JPS635380B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to an antispasmodic agent, and more particularly to an antispasmodic agent for humans or animals containing an α-aryl-α-pyridyl fatty acid derivative or a salt thereof as an active ingredient. [Prior Art] Conventionally, quaternary ammonium salt type drugs such as thimepidium bromide (Japanese Patent Publication No. 48-31886), which has the structure shown below, have been known and widely used as antispasmodics. . Timepidium bromide
Bromide) The compound represented by the general formula [) below, which is the active ingredient of the antispasmodic agent of this invention, is disclosed in Japanese Patent Application Publication No. 59-80664.
It is a known compound described in the publication, and can be produced by the method described in the publication. Although the same publication also describes that the compound has an antiulcer effect, it is not known that it has an antispasmodic effect. [Problems to be solved by the invention] Quaternary ammonium salt type antispasmodics such as the above-mentioned thimepidium bromide have the advantage of having little action on the central nervous system, but the duration of their efficacy is short. However, they have drawbacks such as poor oral absorption and, when used as an injection, a temporary but significant drop in blood pressure. [Means for Solving the Problems] As a result of intensive research to improve the above-mentioned drawbacks of thimepidium bromide, the inventors of the present invention have discovered that a compound represented by the general formula [] below has been developed. This invention was completed after discovering that it has an antispasmodic effect, has excellent oral absorption, does not cause a drop in blood pressure even when used as an injection, and has little effect on the central nervous system. The antispasmodic agent of this invention has the general formula (In the formula, R ⁵ , R ⁶ and R ⁷ each mean a lower alkyl group.) The active ingredient is an α-aryl-α-pyridyl fatty acid derivative or a salt thereof. In the above general formula [], R ⁵ , R ⁶ and
Examples of the lower alkyl group represented by R ⁷ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Salts of these compounds include hydrochloride,
Examples include salts with inorganic acids such as hydrobromide and sulfate, and salts with organic acids such as acetate, citrate, tartrate, and methanesulfonate. Note that the compound [ ] has isomers based on asymmetric carbon atoms in the molecule, and these isomers are also included within the scope of the present invention. The antispasmodic agent according to the invention can be prepared in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. can be used. Pharmaceutical formulations may be solid compositions such as capsules, tablets, dragees or suppositories, or liquid compositions such as solutions, suspensions or emulsions. If necessary, the above formulation may contain auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers, and other commonly used additives. Examples of the above additives used in formulation include starch, lactose, kaolin, calcium phosphate, alginic acid, gelatin, gum arabic, magnesium stearate, peanut oil, liquid paraffin, olive oil, sodium carboxymethylcellulose, polyvinylpyrrolidone, lecithin, Examples of surfactants include commonly used surfactants such as polyoxyethylene sorbitol monooleate. Active ingredients are usually in unit dosages of 0.01mg/Kg to 500
mg/Kg can be administered 1 to 4 times per day. However, the above dosages may vary depending on the patient's age,
The dosage may be increased or decreased as appropriate depending on body weight, symptoms, or administration method. [Examples] (1) Test Examples The test results of the antispasmodic action of representative examples of the compound [] which is the active ingredient of the antispasmodic agent of the present invention are shown below. (i) Test method Mongrel dogs, both male and female, weighing 7 to 14 kg were used. The dog was fasted for 18-24 hours beforehand and treated with morphine hydrochloride 10mg/Kg and urethane 1.5g/Kg.
After the patient was anesthetized by subcutaneous administration, the abdomen was opened, and a balloon was placed in the gastric pylorus or jejunum. The balloon was filled with water to give an internal pressure of 90 to 110 mmH ₂ O, and was connected to a pressure transducer and a strain pressure amplifier via a rubber tube. Waveform recording was performed continuously on a recorder. A cannula was inserted into the left femoral artery, and systemic blood pressure and heart rate were continuously recorded on the same recorder via a pressure transducer, strain pressure amplifier, and tachometer. After each parameter became stable, the test drug was dissolved in water and administered at a volume of 0.2 ml/Kg via a polyethylene tube inserted into the left femoral vein. (ii) Test compound 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)valeramide (iii) Test results

[Table] (2) Formulation example (i) Formulation example 1 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)valeramide (50g), lactose (700g) and low substituted hydroxypropyl Mix cellulose (400g). A solution of hydroxypropyl cellulose type L (5 g) dissolved in water (1 kg) is added dropwise to the mixture, and after kneading, the mixture is dried and sized through a 20-mesh sieve. Magnesium stearate (5 g) is added to the obtained granules, mixed, and then tableted using a tablet machine to obtain tablets (80 mg/tablet). (ii) Formulation Example 2 The granules of the tablet in Formulation Example 1 above were filled into capsules to obtain capsules (80 mg/capsule). (3) Acute toxicity test (i) Test method Ten male rats and A group of 10 female rats (JCL-SD strain) was prepared.The test compound was adjusted to various concentrations using the method described below, administered intravenously, intraperitoneally, subcutaneously, or orally to the rats, and then observed for 14 days. The LD ₅₀ value was calculated by the Probit method. (Adjustment of test compound) The test compound was dissolved in hydrochloric acid, adjusted to pH 6-7 with sodium bicarbonate, and then diluted with physiological saline to various concentrations. (ii) Test compound 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)valeramide (iii) Test results

〔effect〕

As shown in the above test results, the antispasmodic agent according to the present invention has an excellent antispasmodic effect over a long period of time without causing a significant drop in blood pressure. In addition, since the active ingredient is a tertiary amine type,
It has the advantage of excellent oral absorption and can be used as an oral preparation.

Claims (1)

[Claims] 1. General formula (In the formula, R ⁵ , R ⁶ and R ⁷ each mean a lower alkyl group.) An antispasmodic agent containing an α-aryl-α-pyridyl fatty acid derivative or a salt thereof as an active ingredient. 2 The active ingredient is 4-(N,N-dimethylamino)-
The antispasmodic agent according to claim 1, which is 2-phenyl-2-(2-pyridyl)valeramide or a salt thereof.