JPH0798794B2 - Taurine type compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel taurine-type compound useful as a medicine.

Conventional Technology and Problems Thereof A vasodilator is mainly used for the treatment of thrombosis or microcirculation. However, for the improvement of microcirculation under ischemic condition, mere treatment with a vasodilator is completely inadequate, and aggressive blood characteristics from the standpoint of enhancing erythrocyte deformability and controlling platelet function. Improvement is extremely important. Therefore, the treatment method for thrombosis and microcirculation disorder based on this viewpoint has been recently attracting attention, and pentoxyfilin, trapidil, and dilazeptop have been investigated by reviewing existing cardiovascular agents from the viewpoint of hemohydrodynamics. It was confirmed that it is also effective as a blood property improving drug.

However, the effect of improving blood properties of these existing drugs is insufficient, and the erythrocyte deformability-enhancing effect and platelet function, which are important for hemodynamics in microvascular flow, are controlled to control blood properties. There is a demand for the emergence of a drug that is markedly effective for improvement.

Means for Solving the Problems The present invention provides novel compounds that meet the above-mentioned needs.

The present invention has the general formula (In the formula, R ₁ and R ₂ are the same or different, a hydrogen atom,
A lower alkyl group or a cyano group is shown. R ₃ represents a hydrogen atom or a lower alkyl group. R ₄ and R ₅ are the same or different and each represents a phenyl group which may have 1 to 3 lower alkoxy groups as a substituent. Also, l, m and n
Represents an integer of 1 to 4. ) Related to the taurine-type compound.

The taurine-type compound of the present invention is a novel compound that has not been published in the literature, and has an extremely strong erythrocyte deformability-enhancing action, and also has a platelet aggregation-inhibiting action, thus showing a remarkable effect in improving blood properties, and as a drug. It is useful.

Examples of the lower alkyl group in the compound of the present invention include branched groups having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group. Alternatively, a linear alkyl group may be a lower alkoxy group having 1 to 1 carbon atoms such as methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group and sec-butoxy group.
The branched or linear alkoxy group of 6 can be exemplified.

The compound (I) of the present invention can be produced by various methods, and typical methods thereof will be exemplified below.

<Production method A> (In the reaction formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , l, m and n are the same as above.) The starting material is a 2- or 3-substituted amine derivative (II).
Can be obtained, for example, according to the method described in the following documents.

i) Drugs of t
he Future), 10 (12), 1000 (1985), ii) ibid., 9 (2), 108 (1984), iii) JP-A-53-25539.

The di- or tri-substituted amine derivative (II) obtained according to the method described in the above-mentioned literature is mixed with an equimolar or several-fold molar amount of a cyclic sulfonic acid ester (III), a lower alcohol having 1 to 5 carbon atoms, Preferably, methanol, ethanol, propanol, isopropanol, a lower ketone having 1 to 5 carbon atoms, preferably acetone, methyl ethyl ketone, diethyl ketone, or a mixed solvent thereof is added at 0 ° C to room temperature, and then at room temperature to reflux temperature. It is produced by stirring for a period of time to several days. The thus-obtained compound of the present invention collects the formed precipitate and collects water, methanol, ethanol, propanol, isopropanol, acetone,
Methyl ethyl ketone, diethyl ketone, diethyl ether or the like, or recrystallized from a mixed solvent thereof, or after concentration of the reaction solution under reduced pressure, for example, purified by a silica gel column using a mixed solvent of chloroform-methanol as a developing solvent, diethyl ether It is purified and isolated by a method of crystallization in ether, acetone, or a mixed solvent thereof.

<Production method B> (In the reaction formula, X represents a halogen atom, M represents an alkali metal or an alkaline earth metal. R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , l,
m and n are the same as above. ) An equimolar to several molar amount of the sulfonic acid derivative (IV) is added to the di- or tri-substituted amine derivative (II) in water or the production method A.
It is produced by adding the same solvent as used in 1. or a solvent prepared by mixing these in an arbitrary ratio and then reacting at room temperature to reflux temperature for several hours to several days. The compound of the present invention thus obtained is purified and isolated in exactly the same manner as described in Process A.

The compound (I) of the present invention has an excellent erythrocyte deformability-enhancing action and platelet aggregation-inhibiting action, and improves blood fluidity in the microcirculation region, thereby improving arteriosclerosis, cerebral infarction, myocardial infarction. It is useful for the treatment and prevention of peripheral thrombus and occlusion.

The compound (I) of the present invention may be administered in any form of tablets, pills, capsules, granules, powders, orally, or injections such as intravenous injection and intramuscular injection, and parenteral administration such as suppositories. May be The dose is appropriately determined depending on the individual case in consideration of symptoms, age and sex of the subject to be administered, but usually, in the case of oral administration, the compound of the present invention is 1 to 300 mg per day for an adult in 2 to 4 times. Administer separately. In the case of an injection, for example, in the case of intravenous administration, 2 ml of an adult (1 to 10 mg of the compound of the present invention) is usually diluted with physiological saline or glucose injection as needed, and then administered gradually. For suppositories,
Usually, 1 to 300 mg for an adult is administered once or twice a day by inserting it into the rectum at intervals of 6 to 24 hours.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples and pharmacological tests.

Example 1 3- {N-methyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -N- [4- (3,4-dimethoxyphenyl) -4-isopropyl-4-cyanobutyl] Ammonio} propane sulphate (Compound 1): N-methyl-N- [2- (3,4-dimethoxyphenyl)
Ethyl] -N- [4- (3,4-dimethoxyphenyl)-
4-isopropyl-4-cyanobutyl] amine 11.6 g
To a solution obtained by dissolving (25.7 mmol) in 120 ml of methyl ethyl ketone, a solution of 6.3 g (52 mmol) of 1,3-propanesartone in methyl ethyl ketone (30 ml) was added.

After refluxing at the boiling point for 24 hours, the formed crystals were collected. After recrystallization from water-containing acetone, it was dried under reduced pressure at 100 ° C. for 20 hours.

Yield (Yield) 10.3 g (69.5%).

mp 241-244 ° C (decomposition).

TLC Rf = 0.60 (silica gel; chloroform / methanol = 3/1 (V / V)).

IR spectrum (KBr tablet) 2220 cm ^-1 (ν _C≡N ), 1150 cm ^-1 (ν _SO2 (asymmetric)), 1030 cm ^-1 (ν _SO2 (symmetric)).

FAB mass spectrum (m / e) 577 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 0.71 (double line, J = 7 Hz, 3 H, −CH ₃ ), 1.10 (double line, J = 7 Hz, 3 H, −CH ₃ ). , 1.2-2.3 (multiplet _{(broad), 7H, -CH 2 -,} CH-), 2.50 ( multiplet _{(broad), 2H, -CH 2 -)} , 2.94 ( singlet (broad), 5H, 3.36 (multiplet _{(broad), 6H, -CH 2 -)} , 3.73~3.78 ( _{multiplet, 12H, -OCH 3), 6.5~7.0} ( multiplet, 6H, φ-H).

Elemental analysis (as C ₃₀ H ₄₄ N ₂ S ₁ O ₇ (MW576.75)) Calculated value (%) H: 7.69 C: 62.48 N: 4.86, Measured value (%) H: 7.97 C: 62.33 N: 4.90.

Example 2 2- {N, N-bis [2- (3,4-dimethoxyphenyl) ethyl] ammonio} ethane sulphate (Compound 2): N, N-bis [2- (3,4-dimethoxyphenyl) (Enyl) ethyl]
1.15 g (3.0 mmol) of amine / hydrochloride and 0.68 g (3.2 mmol) of sodium 2-bromoethanesulfonate were dissolved in 10 ml of a mixed solvent of water / ethanol of 1/1 (V / V) ratio, and 1N was added at room temperature.
-3.0 ml (3.0 mmol) of aqueous sodium hydroxide solution was added dropwise, and the mixture was refluxed for 4 days.

The residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel, chloroform / methanol = 5/1 (V / V) mixed solvent) and then recrystallized from water-containing methanol.
Then, it was dried under reduced pressure at 100 ° C. for 20 hours.

Yield (Yield) 0.32 g (23.5%).

mp 232-233 ° C.

TLC Rf = 0.23 (silica gel; chloroform / methanol = 5/1 (V / V)).

IR spectrum (KBr tablet) 1150cm ^-1 (ν _{SO2 ^{(asymmetric)), 1030cm -1 (νSO 2}} ( symmetric)).

FAB mass spectrum (m / e) 454 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 3.00 (multiplex line, 4H, -CH _2- ), 3.33 (multiplex line, 8H, -CH _2- ), 3.72 (singlet line, 6H, -OCH ₃ ), 3.76 (single line, 6H, -OCH ₃ ), 6.75 to 6.87 (multiple lines, 6H, φ-H), Elemental analysis (as C ₂₂ H ₃₁ N ₁ S ₁ O ₇ (MW453.55)) Calculated value (%) H: 6.89 C: 58.26 N: 3.09, Measured value (%) H: 6.91 C: 58.43 N: 3.15.

Example 3 3- {N, N-bis [2- (3,4-dimethoxyphenyl) ethyl] ammonio} propane sulphate (compound 3): N, N-bis [2- (3,4-dimethoxyphenyl) (Enyl) ethyl]
1.8 g (5.2 mmol) of amine was dissolved in 15 ml of methyl ethyl ketone, and 0.64 g (5.2 mmol) of 1,3-propanesultone at room temperature.
Of methyl ethyl ketone (5 ml) was added. After stirring at room temperature for 4 days, the formed crystals were collected. Methanol-
After recrystallization from water-acetone, it was dried under reduced pressure at 100 ° C for 20 hours.

Yield (Yield) 1.22 g (50.1%).

mp 189-190 ° C.

TLC Rf = 0.27 (silica gel; chloroform / methanol = 5/1 (V / V)).

IR spectrum (KBr tablet) 1150 cm ^-1 (ν _SO2 (asymmetric)), 1030 cm ^-1 (ν _SO2 (symmetric)).

FAB mass spectrum (m / e) 468 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 2.10,2.70,2.95 (each multiline (wide), each 2H, -CH
₂ −), 3.33 (multiple line, 8H, −CH ₂ −), 3.72 (single line, 6H, −OCH ₃ ), 3.76 (single line, 6H, −OCH ₃ ), 6.76 to 6.87 (multiple line, 6H, φ-H), Elemental analysis (as C ₂₃ H ₃₃ N ₁ S ₁ O ₇ (MW467.58)) Calculated value (%) H: 7.11 C: 59.08 N: 3.00, Measured value (%) H: 7.17 C: 59.05 N: 3.02.

Example 4 4- {N, N-bis [2- (3,4-dimethoxyphenyl) ethyl] ammonio} butane sulphate (compound 4): N, N-bis [2- (3,4-dimethoxyphenyl) (Enyl) ethyl]
1.8 g (5.2 mmol) of amine are dissolved in 15 ml of methyl ethyl ketone and 0.71 g (5.2 mmol) of 1,4-butanesultone in methyl ethyl ketone (5 ml) is added at room temperature. After boiling under reflux for 3 days, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel; chloroform / methanol = 5/1 (V /
V) mixed solvent). After crystallization from diethyl ether, it was dried under reduced pressure at 60 ° C. for 24 hours.

Yield (Yield) 1.0 g (40%).

mp 78-80 ° C.

TLC Rf = 0.20 (silica gel; chloroform / methanol = 5/1 (V / V)).

IR spectrum (KBr tablet) 1150 cm ^-1 (ν _SO2 (asymmetric)), 1030 cm ^-1 (ν _SO2 (symmetric)).

FAB mass spectrum (m / e) 482 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 1.72 (multiline (wide), 4H, -CH _2- ), 2.60 (multiline (wide), 2H, -CH _2- ), 2.92 (multiplet _{(broad), 4H, -CH 2 -)} , 3.17 ( multiplet _{(broad), 6H, -CH 2 -)} , 3.72 ( singlet, 6H, -OCH _3), 3.75 (singlet, 6H, -OCH ₃ ), 6.75 to 6.92 (multiple lines, 6H, φ-H), Elemental analysis (as C ₂₄ H ₃₅ N ₁ S ₁ O ₇ (MW481.61)) Calculated value (%) H: 7.33 C: 58.86 N: 2.91, Measured value (%) H: 7.29 C: 59.13 N: 2.91.

Example 5 2- {N- [2- (3,4-dimethoxyphenyl) ethyl-N- [2- (3,4,5-trimethoxyphenyl) ethyl] ammonio} ethanesulfate (Compound 5) : N- [2- (3,4-dimethoxyphenyl) ethyl] -N
2.1 g (5.1 mmol) of 2- [3- (3,4,5-trimethoxyphenyl) ethyl] amine hydrochloride was added to 15 ml of isopropanol.
Dissolve in 5.2 ml of 1N sodium hydroxide solution (5.2 mmo
l) was added dropwise. Sodium bromoethanesulfonate 2.
After adding a solution of 1 g (10 mmol) in water (10 ml),
Refluxed for 3 days. The residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel; chloroform / methanol = 10/1 (V / V) mixed solvent) and then recrystallized from acetone-diethyl ether. It was dried under reduced pressure at 50 ° C. for 20 hours.

Yield (Yield) 0.54 g (22%).

mp 176-179 ° C.

TLC Rf = 0.22 (silica gel; chloroform / methanol = 5/1 (V / V)).

IR spectrum (KBr tablet) 1140 cm ^-1 (ν _SO2 (asymmetric)), 1025 cm ^-1 (ν _SO2 (symmetric)).

FAB mass spectrum (m / e) 484 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 3.0 (multiple line (wide), 4H, -CH _2- ), 3.3 (multiple line (wide), 8H, -CH _2- ), 3.63 ～3.77 _{(multiplet, 15H, -OCH 3), 6.6~7.0} ( multiplet, 5H, φ-H), Elemental analysis (as C ₂₃ H ₃₃ N ₁ S ₁ O ₈ (MW483.58)) Calculated value (%) H: 6.88 C: 57.13 N: 2.90, Measured value (%) H: 6.85 C: 57.14 N: 2.91.

Example 6 3- {N- [2- (3,4-dimethoxyphenyl) ethyl-N- [2- (3,4,5-trimethoxyphenyl) ethyl] ammonio} propanesulfate (Compound 6) : N- [2- (3,4-dimethoxyphenyl) ethyl] -N
2.1 g (5.6 mmol) of-[2- (3,4,5-trimethoxyphenyl) ethyl] amine was dissolved in 20 ml of acetone, and 0.82 g (6.7 mmol) of 1,3-propanesartone (acetone) was dissolved at room temperature. 5 ml) solution was added. After boiling under reflux for 24 hours, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel; chloroform / methanol = 10/1 (V / V) mixed solvent). After crystallization from diethyl ether at 50 ° C
It was dried under reduced pressure for 24 hours.

Yield (Yield) 1.5 g (54%).

mp 80-83 ° C.

TLC Rf = 0.26 (silica gel; chloroform / methanol = 5/1 (V / V)).

IR spectrum (KBr tablet) 1145 cm ^-1 (ν _SO2 (asymmetric)), 1030 cm ^-1 (ν _SO2 (symmetric)).

FAB mass spectrum (m / e) 498 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 2.1 (Multiline (wide), 2H, -CH _2- ), 2.7 (Multiline (wide), 2H, -CH _2- ), 3.0 (multiplet _{(broad), 2H, -CH 2 -)} , 3.4 ( multiplet _{(broad), 8H, -CH 2 -)} , 3.63~3.77 ( _{multiplet, 15H, -OCH 3), 6.6~6.9} ( multiple Wire, 5H, φ-H), Elemental analysis (as C ₂₄ H ₃₅ N ₁ S ₁ O ₈ (MW497.61)) Calculated value (%) H: 7.09 C: 57.93 N: 2.81, Measured value (%) H: 7.16 C: 57.65 N: 2.80.

Example 7 4- {N- [2- (3,4-dimethoxyphenyl) ethyl-N- [2- (3,4,5-trimethoxyphenyl) ethyl] ammonio} butane sulphate (Compound 7) : N- [2- (3,4-dimethoxyphenyl) ethyl] -N
2.1 g (5.6 mmol) of-[2- (3,4,5-trimethoxyphenyl) ethyl] amine was dissolved in 20 ml of methyl ethyl ketone, and 1.5 g (11 mmol) of 1,4-butanesaltone was dissolved in methyl ethyl ketone (5 ml) at room temperature. Add. After refluxing for 3 days at the boiling point, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel; chloroform / methanol = 10/1 (V /
V) mixed solvent). After crystallization from diethyl ether, it was dried under reduced pressure at 50 ° C. for 24 hours.

Yield (Yield) 1.4 g (49%).

mp 78-82 ° C.

TLC Rf = 0.21 (silica gel; chloroform / methanol = 5/1 (V / V)).

IR spectrum (KBr tablet) 1150 cm ^-1 (ν _SO2 (asymmetric)), 1035 cm ^-1 (ν _SO2 (symmetric)).

FAB mass spectrum (m / e) 512 (M + 1). ¹ H-NMR spectrum (DMSO-d ₆ , TMS internal standard, δ) 1.8 (multiple line (wide), 4H, -CH _2- ), 2.6 (multiple line (wide), 2H, -CH _2- ), 3.0 (multiplet _{(broad), 4H, -CH 2 -)} , 3.2 ( multiplet _{(broad), 6H, -CH 2 -)} , 3.62~3.77 ( _{multiplet, 15H, -OCH 3), 6.6~6.9} ( multiple Wire, 5H, φ-H), Elemental analysis (as C ₂₅ H ₃₇ N ₁ S ₁ O ₈ (MW511.64)) Calculated value (%) H: 7.29 C: 58.69 N: 2.74, Found value (%) H: 7.30 C: 58.02 N: 2.66.

Pharmacological test The pharmacological test for the compound (I) of the present invention is shown below.

Erythrocyte deformability enhancing effect: Experimental example 1 Viscosity measurement method Using an ELD rotational viscometer (0.8 ° cone) manufactured by Tokyo Keiki,
Blood viscosity was measured at a shear rate of 150, 75, and 37.5 sec ^-1 at 37 ° C.

Heparin-added venous blood from Japanese white rabbits was used at 4 ° C for 24 hours.
After storage for a period of time, it was examined under the condition with or without the addition of a drug (20 μg / ml).

As a result, the compound (I) of the present invention showed a stronger decrease in viscosity as compared with the control agents dilazep (“Comelian”, Kowa Co., Ltd.) and pentoxyfilin (“Trental”, Nippon Hoechst Co., Ltd.). Showed action. 3- {N-methyl-N- [2- (3,4-dimethoxyphenyl) ethyl]
The results for -N- [4- (3,4-dimethoxyphenyl) -4-isopropyl-4-cyanobutyl] ammonio} propanesulfate (Compound 1) are shown in Table 1.

Experimental Example 2 Morphological Observation As the erythrocyte suspension, heparinized venous blood of Japanese white rabbit was centrifuged (1100 rpm × 7 minutes, 4 ° C.), and the precipitate was phosphate buffered saline at 4 ° C. (140.5 mM). NaCl, 8mM Na ₂ HPO ₄ , 2mM KH ₂ P
Wash with O ₄ (pH7.4) and centrifuge (2800 rpm × 10 minutes, 4
C.) was added several times to obtain a 46% hematocrit, which was dispersed in phosphate buffered saline at 4.degree.

After adding the drug (20 μg / ml) to the above-mentioned erythrocyte suspension, it was diluted 25 times with phosphate buffered saline of high osmotic pressure (400 mOsm / kg) and observed with an optical microscope. As a result, each of the compounds to which the compound 1 of the present invention was added exhibited an action of normalizing erythrocytes that had been deformed by hyperosmolarity, and the degree thereof was pentoxyfilin (“Trental”, Nippon Hoechst (strain) )), And even stronger than Dilazep (“Comelian”, manufactured by Kowa Co., Ltd.).

Similar results were obtained with other compounds of the invention.

Representative agents showing erythrocyte deformability-enhancing action include pentoxyfilin, trapidil and dilazep, but the degree of erythrocyte deformability enhancement of the compound of the present invention is 10 times that of trapidil and 100 times that of pentoxyfilin. Said dirazep (Susumu Yamamoto et al., Pharmacology and treatment, 11 (10), 427
It was proved from the above tests that it was stronger than that of 3 (1983)).

Inhibition of platelet aggregation: Platelet rich plasma (PRP) and platelet poor plasma (PPP) used
Was prepared from citrated venous blood of Japanese White Rabbit.
The platelet aggregation ability is measured by literature (GVRBorn, Nature, 194 , 927).
(1962)] and measure the platelet aggregation inhibitory effect of the compound on the platelet aggregation ability induced by collagen (final concentration 5 μg / ml) and ADP (final concentration 10 μM) with an aggregometer. did. as a result,
The compound (I) of the present invention has a stronger inhibitory effect on platelet aggregation than the control agents dilazep (“Comelian”, manufactured by Kowa Co., Ltd.) and pentoxyfilin (“Trental”, manufactured by Nippon Hoechst Co., Ltd.). Indicated. 3- {N-methyl-
N- [2- (3,4-dimethoxyphenyl) ethyl] -N
The results for-[4- (3,4-dimethoxyphenyl) -3-isopropyl-3-cyanobutyl] ammonio} propanesulfate (Compound 1) are shown in Table 2.

Claims (1)

[Claims] 1. A general formula (In the formula, R ₁ and R ₂ are the same or different, a hydrogen atom,
A lower alkyl group or a cyano group is shown. R ₃ represents a hydrogen atom or a lower alkyl group. R ₄ and R ₅ are the same or different and each represents a phenyl group which may have 1 to 3 lower alkoxy groups as a substituent. Also, l, m and n
Represents an integer of 1 to 4. ) A taurine-type compound represented by: