JPH0333716B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Fields The present invention has excellent muscle relaxing, spinal reflex suppression, and anticonvulsant effects, and is useful as a therapeutic agent for muscle spasms associated with locomotor diseases such as lumbar back pain, intervertebral disc herniation, and spondylosis osteoarthritis. The present invention relates to a novel 3-pyrrolidino-substituted propiophenone derivative () and a pharmacologically acceptable acid addition salt thereof. BACKGROUND ART Conventionally, as a propiophenone derivative having a muscle relaxing effect, 2,4'-dimethyl-3-piperidinopropionphenone hydrochloride (Japanese Patent Publication No. 40-20390, Japanese Patent Publication No. 52-95674,
(hereinafter abbreviated as tolperisone) and 4'-ethyl-2-methyl-3-piperidinopropionphenone hydrochloride represented by the following formula (
No. 89374 and JP-A-52-85175 (hereinafter abbreviated as eperisone), etc., are currently commercially available as muscle relaxants and are used clinically. On the other hand, as a similar compound of the 3-pyrrolidino-substituted propiophenone derivative () related to the present invention,
2,4'-dimethyl-3-pyrrolidinopropiophenone represented by the following formula ()
), and 4'-tert-butyl-2-methyl-3-pyrrolidinopropiophenone (Japanese Unexamined Patent Publication No. 16845/1984) represented by the following formula () are known, but these compounds are not covered by the present invention. It is stated that these compounds have antiallergic and bactericidal effects, respectively, in contrast to the effects of other compounds. Furthermore, none of these compounds have been put to practical use as antiallergic agents or bactericidal agents. Problems to be Solved by the Invention Although triperisone and eperisone represented by the above formulas () and () are commercially available as muscle relaxants, these are not fully satisfactory in terms of strength of action and toxicity. Under these circumstances, the present inventors conducted extensive research on more useful muscle relaxants, and as a result, discovered a novel 3-pyrrolidino-substituted propiophenone derivative represented by the above formula () and its pharmacological effects. Tolerable acid addition salts have excellent muscle relaxation, spinal reflex suppression,
They discovered that it has anticonvulsant action and high safety, leading to the completion of the present invention. Means for Solving the Problems The compound represented by the formula () of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or a base can be extracted from the generated acid addition salt. It can also be liberated. Examples of the pharmacologically acceptable acid addition salts of the compound represented by the formula () of the present invention include:
Hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,
Examples include mineral acid salts such as phosphoric acid, and organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, and tartaric acid. The novel 3-pyrrolidino-substituted propiophenone derivative of the present invention represented by the above formula () has the following formula () 4'-Butylpropiophenone represented by, formaldehyde in a solvent and the following formula () It can be produced by reacting pyrrolidine or its salts represented by the following by a method known per se (Mannitz reaction). Examples of formaldehydes used include formaldehyde, its linear or cyclic polymers paraformaldehyde, trioxane, and the like. In addition, pyrrolidine is usually used as a mineral acid salt such as hydrochloric acid, hydrobromic acid, or nitric acid, but when using free pyrrolidine, it can be carried out by adding enough mineral acid to make the reaction system sufficiently acidic. can. The reaction equivalent ratio can be selected as appropriate, but in particular, because it is necessary to eliminate residual pyrrolidine in the post-reaction treatment, 4'-butyl represented by the above formula () is added to 1 equivalent of pyrrolidine represented by the above formula (). At least 1 equivalent, preferably 1.1 equivalent, of propiophenone is reacted with at least 1 equivalent, preferably 1.5 equivalent, of formaldehyde. Solvents used in the reaction include alcohol solvents such as methanol, ethanol, propanol, and isopropanol, nitroalkane solvents such as nitromethane and nitroethane, and lower fatty acid lower alkyl ester solvents such as methyl acetate, ethyl acetate, and ethyl propionate. In particular, it is preferable to use lower fatty acid lower alkyl ester solvents. The reaction is carried out at room temperature to reflux, particularly preferably at the reflux temperature of the solvent used. The 4'-butylpropiophenone represented by the above formula (), which is the starting material in the method of the present invention, is a known substance, for example, as described in Pharmazie, Vol. 24, p. 735 (1969). can be manufactured according to the method. The compound represented by the formula () produced in this way can be prepared by a conventional method into oral preparations such as capsules, tablets, fine granules, granules, syrups, and powders, or into preparations such as injections. It is used clinically as a. The dosage depends on the symptoms to be treated and the administration method, but when administered orally to adults, it is usually 10 to 1500 mg per day, preferably 50 to 300 mg per day. Capsules and tablets for oral administration are fixed-dose dosage forms, and excipients include, for example, lactose, starch, cellulose, calcium phosphate, mannitol, etc., and disintegrants include, for example, starch, carboxymethylcellulose, and its sodium or calcium. Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic, etc., and examples of lubricants include:
Examples include magnesium stearate, talc, and silicic anhydride. It can also be suspended in vegetable oil or neutral oil to form soft capsules. The tablets can be coated with a coating, and if necessary, a coloring agent, a flavoring agent, a flavoring agent, etc. can be added. Injections can be used as fixed-dose ampoules or vials, such as dissolved injections, solution injections, and suspension injections before use. This dosage form includes, for example,
Distilled water for injection, vegetable oil, glucose, mannitol, sodium chloride, etc. are used. Suppositories, ointments, and poultices can also be prepared and administered by conventional methods. Effects The excellent pharmacological effects of the compounds of the present invention are shown in Test Examples 1 to 4 below. In addition, the acute toxicity test results are shown in Test Example 5. The following compounds were used as test drugs. [Test drug] ◎Compound of the present invention: 4'-butyl-2-methyl-3-
Pyrrolidinopropiophenone hydrochloride () ◎Comparative drug 1: Triperisone () ◎Comparative drug 2: Eperisone () ◎Known compound 1: 2,4'-dimethyl-3-pyrrolidinopropiophenone hydrochloride () ◎Known compound 2: 4'-tert-butyl-2-methyl-3-pyrrolidinopropiophenone hydrochloride () Test example 1 Muscle relaxant effect (rotating rod test) [Test method] 5-week-old ddy strain Male mice were used in the experiment in groups of 10 mice. 3cm diameter that rotates 10 times per minute
A mouse was placed on a rotating rod, and a mouse that could be held for at least 60 seconds was selected and used. The test drug was orally administered at 200 mg/Kg, and at 10, 20,
After 30 and 60 minutes, the mouse was placed on a rotating rod, and the time until it fell (maintenance time (seconds)) was measured. The results are shown in Table 1. The shorter the maintenance time, the stronger the muscle relaxing effect.

〔Test method〕

Groups of 5-8 ddy male mice aged 5 weeks old
They were used as animals in experiments. 5 to 6 doses of the test drug were administered orally, and 15 minutes later, 5 mg/Kg of nicotine bitartrate was administered intravenously to observe the occurrence of death.
_ED50 values were calculated based on the Probit method. The results are shown in Table 2.

〔Test method〕

Groups of 5-8 ddy male mice aged 5 weeks old
They were used as animals in experiments. Five to six doses of the test drug were administered orally, 15 minutes later, 1 mg/Kg of oxotremorine was administered intraperitoneally, and the degree of tremor that occurred 10 minutes later was measured using the method of Suzuki et al. (Japanese Pharmacological Journal, 83 , 127). (1983))
According to the following, evaluation was made using the following score, and cases with a score of 1 or less were considered valid, and the number of effective animals was expressed. The ED ₅₀ value was calculated based on the Probit method from the effective number of tremors. <Rating> 0 = No tremor at all. 1 = Slight tremor when touched. 2 = Slight tremor. 3 = Moderate tremor. 4 = Severe tremor. The results are shown in Table 3.

〔Test method〕

The left sciatic nerve of rats anesthetized with α-chloralose (100 mg/Kg, intraperitoneal administration (ip)) was cut, and the central stump was electrically stimulated with a bipolar electrode to produce isometric extension movements of the right lower limb. It was recorded on a recorder via a transducer. Drug administration (5 mg/Kg, iv) was administered through a cannula attached to the jugular vein, and the response rate (%) 1 minute after administration was calculated relative to the high response level before administration. In addition, Student's t-test was used for the significance test. The results are shown in Table 4. The smaller the value (reaction rate) in the table, the stronger the reflex suppression effect.

〔Test method〕

Five-week-old DDY male mice were used in experiments as a group of five mice. Five to six doses of the test drug were orally administered, and the 50% lethal dose (LD ₅₀ value) was calculated from the mortality rate 7 days after administration based on the Probit method. The results are shown in Table 5.

[Table] The compound of the present invention had low toxicity compared to the control drug. As a result of these pharmacological tests and acute toxicity tests, it was revealed that the compound of the present invention exhibits excellent pharmacological action and has higher safety than the control substances and known compounds. Examples Hereinafter, the present invention will be explained using examples. Example 1 4'-Butyl-2-methyl-3-pyrrolidinopropiophenone To a solution of 5.40 g of 4'-butylpropiophenone in 15 ml of acetic acid ethyl ester, pyrrolidine, hydrochloride was added.
Add 3.00 g and 1.30 g of paraformaldehyde. Then 22% acetic acid ethyl ester hydrochloric acid 0.5
ml and heated under reflux for 4.5 hours. After the reaction, add an aqueous hydrochloric acid solution, shake, and separate the aqueous layer. The aqueous layer is made alkaline with potassium carbonate and extracted with ether. The ether layer is washed with water and dehydrated. The solvent is distilled off, and ethanolic hydrochloric acid is added to the resulting residue.
The solvent is distilled off, isopropyl ether is added to the resulting residue, and the precipitated crystals are collected by filtration. The filtered product is recrystallized from methyl ethyl ketone to obtain 2.93 g of the hydrochloride of the title compound as colorless flaky crystals with a melting point of 116-117°. IR spectrum ν (KBr) cm ^-1 : 1680 (C=
0) Elemental analysis value C ₁₈ H ₂₇ NO・HCl Theoretical value C, 69.77; H, 9.11; N, 4.52 Experimental value C, 69.51; H, 9.25; N, 4.55 Effect of the invention The above formula produced in this way The novel 3-pyrrolidino-substituted propiophenone derivatives shown in () and their pharmacologically acceptable acid addition salts have excellent muscle relaxation, spinal reflex suppression, anticonvulsant effects, etc. It is extremely useful as a therapeutic agent for muscle spasms associated with musculoskeletal diseases such as back pain, intervertebral disc herniation, and spondylosis osteoarthritis.

Claims (1)

[Claims] 1 formula A 3-pyrrolidino-substituted propiophenone derivative represented by: and a pharmacologically acceptable acid addition salt thereof.