JP2598309B2 - 3-Cyclic aminopropanol derivative and salt thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel 3-cyclic aminopropanol derivative having a central muscle relaxing action [PRIOR ART] As a compound having a central muscle relaxing action, for example, 2 -Methyl-1- (4-methylphenyl) -3-piperidino-
Propanone derivatives such as 1-propanone (generic name tolperisone) are known (Japanese Patent Publication No. 40-20390).

However, it is not known that cyclic aminopropanol derivatives have a central muscle relaxing action.

[Problems to be solved by the invention]

Tolperisone is not always effective enough in terms of its sustainability and the like, and improvement is desired.

[Means for solving the problem]

The present invention relates to a compound of the general formula (I) [Where A is (Wherein R ₁ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, R ₂ represents a hydrogen atom, a lower alkyl group, R ₃
Is a hydrogen atom, a halogen atom, a trihalogenomethyl group, a lower alkyl group, a lower alkoxy group) or (Where R ₄ is a lower alkoxy group), R ₅ is a hydrogen atom, a lower alkyl group, a phenyl group, or a benzyl group, R ₆ is a lower alkyl group, and B is a pyrrolidino group , A piperidino group. However, when B is a pyrrolidino group, R ₅ represents the above groups other than the phenyl group. B is a piperidino group and A is In the case where R ₁ and R ₂ are both hydrogen atoms, R ₅ is a hydrogen atom and R ₆ is a lower alkyl group,
R ₃ represents a hydrogen atom, a fluorine atom or a group other than a lower alkyl group described above, and when R ₁ is a hydrogen atom, R ₅ is a hydrogen atom and R ₆ is a methyl group, R ₂ and R ₃ are in the 2,4 position Represents the above-mentioned groups other than the dimethyl group. And a salt thereof.

The lower alkyl group in the general formula a methyl group, an ethyl group, a propyl group, an alkyl group of C ₁ -C _4, such as butyl group, a methoxy group as the lower alkoxy group, an ethoxy group, a propoxy groups, C such as butoxy alkoxy group ₁ -C ₄ is the halogen atom fluorine, chlorine, iodine, bromine, etc. Examples of the trihalogenomethyl group, a trifluoromethyl group, a trichloromethyl group. R ₁ is a 2-position substituent, R ₂ is a 3-position or 5-position substituent, and R ₃ is a 4- or 5-position substituent. R ₄ is in the 3 or 4 position.

Examples of the compound of the present invention include the following compounds.

1. 2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol 2. syn-2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1 -Propanol 3. anti-2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol 4. (1S, 2R) -2-methyl-3-pyrrolidino-1-
(4-trifluoromethylphenyl) -1-propanol 5. (1R, 2R) -2-methyl-3-pyrrolidino-1-
(4-trifluoromethylphenyl) -1-propanol 6. (1S, 2R) -2-methyl-3-pyrrolidino-1-
(4-trifluoromethylphenyl) -1-propanol 7. (1S, 2S) -2-methyl-3-pyrrolidino-1-
(4-trifluoromethylphenyl) -1-propanol 8.1,2-dimethyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol 9.1-ethyl-2-methyl- 3-pyrrolidino-1-
(4-trifluoromethylphenyl) -1-propanol 10. 2-methyl-1-phenyl-3-pyrrolidino-1
-(4-trifluorotylphenyl) -1-propanol 11. 1-benzyl-2-methyl-3-pyrrolidino-1
-(4-trifluoromethylphenyl) -1-propanol 12.1- (4-chloro-2-methoxyphenyl) -2
-Methyl-3-pyrrolidino-1-propanol 13. syn-1- (4-chloro-2-methoxyphenyl)
-2-methyl-3-pyrrolidino-1-propanol 14. anti-1- (4-chloro-2-methoxyphenyl) -2-methyl-3-pyrrolidino-1-propanol 15. 2-methyl-3-pyrrolidino -1- (2,3-dimethylphenyl) -1-propanol 16. syn-2-methyl-3-pyrrolidino-1- (2,3-
Dimethylphenyl) -1-propanol 17. anti-2-methyl-3-pyrrolidino-1- (2,3-
Dimethylphenyl) -1-propanol 18. 1-ethyl-2-methyl-3-pyrrolidino-1
(2,3-dimethylphenyl) -1-propanol 19. 2-methyl-3-pyrrolidino-1- (2,4-dimethylphenyl) -1-propanol 20. syn-2-methyl-3-pyrrolidino- 1- (2,4-
Dimethylphenyl) -1-propanol 21. anti-2-methyl-3-pyrrolidino-1- (2,4-
Dimethylphenyl) -1-propanol 22. 1- (4-Chloro-2,3-dimethylphenyl) -2
-Methyl-3-pyrrolidino-1-propanol 23. syn-1- (4-chloro-2,3-dimethylphenyl) -2-methyl-3-pyrrolidino-1-propanol 24. anti-1- (4- Chloro-2,3-dimethylphenyl) -2-methyl-3-pyrrolidino-1-propanol 25. 2-methyl-3-pyrrolidino-1- (2-methoxy-3,5-dimethylphenyl) -1- Propanol 26. syn-2-methyl-3-pyrrolidino-1- (2-methoxy-3,5-dimethylphenyl) -1-propanol 27. anti-2-methyl-3-pyrrolidino-1- (2-
Methoxy-3,5-dimethylphenyl) -1-propanol 28. 1-ethyl-2-methyl-3-pyrrolidino-1-
(2-methoxy-3,5-dimethylphenyl) -1-propanol 29. 2-methyl-3-pyrrolidino-1- (4-methoxy-2,5-dimethylphenyl) -1-propanol 30. syn- 2-methyl-3-pyrrolidino-1- (4-methoxy-2,5-dimethylphenyl) -1-propanol 31. anti-2-methyl-3-pyrrolidino-1- (4-
Methoxy-2,5-dimethylphenyl) -1-propanol 32. syn-1- (3-methoxy-5,6,7,8-tetrahydro-2-naphthyl) -2-methyl-3-pyrrolidino-1
-Propanol 33. anti-1- (3-methoxy-5,6,7,8-tetrahydro-2-naphthyl) -2-methyl-3-pyrrolidino-1
-Propanol 34. syn-2-ethyl-1- (4-methoxy-5,6,7,8
-Tetrahydro-1-naphthyl) -3-pyrrolidino-1
-Propanol 35.anti-2-ethyl-1- (4-methoxy-5,6,7,8
-Tetrahydro-1-naphthyl) -3-pyrrolidino-1
-Propanol 36. 1- (4-ethylphenyl) -2-methyl-3-
Pyrrolidino-1-propanol 37. syn-1- (4-ethylphenyl) -2-methyl-
3-pyrrolidino-1-propanol 38. anti-1- (4-ethylphenyl) -2-methyl-3-pyrrolidino-1-propanol 39. syn-1- (4-methylphenyl) -2-methyl-
3-piperidino-1-propanol 40. anti-1- (methylphenyl) -2-methyl-3
-Piperidino-1-propanol 41. 1- (4-ethylphenyl) -2-methyl-3-
Piperidino-1-propanol 42. syn-1- (4-ethylphenyl) -2-methyl-
3-piperidino-1-propanol 43. anti-1- (4-ethylphenyl) -2-methyl-3-piperidino-1-propanol Among these compounds, preferred are, for example, 1,2,3,4, And compounds such as 5,6,7,41,42 and 43.

The compound of the present invention is produced by two methods. First, when R ₅ = H in the general formula (I), a 3-cyclic aminopropiophenone represented by the general formula (II) (A, R ₆ , and B are the same as described above): lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride (Dival),
And in the presence of a metal hydride such as bis (methoxyethoxy) aluminum sodium hydride or the like, an ether such as ether or dioxane, an alcohol such as methanol or isopropyl alcohol, a solvent such as tetrahydrofuran or dichloromethane, from 0 ° C. to the boiling point of the solvent. At a temperature of

Next, when R ₅ = H in the general formula (I), a 3-cyclic aminopropiophenone represented by the general formula (II) is used.
Conventional Grignard reagents such as methylmagnesium iodide, ethylmagnesium bromide, benzylmagnesium chloride and phenylmagnesium bromide, and anhydrous ether;
It is obtained by reacting in an anhydrous ether solvent such as anhydrous tetrahydrofuran.

Since the compound of the present invention represented by the general formula (I) has two asymmetric carbons in the molecule, there are two diastereoisomers, and each isomer has two optically active The present invention includes all of these isomers, and these isomers can be obtained by a chromatography method or by using an optically active substance as a raw material.

The free base can be converted into an acid addition salt by a conventional method, if desired. Acid addition salts include hydrochloride, hydrobromide,
Inorganic acid salts such as sulfates, phosphates, etc., formate, acetate, citrate, maleate, fumarate, tartrate, lactate, methanesulfonate, etc. .

[Action]

 Next, the action of the compound of the present invention will be described.

1. Suppressing action of spinal reflex (flexion reflex) Using male Wistar rats, exfoliate the tibial nerve under urethane α-chloralose anesthesia and stimulate with an electron tube stimulator (Nihon Kohden: MSE-3 type) (0.1 msec) , 0.
(1 Hz, ultra-maximal stimulation) to amplify the evoked electromyogram recorded via a needle electrode inserted into the ipsilateral tibialis anterior muscle (flexor) and plotted on a CRT oscilloscope. The amplitude of this electromyogram was recorded on a pen recorder via a homemade peak holder as an index of flexion reflex. The effect of the drug was expressed by the bending reflex inhibition rate taking into account the sustainability.

That is, the average amplitude of the electromyogram for 10 minutes before the administration of the test compound was defined as (a), the test compound was dissolved in physiological saline, and intravenously administered at 5 mg / kg (iv), followed by electromyography for 30 minutes. (B) was used as the average amplitude, and the perpendicular / direct reflection suppression rate was calculated by equation (A).

The results are shown in 4 below.

2.Effect on anemic decerebrate rigidity in rats Fukuda et al. [H. Fukuda, TI to, S. Hashimoto, and
Y. Kudo, Japan. J. Pharmacol., 24 , 810 (1974)]
An anemia-induced decerebrate rigidity sample was prepared, and the effect of the compound of the present invention on relaxation of rigidity was examined. This specimen causes rigidity in the limbs (particularly the forelimbs) due to the enhancement of the α-motor system, and is regarded as an excellent pathological model for abnormally increased muscle tone such as spasticity in clinical practice. It is considered that a drug having a remission action on the same sample acts on the brainstem or spinal cord level and exhibits a central muscle relaxation action.

Using Wistar male rats (350-500 g), the tracheal cannula was inserted under ether anesthesia, the bilateral common carotid artery was ligated, and the basal artery was bipolar coagulator (Mizuho Medical, MICRO-I
Blood flow was stopped by cauterizing in C), and a rigid specimen was prepared. The recording of the rigidity was performed as follows.

The rat was fixed on a fixed base in a dorsal position, and the forelimb was grasped by one end of a celluloid plate fitted with strain gauges on both sides. The change in resistance that occurred in response to the force pushing up the celluloid plate due to rigidity of the forelimbs was recorded as tension on an ink oscillograph through a bridge circuit.

Assuming that the tension before administration was 100%, the rate of inhibition of rigidity was calculated by equation (B).

3. Acute toxicity 50% lethal dose (LD ₅₀ , m
g / kg) was determined by the up and down method.

4. Results Next, the results of typical compounds of the present invention are shown.

[Effect] The compound of the present invention obtained as described above has a strong central muscle relaxing action, and the action is long lasting. Therefore, the compound of the present invention is expected as a central muscle relaxant.

When the compound of the present invention is used as a central muscle relaxant,
It can be administered either orally or parenterally. The dose varies depending on the condition, age, and administration method of the patient to be administered, but is usually 0.1 to 30 mg / kg / day.

The compound of the present invention is administered in the form of a preparation prepared by mixing with an appropriate preparation carrier. As the form of the preparation, tablets, granules, fine granules, powders, capsules, injections, suppositories and the like are used.

〔Example〕

Hereinafter, the compound of the present invention will be described more specifically with reference to examples.

Example 1. 2-Methyl-3-pyrrolidino-1- (4-trifluoro
Methylphenyl) -1-propanol (Compound No. 1) average
And its syn (compound No. 2) and anti-compound (compound No. 2)
3) dl-2-methyl-3-pyrrolidino-1- (4-trif
3.99 g of (fluoromethylphenyl) -1-propanone (0.014
mol) in 50 ml of toluene, and vitride the solution. [B
Sodium (methoxyethoxy) aluminum hydride
70% toluene solution] 15 g (0.0519 ml) in toluene 50 m
Add dropwise to the solution dissolved in l. This toluene solution
Heat to reflux for 4 hours. After completion of the reaction, add water and
After decomposing the base material, extraction is performed with dichloromethane. this
After washing the organic layer with water, drying over anhydrous magnesium sulfate,
When the solvent is distilled off under reduced pressure, syn and anti
2-Methyl-3-pyrrolidino of diastereomeric mixture
-1- (4-trifluoromethylphenyl) -1-pro
3.5 g of panol (Compound No. 1) are obtained. In addition, this residue
Was repeatedly recrystallized from n-hexane to give colorless prism crystals.
As syn-2-methyl-3-pyrrolidino-1- (4-
Trifluoromethylphenyl) -1-propanol
Compound No. 2) 1.9 g (mp. 98-100 ° C.) is obtained. Reduce the filtrate
The residue is concentrated under reduced pressure and the residue is subjected to alumina column chromatography.
[Dichloromethane-n-hexane mixed solvent (dichloromethane
Elution with tan: n-hexane = 3: 7)]
From the effluent, anti-2-methyl-3-pyrrolidino-1- (4
-Trifluoromethylphenyl) -1-propanol
(Compound No. 3) 1.1 g is obtained. This product was re-used with n-hexane.
Crystallized and 1.1 g (mp. 61-63 ° C) as colorless prisms
obtain. From the second eluate, 0.1 g of the sys form is obtained. Total syn-2
-Methyl-3-pyrrolidino-1- (4-trifluoromethyl
2.0 g of tilphenyl) -1-propanol are obtained. syn-
2-methyl-3-pyrrolidino-1- (4-trifluoro
Methylphenyl) -1-propanol anti-2-methyl-3-pyrrolidino-1- (4-tri
Fluoromethylphenyl) -1-propanol Dl-2-methyl-3-pyrrolidino-1- of Example 1
(4-trifluoromethylphenyl) -1-propanone
Except that the following raw materials are used instead of
The desired products are obtained by post-treatment.

Example 2. (1S, 2R)-(Compound No. 4) and (1R, 2R) -2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol (Compound No. 5) (2R-(-)-2-methyl-3-pyrrolidino-1-
(4-trifluoromethylphenyl) -1-propanone
2.8 g (9.81 × 10 ⁻³ mol) is dissolved in 50 ml of dichloromethane, and 40 ml of a 1 molar toluene solution of diisobutylaluminum hydride is added little by little at an internal temperature of −70 ° C. under an argon stream, followed by stirring for 4 hours. After the reaction, 20 ml of water is added to the reaction solution to decompose excess diisobutylaluminum hydride. The colorless decomposition precipitate is filtered. The obtained decomposition precipitate is dissolved in a mixed solvent of water and dichloromethane, and extracted with dichloromethane. The dichloromethane layer is combined with the previous filtrate, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is purified by alumina camula chromatography [eluted with a dichloromethane-n-hexane mixed solvent (dichloromethane: n-hexane = 3: 7)]. The crystals obtained as the first fraction are recrystallized with n-hexane. As a colorless prism, (1R, 2
R) -2-Methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol 0.96 g (mp8
3-84 ° C.) as a second fraction of oily (1S, 2
R) -2-Methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol 0.98 g, which is converted into the hydrochloride by introducing dry hydrochloric acid gas in dichloromethane. Recrystallized from dichloromethane-ethyl acetate. 0.1 g of (1R, 2R) -2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol hydrochloride (mp 215-217 ° C)
Get. (1S, 2R) -2-methyl-3-pyrrolidino-1
-(4-trifluoromethylphenyl) -1-propanone (1S, 2R) -2-methyl-3-pyrrolidino-1- (4-
Trifluoromethylphenyl) -1-propanone 4.92 (1H, drS, -CH (OH)-) 7.36 (2H, d, J, = 8.0Hz, aromalH) 7.60 (2H, d, J, = 8.0Hz, aromalH) Example 3. (1R, 2S) -(Compound No. 6) and (1S, 2S) -2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol (Compound No. 7) Example 1 (2R) -(-)-2-Methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-
(2S)-(+)-2-methyl-3 instead of propanone
(1R, 2S-2-methyl-3-pyrrolidino-1- (4-tripyridino-1- (4-trifluoromethylphenyl) -1-propanone) Fluoromethylphenyl) -1-
Propanol hydrochloride (compound No. 6) (mp 217-218) and d-anti-2-methyl-3-pyrrolidino-1- (1S, 2
S)-(4-Trifluoromethylphenyl) -1-propanol (Compound No. 7) (mp 83-84) is obtained, respectively.

(1R, 2S-2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol 4.92 (1H, br s-C H (OH) -), 7.36 (2H, d, J = 8.0Hz; aromaticH) 7.60 (2H, d, J = 8.0Hz; aromaticH) (1S, 2S) -2- methyl -3-Pyrrolidino-1- (4-
Trifluoromethylphenyl) -1-propanol Example 4. 1-ethyl-2-methyl-3-pyrrolidino-1- (4-
Trifluoromethylphenyl) -1-propanol (Compound No. 9) Reagent prepared from 50 ml of anhydrous ether, 204 mg of magnesium (8.4 × 10 ⁻³ mol), and 0.96 g of ethyl bromide (8.8 × 10 ⁻³ mol) 2-Methyl-3-pyrrolidino-
A solution of 2.0 g (7 × 10 ⁻³ mol) of 1- (4-trifluoromethylphenyl) -1-propanone in 50 ml of anhydrous ether is added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 5 hours.
After completion of the reaction, a saturated aqueous solution of ammonium chloride is added to the reaction solution, and an ether layer is extracted. After washing twice with water, the ether layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with chloroform) to give 1-ethyl-2-methyl-3-pyrrolidino as colorless prisms.
1.37 g of 1- (4-trifluoromethylphenyl) -1-propanol (mp 64-66 ° C.) are obtained.

1.25 g of this free base is dissolved in ether, and dry hydrochloric acid gas is introduced. The precipitated crystals are collected by filtration and dried with a vacuum pump. 1-ethyl-2-methyl-3 as a colorless powdery crystal
-Pyrrolidino-1- (4-trifluoromethylphenyl) -1-propanol hydrochloride 1.33 g (mp 184.5-185
° C).

A target compound is obtained by the same treatment and post-treatment except that the following raw materials are used in place of ethyl bromide of Example 4.

Example 5. 1- (4-Ethylphenyl) -2-methyl-3-piperi
Dino-1-propanol (Compound No. 41) and its s
yn (Compound No. 42) and anti form (Compound No. 43) Vitride [Bis (methoxyethoxy) aluminum hydride
Sodium 70% toluene solution] 45 g
In a solution diluted to 00 ml, dl-1- (4-ethylphenyl) was added.
L) -2-Methyl-3-piperidino-1-propanone 1
0.94g (43.9 × 10^-3mol) dissolved in 200 ml of toluene
The solution is added dropwise while heating under reflux. After dropping, add for 1 hour
The reaction is completed by heating under reflux. After the reaction, add water.
After decomposing excess reducing agent, extraction is performed with toluene.
This organic layer is washed with water and dried over anhydrous magnesium sulfate.
Then, the solvent is distilled off under reduced pressure.
1- (4-ethylphenyl) of the diastereomeric mixture of
L) -2-Methyl-3-piperidino-1-propanol
(Compound No. 41) 11.0 g is obtained. 6.25 g of a part of this product
Lumina column chromatography [n-hexane-acetic acid
Ethyl ester mixed solvent (n-hexane: ethyl acetate
Eluting with steal = 20.1). 1st fluxi
Anti-1- (4-ethylphenyl)
-2-methyl-3-piperidino-1-propanol
Compound No.41) 2.49 g, sy as oil in the second fraction
n-1- (4-ethylphenyl) -2-methyl-3-pi
2.45 g of peridino-1-propanol (compound No. 42) were obtained.
You. These are each dissolved in methylene chloride, and concentrated hydrochloric acid is added.
And then recrystallized from acetone. anti-body hydrochloride
2.3 g of a salt and 1.8 g of a syn-hydrochloride are obtained.

anti body hydrochloride syn-body hydrochloride

Continuation of front page (56) References JP-A-54-151983 (JP, A) US Patent 3,317,380 (US, A) Prakt. Chem. , 323 [5] (1981) p. 793-800 Tetrahedron, 26 [22] (1970) p. 5247-5253 Tetrahedron, 26 [16] (1970) p. 3959-3964J. Med. Chem. , 13 [3] (1970) p. 480-488 Tetrahedron, 21 [2] (1970) p. 421-425

Claims (1)

(57) [Claims] (1) General formula [Where A is (Wherein R ₁ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, R ₂ represents a hydrogen atom, a lower alkyl group, R ₃
Is a hydrogen atom, a halogen atom, a trihalogenomethyl group, a lower alkyl group, a lower alkoxy group) or (Where R ₄ is a lower alkoxy group), R ₅ is a hydrogen atom, a lower alkyl group, a phenyl group, or a benzyl group, R ₆ is a lower alkyl group, and B is a pyrrolidino group , A piperidino group. However, when B is a pyrrolidino group, R ₅ represents the above groups other than the phenyl group. B is a piperidino group and A is In the case where R ₁ and R ₂ are both hydrogen atoms, R ₅ is a hydrogen atom and R ₆ is a lower alkyl group,
R ₃ represents a hydrogen atom, a fluorine atom or a group other than a lower alkyl group described above, and when R ₁ is a hydrogen atom, R ₅ is a hydrogen atom and R ₆ is a methyl group, R ₂ and R ₃ are in the 2,4 position Represents the above-mentioned groups other than the dimethyl group. 3-cyclic aminopropanol derivative represented by the formula: