JPS6185379A - 3',4'-methylenedioxypropiophenone derivative and central muscule relaxant containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The 3',4'-methylenedioxypropiophenone derivative of formula I (R1 is alkyl, cyclopentyul, cyclohexyl or cyclopentylmethyl; R2 is H, alkyl or alkoxy; A is pyrrolidino, piperidino, hexamethyleneimino or heptamethylenei mino) or its physiologically permissible salt. EXAMPLE:2-Methyl-3',4'-methylenedioxy-3-piperidinopropiophenone. USE:Central muscle relaxant, and remedy for spastic paralysis and myospasm dolorosa caused by locomotorium disease. It has long-acting effect. PREPARATION:The compound of formula I can be prepared by reacting 3,4- methylenedioxybenzene of formula II with a fatty acid halide of formula III (X is halogen) in the presence of stannic chloride, and subjecting the resultant 3',4'-methylenedioxyphenone compound of formula IV to Mannich reaction with an acid salt of a cyclic amine of formula A-H in the presence of paraformaldehyde.

Description

Detailed Description of the Invention [Object of the Invention] Industrial Field of Application The present invention relates to a 3,4'-methylenedioquine probiophenone derivative represented by the following general formula [T] and its physiologically acceptable 1) These compounds have a central muscle relaxant effect, so they are effective against spasticity and paralysis.
, is useful as a medicine for treating painful muscle spasms associated with musculoskeletal diseases.

(1 in formula). , represents a linear or branched lower alkyl group having 1 to 6 carbon atoms, a cyclopentyl group, a cyclohexyl group, or a /clopentylmethyl group, R, , represents a hydrogen atom T
-, a lower alkyl group or a lower alkoxy group.

8 represents a pyrrolidino group, piperidino group, hexamethyleneimino group or heptamethyleneimino group which may have a substituent. ) Prior Art Several propiophenone derivatives having central muscle relaxing effects are known.

For example, 2.7I'-dimethyl-3-piperidinoprobiophenone (generic name: tolperisone) was published in Japanese Patent Publication No. 20390-1983, and a compound with better pharmacological action than tolperisone was published in Japanese Patent Publication No. 1987-2791/1. as 4-
Ethyl-2-methyl-3-piperidinoprobiophenone (common name Vericin) has been disclosed, and tolperisone hydrochloride and eperisone hydrochloride are currently commercially available as central muscle relaxants.

Journal of the American Chemical Society
n C1+cm-ical 5ociety),
7], 204s-50 (1949), in the general formula (1), rL, , Ft are hydrogen dioxypropiophenone derivatives have anticonvulsant action and l
Although it is disclosed that the activity is enhanced when a phenyl group is introduced into RI, there is no description of the specific effects of these compounds.

Problems to be Solved by the Invention The above-mentioned tolperisone hydrochloride is a representative probiofuenone derivative having a central muscle relaxing effect.

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 general formula CI) and a physiologically acceptable salt thereof, which are superior in terms of strength and persistence of pharmacological action, and have completed the present invention.

[Structure of the invention]

In the compound of the present invention of the general formula [T'l, the linear or branched lower alkyl group having 1 to 6 carbon atoms represented by R8 is a methyl group, an ethyl group, a lopropyl group, an isopropyl group, and a n-butyl group. group, 5ec-butyl group, isobutyl group, 1erl-butyl group, n-pentyl group, n-
Examples of lower alkyl groups represented by 1t2 include methyl group, ethyl group + n-propyl group, isopropyl a, n-butyl group, 5ec-butyl group, isobutyl group, pentyl group, etc. The groups include methoxy group, ethoxy group, low propoxy group,
Impropoxy group.

Examples include n-butoxy group, 5ec-butoxy group, isobutoxy group, and pentoxy group. A is a pyrrolidino group,
A piperidino group, a hexamethyleneimino group, or a hebutamethyleneimino group, which has a hydroxyl group, lower alkyl group, or phenyl group at any position.

It may be substituted with a phenyl lower alkyl group, a carphokyfur group, a lower alkoxycarbonyl group, or the like. Here, "lower alkyl" and "lower alkoxy" have the same meanings as above.

The compound of the present invention represented by the general formula [■] has four optical isomers and one optical isomer because the carbon atom at the 2-position is an asymmetric carbon.

Physiologically acceptable salts of the compound of the present invention of general formula CI' include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, citrate, succinate, maleate, etc. , 7-malate, tartrate, lactate, and other organic acid salts.

The compound of the present invention can be produced by the following reaction formula.

[■] [■] [rV] + A41 + paraformaldehyde→(V,) (In each formula, R, , R2, and A have the same meanings as above.

X represents a halogen atom. ) 3. 4-Methylenedioxybenzene IJD and fatty acid halide [■] are heated at -75 to 100C for 10 minutes to 6 hours in the presence of equimolar or more of onitin chloride (anhydrous). The reaction was carried out to form a 3',4'-methylenedioxyphenone compound [
■]. As a catalyst, aluminum chloride, iron chloride, titanium tetrachloride, etc. can be used instead of onitin chloride. Fatty acid anhydride may be used instead of fatty acid halide [1]. Chloroform, carbon tetrachloride, methylene chloride, carbon disulfide, nitrobenzene, etc. are used as a reaction solvent.

The resulting compound OVI was then treated with Mannich (M
annich) reaction 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 IO to 150C, and one reaction time is 5 minutes to 20 hours. Reaction solvents are methanol, ethanol, and propanol.

Isopropanol, butanol, 5ec-butanol.

1erj -phthanol, amyl alcohol, benzene.

Toluene, xyl/lene, 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 is separated, dehydrated and dried over anhydrous sodium sulfate, the solvent is distilled off, and the resulting residue is purified by recrystallization or column chromatography to obtain 3'
An acid salt of 4'-methylenedioxy-2-alkyl-propiophenone compound CD is obtained. I cut it. The obtained reaction solution was cooled, and Improvil ether, a7ton,
Crystals may be precipitated by adding an organic solvent such as ethyl ether or tetrahydrofuran that hardly dissolves the reaction product, and recrystallization may be performed after P is removed.

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 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 administration.9 Intermittent administration is usually 1 to 50 doses at a time for adults.
~, and the daily tolerance is preferably 300 mg or less.

The compound (r) of the present invention or a physiologically acceptable salt thereof can be prepared into tablets, capsules, powders, and granules by conventional methods using commonly used pharmaceutical additives.

It can be made into formulations such as injections, tablets, suspensions, emulsions, and suppositories. Cellulose as additives for formulations,
Milk L Potato L Mannitol, sorbitol, starch (
Potatoes, corn, and rice.

barley, etc.), gelatin, gum arabic, gum tragacanth, polyvinylpyrrolidone, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose.

Talc, magnesium stearate, carunium stearate, polyethylene glycol, polysorbate, glycerin, cocoa butter, macrogol, etc. are used as appropriate depending on the dosage form.

Effects It was confirmed through animal experiments that the compound of the present invention [■] and its physiologically acceptable salts have a central muscle relaxing effect.

Nicotine has a stimulating effect on the central nervous system and skeletal muscles.
Tremorine caused convulsions, breathing difficulties, and finally death.The broken tremoline increases the amount of acetylcholine in the brain and at the same time causes tremors in the head, limbs, etc. due to muscle contraction (1[elnO
r), so if the action of kneading is suppressed, a central muscle relaxant effect can be expected.

Representative compounds of the present invention used in the test are as follows.

(Left below) Tolperisone hydrochloride and eperisone hydrochloride were used as comparative compounds.

Tolperisone hydrochloride C1]3 Eperisone hydrochloride (a) Anti-nicotinic effect A group of 12 ddY male mice weighing 28 to 32 grams were used. Test compound was dissolved in distilled water at 200 mFlA.
9 was orally administered, and 1 hour later nicotine was administered at 2 rrvt/k.
g was administered intravenously, and subsequent convulsive lethality was observed for 1 hour.

Table 1 (o) Anti-tremolin effect One group of 10 d d Y male mice weighing between 28 and 321
I used two. Dissolve the test compound in distilled water.

50 myAc9 was administered orally, and 30 minutes later, 20 m27 kg of tremoline hydrochloride was administered subcutaneously. Thereafter, the presence or absence of tremor was observed after 30 and 60 minutes had elapsed.

(Margins below) Table 2 (a) 1 ・Number of animals (individuals) that did not develop tremor (h
) * ・Pregnancy suppression rate (%) (c) Muscle relaxing effect 10 d d Y inseparable mice weighing 30 to 35 kg per group
I used two. Dissolve the test compound in saline,
9 was administered intraperitoneally to 5 Tnl/. The muscle relaxing effect was evaluated by suspending the forelimbs on a horizontal wire (diameter 2 mm) with a height of 20 cm and pulling up the hind limbs (fraction reaction).
st) for Courv++1sier et al.'s method (
”Psycho+ropic l)rugs,
” CD, by C1ara day ini, S, and
Ohelli, Vl To]1scvicr Pt
mouth), Co,, Ams+erd sm.

1957, P. 373).

Fifteen minutes after drug administration, the forelimbs of the mice were hung on a wire.

When the hind limbs did not fall into the wire within 5 seconds, it was determined that there was a muscle relaxing effect. In a preliminary test, the mice were allowed to hang their forelimbs on a wire, and those mice that showed signs of age when their hind legs were placed on the wire within 5 seconds were selected for use in the main test.

Table 3) Effect on decerebrate condensation between the upper and lower colliculus: weight 30
Wistar male rats of Q~400p were used.

The test compound was dissolved in physiological saline and administered intravenously at 9°/20 ml/ml.

Solid cotton specimens were prepared using the method of Hazayo et al. [The Japanese
o fJournal Pharmacology
22. 4 57 (1972)).

After fixing the rat in duplex 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 spatyl. After more than 2 hours had passed after the surgery, the rats were placed on a fixed table and the effect of the test compound was examined using as an indicator the firmness appearing in the antigravity muscles of the limbs.

Results: Each test compound such as A, E, F etc. was 10 ml 17 kg
The administration of 20 ml/9 doses more reliably alleviated the stiffness in the forelimbs and hind legs.

(e) Acute toxicity Five ddY male mice weighing 25 to 30 Ff were used in each group. The test compound was dissolved in distilled water and each dose was administered orally. Observation was made for 7 days after administration, and the lethal dose ('D50
value) was determined by the 1-chrens-Karhcr method.

Table 4 From the results of the above pharmacological and toxicity tests, the following can be found.

■ The anti-nicotinic effects of the compounds of the present invention are significantly stronger than tolperisone hydrochloride, except for compound 1), compound f( is stronger than eperisone hydrochloride, and compound A, rl, (:.

T), P, (7Fi eperisone hydrochloride and the same strength as in August.

■The anti-tremolin effect of the compounds of the present invention was significantly stronger than that of tolperisone hydrochloride after 30 minutes.

With the exception of Compound G, it is as strong as, or even stronger than, eperisone hydrochloride. Moreover, after 60 minutes, all of them except Compound G exhibited significantly stronger and longer duration of action than tolperisone hydrochloride and eperisone hydrochloride.

(2) The muscle relaxing effects of the compounds of the present invention are all stronger than tolperisone hydrochloride; compounds 1'), E, and P are stronger than eperisone hydrochloride, and compounds A, R, and C have similar strength as eperisone hydrochloride.

(2) The compound of the present invention exhibits a remarkable alleviating effect on decerebrate abscission between the two colliculus and the inferior colliculus.

(2) The acute toxicity of the compounds of the present invention is comparable to that of tolperisone hydrochloride and eperisone hydrochloride.

Next, the formulation will be explained with specific examples, but the present invention is not limited to these examples. ---
--100p crystalline cellulose------
-----150? Corn starch---
---142@-Lactose-----
----------300p carboxymethylcellulose calcium---59 total
7001 Thoroughly mix each of the above ingredients using a general mixer.

5000 tablets are prepared by compression molding as it is or after making into fine particles or granules. The weight of one tablet is 140m
7 and the amount of active ingredient compound A contained is 20 ml. The molded plain tablets are converted into sugar-coated tablets or film-coated tablets according to conventional methods, if necessary.

Capsule Compound D
---50p powdered lactose-----
−−−−−−−146p Tarku−−−−−=−−−
−−−−−−−−−−−−−−47 total
2001 The above acids were thoroughly mixed and filled into 1000 capsules using a capsule filling machine.

1 capsule contains 50 active ingredients in 20 OWLt
Capsules containing m1 can be produced.

10 g of Injectable Compound E is dissolved in 1000 WLt of distilled water for injection and filled into 1000 ampoules using a dispensing machine to produce 1 ml ampules containing 10 ml of active ingredient Compound E. Alternatively, an aqueous solution of this concentration may be filled into a vial of a desired capacity.

Next, the method for producing 9 compounds of the present invention [■] and their acid salts will be explained with specific examples.

A 3,4-methylenedioxyphenone compound (rV), which is a production intermediate, was produced according to the following reference example.

Reference example 1 3',4'-methylenedioxybutyrophenone 1.2-
2s1y- of methylene dioxybenzene and 26.6g of butyryl chloride were dissolved in 200ml of methylene chloride, and 750y- of onitin chloride (anhydrous) was dissolved in IOt:' or less.
The dropwise addition took 0 minutes. After stirring for another 10 minutes, the reaction solution was diluted with concentrated hydrochloric acid (150 ml)' - 200 ml of ice blocks.
Pour into P and stir 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 obtain 33.1 p (75%) of 3',4'-methylenedioxybutyrophenone as white crystals. Melting point 41
0-430C NMrl, (CIlC+3) bppm: 1.00
(31), t ) + 173 (21).

5eXle weight) + 2.83 (21), word),
5.97 (21), s ), 6.76 (eye 1
．． d), 7.38 (Ill, +1), 7.50 (I,
d (1) Reference Examples 2 to 13 Target 3,4-methylenedioquinephenone compound [■]
3,4-methylenedioxybenzene [1)]
and fatty acid halide [■1] as appropriate.

The compounds shown in Table 5 were obtained according to the method of Reference Example 1.

(Left below) JP-A-08G1-85379 (10) ^nQ Example 1 Veridinoprobiophenone hydrochloride 3,4-methylenedioxybutyrophenone produced in Reference Example 1 3.00 y, Halaformaldehyde 0.6
35', piperidine hydrochloride 229r and 1 drop of concentrated hydrochloric acid were added to Impropatool 2. The mixture was added to Ome and heated under reflux for 3 hours. After cooling, add 50 Il of chloroform to the reaction solution and add 30 ml of saturated saline! Washed 3 times with 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 obtain white crystals of 2-ethyl-3,4-methylenedioquine-3-piperidinopropio. Phenone hydrochloride at 4.12y-(81%
)Obtained. Melting point 1750-177.0 Cr II (K Hr ) cm-': 2940.2
860.2760~2]50,1660°1600.1
490,1440.126ONMR(CDCI,)δ
ppm: 0.92 (31), t), 1.1
8~4.13 (14+1.m), 4.20~4.73
(III, m), 6.03 (21+, s), 6.
85 (III, d), 7.45 (IH, d),
7.73 (Ill, dd), 12. Q5 (41-1
, broad) elemental analysis value (C, 71423No3・I
(as IC+) CII N Theoretical value % 62,67 7,43 4.30 Experimental value % 62,59 7.51 4.38 Example
2 Piperidinopropiophenone 2-ethyl-3,4-methylenedioxy-3-piperidinopropiophenone hydrochloride 1501 obtained in Example 1 was dissolved in 25 ml of water, and dissolved in a 20% aqueous sodium hydroxide solution. It was made alkaline. The precipitated oil was extracted with ethyl ether and washed three times with saturated brine. The ethyl ether layer was separated, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting oily residue was purified by silica gel column chromatography [Wakogel C-200, eluent was chloroform-ethanol (20:1)] to obtain 2-ethyl-3,4-methylenedioxy-3-piperidino. 1.221 (92%) of propiophenone was obtained as an oil.

T J Neat ) cm-': 29
60.2930, 2850, 2800, 1670°16
05.1500,1490,1440,126ONMR
(CDCI 3) δl) pm: 0.70-3.
03 (] 7H, m), 3.23-3.80 (IH
, m), 6.02 (214, s), 6.82 (1)
-1, d).

7.43 (III, d), 7.56 (II-1, dd)
Example 3 2-ethyl-3,4-methylenedioxy-3-hyheridinopropiophenone nitrate 2-ethyl-3,4-methylenedioxy-3-piperidinopropiophenone obtained in Example 2 1.00 ml of the solution was dissolved in 10 ml of methanol, and 30% nitric acid was added to make it acidic. Then, the solvent was distilled off under reduced pressure, and ethyl ether was added to the resulting residue, followed by thorough stirring. Collect the precipitated crystals,
Recrystallized from a mixed solvent of inglobanol and tetrahydrofuran to obtain 0.9 Jl of 2-lysinoglobiophenone nitrate.
Obtained 5Lif (78ch).

Melting point 1670-169.5C (decomposition) 1) (, (Kl
lr) Cm-': 3050.2960.2880
．． 2830-2200.

1660.1600,1440,1380,1345° 25O NMR, (CI)CI 3) δ ppm:
0.90 (31), 1), 1.10-4.33
(151), m), 6.03(21), s),
6.85 (Ill, d), 7.40 (Ill, d),
7.63 (III, dd), 10.90 (Il
l, broad elemental analysis value (C, 71) 23NO3・
(as llNO3) CII N Theoretical value % 57,94 6,87 7.95 Experimental value % 57,88 6,90 8.03 Example
4 Virolidinoprobiophenone hydrochloride 3',4'-methylenedioquine butyrophenone produced in Reference Example 1 300! il-, paraformaldehyde 06
3y, Pyrrolidine hydrochloride 203y and a 1 drop of hydrochloric acid was added to ethanol 2me and heated under reflux for 4 hours. 1. After cooling, 1 chloroform 1, 50ml was added to the reaction solution and washed three times with 30ml of saturated brine. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was reconstituted with tetrahydrofuran to dilute dioxy-3-pyrrolidinopropiophenone hydrochloride (3.89j7-(80%)).
Obtained. Melting point 1570-159. Or r H, (K Rr ) crn-': 2960.2
880.2800~2150,1670°1600,+
495.1440.127ONMlt(CI)CI 3
) δppm: 0.90 (31), 1), 1.
37-4.20 (121+, m), 4.23-4.7
7 (1) 1, m), 6.06 (21+, s) 6
．． 89 (III, d), 7.50 (III, d),
7.82 (Ill, dd), 12.45 (III, b
road) Elemental analysis value (C,, II2.No3・1)
C1) CIT N Theoretical value Chi 61,63 7,1) 4.49 Experimental value% 6], 56 7,08 4.59 Example
5 2-Methyl-3',4-methylenedioxy-3-piperidinoprobiophenone hydrochloride 3',4'-methylenedioxypropiophenone produced in Reference Example 2 3.01p, no(laformaldehyde 0 .66?, piperidine hydrochloride 2461 and 1 drop of concentrated hydrochloric acid were added to 2 me of a mixed solvent of isopro-ethanol-ethanol (1:1) and heated under reflux for 4 hours.

After cooling, add 40 rJ of chloroform to the reaction solution! Add.

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 using Improper Tools to obtain white crystals of 2-methyl-3,4-methylenedioquine-3-pyrin. Peridinoprobiophenone hydrochloride 3.847- (73%)
Obtained.

Melting point 1890-190. Or (decomposition) T R, (K
84) cm-' :2970.2940.2770
~2]50. +665°1595.1480,1430
．． 125ONMR (CDCI 3) δppm:
0.95-4.15 (121), rr+), 1.29 (
31), d), 4.18-4.88 (+1). m),
6.05 (2+1.S).

6.55 (II1.d), 7.44 (+II, a),
7.73 (III, dd).

1). 98(]ll,1)road) Elemental analysis value (C
,,II,,NO3・1) As C1) CII
N Theoretical value % 6], 63 7.1) 4.19 Experimental value % 61,49 7,19 4.48 Example
6-33 The 3,4-methylenediogysiphenone compound synthesized in Reference Examples 1 to 13, piperidine hydrochloride, pyrrolidine hydrochloride, and hexamethyleneimine hydrochloride.

Heptamethyleneimine hydrochloride, 4-methylpiperidine hydrochloride, 3-methylpiperidine hydrochloride, 3.5-dimethylpiperidine hydrochloride, 4-phenylpiperidine hydrochloride, 4
-Benzylpiperidine hydrochloride.

It was produced in the same manner as in Example 1, except that 4-ethquincarbonylpiperidine hydrochloride or 4-hydroxy/piperidine hydrochloride was arbitrarily selected to suit the target compound. The obtained compounds and their physical properties are shown in Table 6.

(The following is a blank space) nn [Machining aG1-85379 (21) --Ql'l- [Effects of the Invention] The compound of the present invention [■] and its physiologically acceptable salts are shown in Tables 1, 2 and 3 above. As is clear, it has a superior anti-nicotinic effect compared to tolperisone hydrochloride and eperisone hydrochloride,
It had anti-tremorinic and muscle relaxing effects, and also had rigidity-relaxing effects. 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 [I] of the present invention and its physiologically acceptable salts can be used as a central muscle relaxant that is improved in potency and duration of action compared to conventional compounds, and can be used to treat post-stroke symptoms, cerebral palsy, and spasticity. It is extremely useful for treating spastic paralysis caused by head trauma and painful spasticity such as lumbar back pain and cervico-shoulder-brachial pain.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is a linear or branched lower alkyl group having 1 to 6 carbon atoms, cyclopentyl group, cyclohexyl group, or cyclopentylmethyl group, R_2 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and A represents a pyrrolidino group, a piperidino group, a hexamethyleneimino group, or a heptamethyleneimino group that may have a substituent. - Methylenedioxypropiophenone derivatives and physiologically acceptable salts thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and A represents a pyrrolidino group, a piperidino group, a hexamethyleneimino group, or a heptamethyleneimino group that may have a substituent. - A central muscle relaxant containing a methylenedioxypropiophenone derivative or a physiologically acceptable salt thereof as an active ingredient.