JPH0333717B2 - - 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-amino-2-methyl-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-piperidinopropiophenone hydrochloride represented by the following formula () (JP-A-50-89374
No., JP-A No. 52-85175 (hereinafter abbreviated as eperisone), etc., and these are currently commercially available as muscle relaxants and are used clinically. Further, as a similar compound of the 3-amino-2-methyl substituted propiophenone derivative () related to the present invention, 4'-fluoro-2 represented by the following formula ()
-Methyl-3-piperidinopropiophenone (French Patent No. 1301863) is known, but there is no specific description of its pharmacological action in this specification, but there is a statement that it is useful as a raw material for manufacturing pharmaceuticals. only. 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 intensive research on more useful muscle relaxants, and as a result, they discovered a novel 3-amino-2-methyl substituted propiophenone derivative represented by the above formula (), and The present inventors have discovered that a pharmacologically acceptable acid addition salt thereof has excellent muscle relaxation, spinal reflex suppression, anticonvulsant effects, and high safety, and has completed 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,
Mineral acid salts such as phosphoric acid, or acetic acid, maleic acid,
Examples include organic acid salts such as fumaric acid, citric acid, oxalic acid, and tartaric acid. The novel 3-amino-2-methyl-substituted propiophenone derivative of the present invention represented by the above formula () has the following formula () 3'-Fluoropropiophenone represented by, formaldehyde in a solvent and the following formula () It can be produced by reacting piperidine 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, piperidine is usually treated with hydrochloric acid, hydrobromic acid,
It is used as a mineral acid salt such as nitric acid, but when using free piperidine, it can be carried out by adding enough mineral acid to make the reaction system sufficiently acidic. Although the reaction equivalent ratio can be selected as appropriate, in particular, because it is necessary to eliminate residual piperidine in the post-reaction treatment, 1 equivalent of piperidine represented by the above formula () is replaced with 3'-fluoro fluoride 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 3'-fluoropropiophenone represented by the above formula (), which is the starting material in the method of the present invention, is a known substance, and for example, according to the method described in West German Patent Publication No. 2059618,
can be manufactured. 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 ready-to-use injections, solution injections, and suspension injections. 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 and 2 below. The following compounds were used as test drugs. ◎Compound of the present invention: 3'-fluoro-2-methyl-3
-Piperidinopropiophenone hydrochloride ◎Known compound: 4'-fluoro-2-methyl-3-
Piperidinopropiophenone hydrochloride (formula) Test Example 1 Oxotremorine-induced tremor suppression effect [Test method] Five-week-old DDY male mice were used in experiments in groups of five. The test drug was administered orally at 100 mg/Kg, 15 minutes later oxotremorine was administered intraperitoneally at 1 mg/Kg, and the degree of tremor that occurred 15 and 30 minutes later was measured using the method of Suzuki et al . ,127
(1983)), evaluation was made using the following rating scale, and cases with a rating of 2 or less were considered effective (inhibition), and the inhibition rate (number of effective animals/number of test animals) was determined. <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 1.

〔Test method〕

Five-week-old DDY male mice were used in experiments as a group of five mice. A mouse was placed on a rotating rod that rotated 13 times per minute, and a mouse that could be kept on it for at least 60 seconds was selected in advance. 100 mg/Kg of the test drug was administered orally, 5 minutes after administration,
After 15 minutes, the mouse was placed on a rotating rod, and the mouse was considered effective if it fell within 60 seconds, and the effectiveness rate (number of effective animals/number of test animals) was determined. The results are shown in Table 2.

[Table] The compounds of the present invention showed excellent muscle relaxing effects, but the known compounds showed almost no efficacy. Examples Hereinafter, the present invention will be explained using examples. Example 1 3'-Fluoro-2-methyl-3-piperidinopropiophenone To a solution of 9.00 g of 3'-fluoropropiophenone in 30 ml of ethyl acetate, 4.00 g of piperidine and 2.20 g of paraformaldehyde are added. Then,
While stirring, hydrogen chloride gas was introduced to make the mixture acidic, and the mixture was heated under reflux for 5 hours. After the reaction, add water and shake.
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. After evaporating the solvent and dissolving the resulting residue in ether, 40% ethanolic hydrochloric acid is added. The precipitated crystals were collected by filtration to obtain 7.97 g of the hydrochloride of the title compound. Recrystallization from a mixture of ethanol and ether gives colorless platelets with a melting point of 173-174°. IR spectrum ν (KBr) cm ^-1 : 1680 (C=
0) Elemental analysis value C ₁₅ H ₂₀ FNO・HCl Theoretical value C, 63.04; H, 7.41; N, 4.90 Actual value C, 63.12; H, 7.51; N, 5.00 Effect of the invention The above formula produced in this way The novel 3-amino-2-methyl-substituted propiophenone derivatives represented by () and their pharmacologically acceptable acid addition salts have excellent muscle relaxing, spinal reflex suppression, anticonvulsant effects, etc. lumbar back pain, herniated disc,
It is extremely useful as a therapeutic agent for muscle spasms associated with motor organ diseases such as spondylosis osteoarthritis.

Claims (1)

[Claims] 1 formula A 3-amino-2-methyl-substituted propiophenone derivative represented by: and a pharmacologically acceptable acid addition salt thereof.