JPH0474B2 - - Google Patents

Description

[Detailed description of the invention]

[Objective of the invention] Industrial field of application The present invention relates to 1-(2,
We provide 3-dihydro-5-benzofuranyl)-1-propanone derivatives and physiologically acceptable salts thereof, and these compounds have a central muscle relaxing effect, so they are effective against spastic paralysis and musculoskeletal disorders. It is useful as a medicine for treating painful muscle spasm and the like. (In the formula, R is a hydrogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms, a cyclopentyl group, a cyclohexyl group, or a cyclopentylmethyl group, and A is a pyrrolidino group which may have a substituent,
Represents a piperidino group, a hexamethyleneimino group or a heptamethyleneimino group. ) PRIOR ART Several propiofenone derivatives having central muscle relaxing effects have been known. For example, 2,4'-dimethyl-3-piperidinopropiophenone (generic name: tolperisone) was listed in Japanese Patent Publication No. 40-20390, and 2,4'-dimethyl-3-piperidinopropiofenone (generic name: tolperisone) was listed as a compound with better pharmacological action than tolperisone in Japanese Patent Publication No. 55-27914. 4'-Ethyl-2-methyl-3-piperidinopropiophenone (generic name eperisone) has been disclosed, and tolperisone hydrochloride and eperisone hydrochloride are currently commercially available as central muscle relaxants. Pharmaceutical Journal 97(5), 540-552 (1977) states that in the general formula [], R is a hydrogen atom or a methyl group,
There is a disclosure of a compound in which A is a piperidino group and a dimethyl group is further introduced into the 2-position of the dihydrobenzofuran ring, among which 1-
(2,2-dimethyl-2,3-dihydro-5-benzofuranyl)-2-methyl-3-piperidino-
It is stated that 1-propanone has an anti-reserpine effect and does not show any effect on locomotor activity.
Although it is expected to be an antidepressant, it is suggested that it does not exhibit muscle relaxing effects. Problems to be Solved by the Invention The above-mentioned tolperisone hydrochloride, which is representative of propiophenone derivatives having central muscle relaxing effects,
Eperisone hydrochloride is commercially available as a central muscle relaxant, but they are not fully satisfactory in terms of strength and duration of action. The present inventors have discovered a compound of the general formula [] and a physiologically acceptable salt thereof, which are superior in terms of strength and durability of pharmacological action, and have completed the present invention. [Structure of the Invention] Means for Solving the Problems In the compound of the present invention of the general formula [], the linear or branched lower alkyl group having 1 to 6 carbon atoms represented by R includes a methyl group and an ethyl group. , n-
Propyl group, isopropyl group, n-butyl group,
sec-butyl group, isobutyl group, tert-butyl group,
Examples include n-pentyl group and n-hexyl group. In the general formula [], A is a pyrrolidino group, a piperidino group, a hexamethyleneimino group, or a heptamethyleneimino group, and these include a hydroxyl group, a lower alkyl group, a phenyl group, a phenyl lower alkyl group, a carboxyl group, a lower alkoxy It may be substituted with a carbonyl group or the like. Here, “lower alkyl”, “lower alkoxy”
has the same meaning as above. In the present compound of the general formula [], when R is other than a hydrogen atom, the carbon atom at the 2-position is an asymmetric carbon, so that optical isomers of (+)- and (-)-isomers exist. Physiologically acceptable salts of the compound of the present invention of general formula [] include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, citrate, succinate, maleate, fumarate, tartrate,
Examples include organic acid salts such as lactate. The compound of the present invention can be produced by the following reaction formula. (In each formula, R and A have the same meanings as above, and
represents a halogen atom. ) 2,3-dihydrobenzofuran [ ] and fatty acid halide [ ] in the presence of equimolar or more of stannic chloride (anhydrous) at -75 to 100°C for 10 minutes to 6 hours using Friedel-Crafts Perform the reaction to obtain a ketone compound []. As a catalyst, aluminum chloride, ferric chloride, titanium tetrachloride, etc. can be used instead of stannic chloride. Fatty acid anhydride may be used instead of fatty acid halide [ ].
Chloroform, carbon tetrachloride, methylene chloride, carbon disulfide, nitrobenzene, etc. are used as a reaction solvent. Next, the produced ketone compound [ ] is subjected to a Mannich reaction with the acid salt of the cyclic amine [ ] in the presence of paraformaldehyde to obtain the target compound [ ] as the same acid salt as the acid salt of the cyclic amine. It is recommended to add a small amount of acid such as concentrated hydrochloric acid or concentrated sulfuric acid to accelerate the reaction. The reaction temperature is 10~
The temperature is 150°C and the reaction time is 5 minutes to 20 hours.
Reaction solvents include methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, amyl alcohol,
Benzene, toluene, xylene, etc. are used alone or in combination. The reaction solution thus obtained is separated into layers from water, poured into an organic solvent capable of dissolving the target compound, preferably chloroform, and washed appropriately with saturated saline.
The organic solvent layer containing the target compound was separated, dehydrated and dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by recrystallization or column chromatography to obtain 1-(2,3-dihydrohydrochloride). -5-Benzofuranyl)-1-propanone compound [ ] is obtained. Alternatively, the resulting reaction solution may be cooled, and an organic solvent in which the reaction product is difficult to dissolve, such as isopropyl ether, acetone, ethyl ether, or tetrahydrofuran, may be added to the reaction solution to precipitate crystals. good. The acid salt of the target compound [] thus obtained is converted to a basic compound by treatment with a conventional deoxidizing agent, and further treated with a suitable acid to obtain the desired acid acid salt. The optical resolution of the compound of the present invention is carried out by a fractional crystallization method that utilizes the difference in solubility of two diastereoisomers produced by the action of optically active N-acetyl-α-phenylglycine in a solvent. The (±)-isomer of the compound of the present invention [] is (-)-N-
When reacted with acetyl-D-α-phenylglycine, (+)-[]・(-)-N-acetyl-D-α
-Phenylglycine salt and (-)-[]・(-)-N
-acetyl-D-α-phenylglycine salt is produced. These are crystallized and/or recrystallized from a mixed solvent such as acetone-isopropyl ether, acetone-ethyl ether, or ethyl acetate to form a poorly soluble (+)-[]/(-)-N-acetyl-D-α. - Phenylglycine salts can be purified in fractions. The obtained salt is converted into a free form in an alkaline aqueous solution, and this is extracted with benzene, ethyl ether, ethyl acetate, chloroform, etc. to obtain the (+)-form of the compound of the present invention. It can be salt. Next, easily soluble (-)-[]・(-)-N-
Crystallization and/or recrystallization mother liquor of (+)-[]/(-)-N-acetyl-D-α-phenylglycine salt containing a large amount of acetyl-D-α-phenylglycine salt. Concentrate under reduced pressure. The obtained residue is converted into an educt with an alkaline aqueous solution, and this is extracted with an organic solvent such as benzene, ethyl ether, ethyl acetate, or chloroform to obtain the (-)-
An educt containing a large amount of body is obtained. Dissolve the obtained educt in an organic solvent such as acetone or ethanol,
When (+)-N-acetyl-L-α-phenylglycine is added to this, poorly soluble (-)-[]・(+)
A salt containing a large amount of -N-acetyl-L-α-phenylglycine salt can be obtained. This is crystallized and/or recrystallized from a mixed solvent such as acetone-isopropyl ether, acetone-ethyl ether, or a solvent such as ethyl acetate to form a poorly soluble (-)-[].
(+)-N-acetyl-L-α-phenylglycine salt can be purified by division. The obtained salt is subjected to the same operation as in the case of the (+)-form described above to obtain the (-)-form of the compound of the present invention, which can be converted into an acid salt if desired. In addition, the (±)-isomer is (-)-N-acetyl-L-
The same operations as above may be performed sequentially to separate and purify the (-)-isomer and then the (+)-isomer by reacting with α-phenylglycine. In addition, (+)-[]・(-)-N-acetyl-D-
α-phenylglycine salt, (-)-[]・(+)-N
-Acetyl-L-α-phenylglycine salt, (+)
-[]・(+)-N-acetyl-L-α-phenylglycine salt and (-)-[]・(-)-N-acetyl-D-α-phenylglycine salt diastereoisomers are also new It is a compound. The dose of the compound of the present invention [ ] or a physiologically acceptable salt thereof to be administered to a patient varies depending on the age, symptoms of the disease, and continuous or intermittent administration, but is usually 1 to 50 mg at a time for adults. Daily allowance is 300
mg or less is desirable. The compound of the present invention [ ] or a physiologically acceptable salt thereof can be prepared into tablets, capsules, powders, granules, injections, syrups, suspensions, and emulsions by conventional methods using commonly used pharmaceutical additives. , it can be made into formulations such as suppositories. Additives for formulations include cellulose, lactose, sucrose, mannitrate, sorbitol, starches (yam, corn, rice, wheat, etc.), gelatin, acacia, gum tragacanth, polyvinylpyrrolidone, carboxymethylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose, etc. Methylcellulose calcium, talc, magnesium stearate,
Calcium stearate, polyethylene glycol, polysorbate, glycerin, cacao butter, macrogol, etc. are used as appropriate depending on the dosage form. Effects It was confirmed through animal experiments of anti-nicotinic, anti-tremolinic, muscle-relaxing and rigidity-relaxing effects that the compound of the present invention and its physiologically acceptable salts have central muscle relaxing effects. . Representative compounds of the present invention used in the test are as follows.

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【table】

[Table] Tolperisone hydrochloride and eperisone hydrochloride were used as comparative compounds. (a) Anti-nicotinic effect A group of 12 male ddY mice weighing 29 to 33 g were used. Dissolve the test compound in distilled water and add 200mg/Kg.
was administered orally, and 1 hour later, 2 mg/Kg of nicotine was administered intravenously, and death due to convulsions was observed for the next 1 hour. Lethality suppression rate = number of animals that survived/number of animals used x 100

[Table] (b) Anti-tremolin effect A group of 10 ddY male mice weighing 28 to 32 g were used. Test compound dissolved in distilled water, 50mg/Kg
was administered orally, and 30 minutes later, tremoline hydrochloride 20mg/Kg
was administered subcutaneously. The presence or absence of tremor was observed after 30 and 60 minutes had elapsed. Tremor suppression rate = number of animals without tremor/number of animals used x 100

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[Table] (c) Muscle relaxing effect A group of 10 male ddY mice weighing 33 to 37 g were used. The test compound was dissolved in saline and
mg/Kg was administered intraperitoneally. The muscle relaxing effect was evaluated using the method of Courvoisier et al. (“Psychotropic
Drugs,” ed. by Garattini, S. and Ghetti, V.,
Elsevier Pub.Co., Amsterdam, 1957, P.373)
It was carried out in accordance with. 15 minutes after drug administration, the forelimbs of the mice were hung on a wire.
When the hind limbs were not caught on the wire within 5 seconds, it was determined that there was a muscle relaxing effect. The mice were allowed to hang their forelimbs on a wire in a preliminary test, and those that could hang their hind legs on the wire within 5 seconds were selected for use in the main test. Muscle relaxation rate = number of animals showing relaxation/number of animals used x 10
0

[Table] (d) Effect on decerebrate rigidity after cutting between the superior and inferior colliculus Male Wistar rats weighing 300 to 400 g were used. Test compounds were dissolved in saline and 10
mg/Kg, 20 mg/Kg was administered intravenously. For rigid specimens, the method of Fukuda et al. [The Japanese
Journal of Pharmacology 22, 457 (1972)]. After fixing the rat in the prone position under ether anesthesia,
The head was incised and the skull was removed, centering on the occiput, to expose the brain parenchyma. Next, the dura mater on the surface of the cerebellum was incised, and the midbrain was cut between the superior and inferior colliculus using a spatula. After more than 2 hours had passed after the surgery, the rats were placed in a dorsal position on a fixed table, and the effects of the test compounds were examined using the rigidity that appeared in the antigravity muscles of the limbs as an index. Result: 10mg/Kg of each test compound such as A, B, C etc.
The rigidity of the forelimbs and hindlimbs was mildly alleviated by administration, and even more reliably by administration of 20 mg/Kg. (e) Acute toxicity Five ddY male mice weighing 25 to 29 g were used in each group. The test compound was dissolved in distilled water and each dose was administered orally. After administration, the animals were observed for 7 days, and the 50% lethal dose (LD ₅₀ value) was determined by the Behrens-Krber method.

[Table] Next, the formulation of the compound of the present invention will be explained using specific examples, but the present invention is not limited to these examples. Tablets Compound A...100g Crystalline cellulose...150g Corn starch...142g Lactose...300g Carboxymethylcellulose calcium...5g Magnesium stearate...3g Total 700g Thoroughly mix each of the above ingredients with a general mixer. , as it is, or after making it into fine particles or granules, compression molding to prepare 5000 tablets. The weight of one tablet is 140 mg, and the amount of active ingredient Compound A contained is 20 mg. The molded plain tablets are converted into sugar-coated tablets or film-coated tablets according to conventional methods, if necessary. Capsule Compound B...50g Powdered lactose...146g Talc...4g Total 200g The above ingredients are thoroughly mixed and filled into 1000 capsules using a capsule filling machine. 1 capsule 200
Capsules containing 50 mg of active ingredient Compound B in mg can be produced. Injection Dissolve Compound C in 1000ml of distilled water for injection, fill 1000 ampoules with a dispenser, and add the active ingredient Compound C.
An ampoule with an internal liquid volume of 1 ml containing 10 mg of is prepared. Alternatively, an aqueous solution of this concentration may be filled into a vial of a desired capacity. Next, the method for producing the compound of the present invention [] and its acid salt will be explained using specific examples. The ketone compound [], which is a production intermediate, was produced according to the following reference example. Reference example 1 5-propionyl-2,3-dihydrobenzofuran 18.4 g of 2,3-dihydrobenzofuran and 15.3 g of propionyl chloride were added to 120 ml of methylene chloride.
50.0g of stannic chloride (anhydrous) dissolved in below 10℃
was added dropwise over a period of 30 minutes. 10 more after dripping
After stirring for a minute, the reaction solution was mixed with 100 ml of concentrated hydrochloric acid and 200 ml of ice blocks.
g and stirred well. The methylene chloride layer was separated, washed with water, and then dried over anhydrous sodium sulfate.
The residue obtained by distilling off the solvent under reduced pressure was recrystallized from hexane to give white crystals of 5-propionyl-2,3-
20.5 g (76%) of dihydrobenzofuran was obtained. Melting point 60.0-61.0℃ NMR (CDCl ₃ ) δ, ppm: 1.18 (3H, t), 2.88
(2H, q), 3.15 (2H, t), 4.58 (2H,
t), 6.69 (1H, d), 7.58-7.88 (2H, m) Reference examples 2 to 12 2,3-dihydrobenzofuran and a fatty acid halide [] corresponding to the desired ketone compound [] are appropriately selected and reference examples are prepared. The ketone compounds shown in Table 5 were obtained according to the method of 1.

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[Table] Example 1 1-(2,3-dihydro-5-benzofuranyl)
-2-Methyl-3-piperidino-1-propanone hydrochloride 5-propionyl-2,3 produced in Reference Example 1
4.0 g of -dihydrobenzofuran, 0.91 g of paraformaldehyde, and 3.33 g of puperidine hydrochloride were added to 3 ml of isopropanol and heated under reflux for 2 hours. After cooling, 50 ml of chloroform was added to the reaction solution, and the mixture was washed three times with 40 ml of saturated saline. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain white crystals of 1-(2,3-dihydro-5-benzofuranyl).
5.83g (83%) of -2-methyl-3-piperidino-1-propanone hydrochloride was obtained. Melting point 193.0~194.0℃ (decomposition) IR (KBr) cm ^-1 : 2960, 2810~2200, 1670,
1605, 1590, 1250 NMR ( _CDCl3 ) δppm: 0.93-4.93 (13H, m),
1.28 (3H, d), 3.27 (2H, t), 4.68 (2H,
t), 6.81 (1H, d), 7.77-8.10 (2H,
m), 12.03 (1H, broad) Elemental analysis value (as C ₁₇ H ₂₃ NO ₂・HCl) C H N Theoretical value % 65.90 7.81 4.52 Experimental value % 65.79 7.84 4.32 Example 2 1-(2,3-dihydro- 5-Benzofuranyl)
-2-methyl-3-piperidino-1-propanone 1-(2,3-dihydro-5- obtained in Example 1)
Dissolve 6.0 g of benzofuranyl-2-methyl-3-piperidino-1-propanone hydrochloride in 75 ml of water,
It was made alkaline by adding 10 ml of 20% aqueous sodium hydroxide solution. The precipitated oil was extracted with ethyl ether and washed three times with saturated brine. After separating the ether layer and drying it with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography [Wakogel C-
200 (manufactured by Wako Pure Chemical Industries, Ltd.), the eluent was chloroform:ethanol (20:1)] to obtain 1-(2,3-dihydro-5-benzofuranyl)-2-methyl-3-
Piperidino-1-propanone as oil 4.77
g (90%) was obtained. IR (Neat) cm ^-1 : 2970, 2940, 2860, 2800,
1670, 1600, 1585, 1240 NMR ( _CDCl3 ) δppm: 0.97-1.77 (6H, m),
1.18 (3H, d), 2.13-3.90 (7H, m), 3.22
(2H, t), 4.63 (2H, t), 6.75 (1H,
d), 7.67-7.97 (2H, m) Example 3 1-(2,3-dihydro-5-benzofuranyl)
-2-Methyl-3-piperidino-1-propanone nitrate 1-(2,3-dihydro-5- obtained in Example 2)
2.0 g of benzofuranyl-2-methyl-3-piperidino-1-propanone was dissolved in 30 ml of methanol, and 30% nitric acid was added to make the solution acidic. Next, the solvent was distilled off under reduced pressure, and ethyl ether was added to the resulting residue, followed by thorough stirring. Take the precipitated crystals,
Recrystallization from ethanol yielded 1.82 g (74
%)Obtained. Melting point 175.5-177.0℃ (decomposition) IR (KBr) cm ^-1 : 2960, 2870, 2850-2200,
1670, 1600, 1585, 1330, 1245 NMR ( _CDCl3 ) δppm: 1.08-4.37 (13H, m),
1.24 (3H, d), 3.27 (2H, t), 4.68 (2H,
t), 6.83 (1H, d), 7.73~8.03 (2H,
m), 10.97 (1H, broad) Elemental analysis value (as C ₁₇ H ₂₃ HNO ₃ ) C H N Theoretical value % 60.70 7.19 8.33 Experimental value % 60.62 7.21 8.45 Example 4 1-(2,3-dihydro-5- benzofuranyl)
-2-methyl-3-piperidino-1-propanone succinate 1-(2,3-dihydro-5- obtained in Example 2)
Benzofuranyl)-2-methyl-3-piperidino-1-propanone (2.0 g) was dissolved in methanol (30 ml), and succinic acid (0.86 g) was dissolved in methanol.
Added 40ml. After stirring well, the solvent was distilled off under reduced pressure, and ethyl ether was added to the resulting residue and the mixture was stirred well, resulting in crystallization. This was collected and recrystallized from acetone to give 1-(2,3-dihydro-5-benzofuranyl)-2-methyl-3-piperidino-
2.15 g (75%) of 1-propanone succinate was obtained. Melting point 110.5~111.5℃ IR (KBr) cm ^-1 : 2980, 2950, 2870, 2800~
2200, 1730, 1675, 1600, 1585, 1555,
1260 NMR ( _CDCl3 ) δppm: 0.97-2.10 (6H, m),
1.20 (3H, d), 2.48 (4H, s), 2.67-4.33
(7H, m), 3.27 (2H, t), 4.63 (2H,
t), 6.84 (1H, d), 7.73~8.03 (2H,
m), 13.62 (2H, s) Elemental analysis value [as C ₁₇ H ₂₃ NO ₂・(-CH ₂ COOH) ₂ ] C H N Theoretical value % 64.43 7.47 3.58 Experimental value % 64.39 7.28 3.50 Example 5 1-( 2,3-dihydro-5-benzofuranyl)
-2-ethyl-3-piperidino-1-propanone hydrochloride 3.0 g of 5-butyryl-2,3-dihydrobenzofuran obtained in Reference Example 3, paraformaldehyde
After adding 0.63 g and 1.62 g of piperidine to 2 ml of isopropanol, 1.7 ml of concentrated hydrochloric acid was added with stirring, and the mixture was heated under reflux for 3 hours. After cooling, 40 ml of chloroform was added to the reaction solution, and the mixture was washed three times with 30 ml of saturated saline. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from tetrahydrofuran to give white crystals of 1-(2,
3-dihydro-5-benzofuranyl)-2-ethyl-3-piperidino-1-propanone hydrochloride
4.14g (81%) was obtained. Melting point 181.0~182.0℃ IR (KBr) cm ^-1 : 2930, 2860, 2800~2100,
1675, 1605, 1250 NMR ( _CDCl3 ) δppm: 0.93 (3H, t), 1.18~
4.98 (15H, m), 3.28 (2H, t), 4.68 (2H,
t), 6.82 (1H, d), 7.78-8.18 (2H,
m), 11.95 (1H, broad) Elemental analysis value (as C ₁₈ H ₂₅ NO ₂・HCl) C H N Theoretical value % 66.76 8.09 4.33 Experimental value % 67.82 8.19 4.38 Examples 6 to 42 Synthesized according to Reference Examples 1 to 12 Ketone compounds and piperidine hydrochloride, pyrrolidine hydrochloride, hexamethyleneimine hydrochloride, heptamethyleneimine hydrochloride, 4
-Methylpiperidine hydrochloride, 2-methylpiperidine hydrochloride, 3-methylpiperidine hydrochloride, 3,5
-dimethylpiperidine hydrochloride, 4-phenylpiperidine hydrochloride, 4-benzylpiperidine hydrochloride,
4-Ethoxycarbonylpiperidine hydrochloride or 4
-Hydroxypiperidine hydrochloride was arbitrarily selected to suit the target compound, but was produced in the same manner as in Example 1. The obtained compounds and their physical properties are shown in Table 6.

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〔Effect of the invention〕

As is clear from Tables 1, 2 and 3 above, the compound of the present invention [] and its physiologically acceptable salts have superior anti-nicotinic, anti-tremolin and muscle-relaxing effects compared to tolperisone hydrochloride and eperisone hydrochloride. It also had a rigidity-relaxing effect.
In particular, the difference in effectiveness became more pronounced 60 minutes after the anti-tremorin action, and it was found that the duration of action was longer than that of tolperisone hydrochloride and eperisone hydrochloride. Therefore, the compound of the present invention [ ] and its physiologically acceptable salts can be used as central muscle relaxants that are improved in potency and duration of action over conventional compounds, and can be used to treat post-stroke sequelae, cerebral palsy, and spasticity. It is extremely useful for the treatment of spinal paralysis, spastic paralysis due to head trauma, etc., and painful spasticity such as lumbar back pain and cervico-shoulder-brachial pain.

Claims (1)

[Claims] 1. General formula (In the formula, R is a hydrogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms, a cyclopentyl group, a cyclohexyl group, or a cyclopentylmethyl group, and A is a pyrrolidino group which may have a substituent,
Represents a piperidino group, a hexamethyleneimino group or a heptamethyleneimino group. ) 1-
(2,3-dihydro-5-benzofuranyl)-1-
Propanone derivatives and physiologically acceptable salts thereof. 2 General formula (In the formula, R is a hydrogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms, a cyclopentyl group, a cyclohexyl group, or a cyclopentylmethyl group, and A is a pyrrolidino group which may have a substituent,
Represents a piperidino group, a hexamethyleneimino group or a heptamethyleneimino group. ) 1-
(2,3-dihydro-5-benzofuranyl)-1-
A central muscle relaxant containing a propanone derivative or a physiologically acceptable salt thereof as an active ingredient.