood flow and decreases peripheral vascular resistance. It is expected to be a useful agent for improving peripheral circulation in the extremities, such as in the treatment of sexual arteriosclerosis, frostbite, and chilblains, as well as in preventing the worsening of symptoms and preventing recurrence.

The compound of general formula (I) also has a vasospasm-alleviating effect, and can be used in the treatment of various diseases based on vasospasm,
Vasospasm inhibitor useful for alleviating vasospasm, such as Raynaud's disease, arterial spasm diseases (e.g., acrocyanosis, reticular congestive plaques, etc.), arterial spasm after subarachnoid hemorrhage, and vasospasm caused by administration of ergot drugs. It is expected to be used as a drug.

[0030]

【Example】

Formulation Example 1 After dissolving 30 parts by weight of NKH477 and adding purified water to make a total of 2000 parts, millipore filter-G
Filter for sterilization using S type. 2g of this filtrate
Lyophilize in a 1-liter vial, 30 ml per vial.
A lyophilized injection containing g of NKH477 was obtained.

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 thoroughly mixed, and the mixture was prepared using a roll compressor (roll type compressor).
The mixture was compressed using a La Compactor (registered trademark), crushed, and passed through a sieve between 16 mesh and 60 mesh to obtain granules containing 50 mg of NKH477 per gram.

Formulation Example 3 10 parts by weight of tablet NKH477, 30 parts of horse starch, 150 parts of crystalline lactose, 108 parts of crystalline cellulose and 2 parts of magnesium stearate were mixed in a V-type mixer.
Compressed into 60mg tablets, each tablet contains 2mg of NKH47.
Tablets containing 7 were prepared.

Claims (2)

[Claims] [Claim 1] General formula (I) [In the formula, R1 is the formula -CO-(-CH2-)n-NR]
A group represented by 3R4 (where R3 and R4 are hydrogen or a lower alkyl group, or a lower alkylene group in which R3 and R4 are bonded and which may contain an oxygen atom or a nitrogen atom in the bonded chain, and n is 1 ~5 integer), R2 has 2 to 3 carbon atoms
The hydrocarbon group Ac represents an acetyl group] A forskolin derivative or a physiologically acceptable salt thereof as an active ingredient for improving peripheral circulation in the extremities [Claim 2] General formula (I) [In the formula, R1 is of the formula -CO-(-CH2-)n-NR]
A group represented by 3R4 (where R3 and R4 are hydrogen or a lower alkyl group, or a lower alkylene group in which R3 and R4 are bonded and which may contain an oxygen atom or a nitrogen atom in the bonded chain, and n is 1 ~5 integer), R2 has 2 to 3 carbon atoms
The hydrocarbon group Ac represents an acetyl group] A vasospasm inhibitor containing a forskolin derivative or a physiologically acceptable salt thereof as an active ingredient