JPS6231685B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel therapeutic agent for hyperglycemia. For more details, use the formula below It is expressed as The present invention relates to a therapeutic agent for hyperglycemia comprising α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol or a pharmacologically acceptable acid addition salt thereof as an active ingredient. α-(3,4,5-trimethoxyphenethylaminomethyl)-3,4-dihydroxybenzyl alcohol and α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dihydroxybenzyl alcohol are , 4-dibenzyloxybenzyl alcohol or 3,4-dibenzyloxyacetophenone derivatives are known to be obtained by catalytic reduction with palladium carbon (US Pat. No.
3869474 and 3952021). These compounds selectively activate adrenergic β ₁ -receptors,
Although it is useful as a cardiotonic agent, it has no hypoglycemic effect. Furthermore, it is also known that α-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol has a hypoglycemic effect and can be used as a therapeutic drug for diabetes (Japanese Patent Laid-Open No. 52-51333). , the compound has almost no platelet aggregation inhibitory effect. In general, hyperglycemic patients often suffer from diabetes, and diabetic patients often also have vascular disorders such as arteriosclerosis and blood clots. It is thought that it begins with what happens. Therefore, the platelet aggregation inhibitory effect inhibits the formation of blood clots in blood vessels, and is therefore considered to be a favorable effect in the treatment of uriasis and even hyperglycemia [Diagnosis and Treatment, Vol. 62, 265 ~274 pages (1974)]. The present inventors have developed benzyl alcohol derivatives []
It has been found that it has a remarkable hypoglycemic effect and also has a platelet aggregation inhibiting effect, making it useful as a therapeutic agent for hyperglycemia. The hypoglycemic effect of benzyl alcohol derivative [ ] is about the same as that of phenformine (chemical name: 1-phenethyl biguanide).
It's 10 times more powerful. For example, dl−α−(2,3,4
Immediately after oral administration (dose: 10 mg/Kg) of 2-hydroxybenzyl alcohol 1/2 oxalate (trimethoxyphethylaminomethyl) to mice, glucose was injected subcutaneously (1 g/Kg). The rate of increase in blood sugar levels was about 50% lower than in the group of mice injected with the drug alone. On the other hand, in the case of experiments under the same conditions as above, in order to show almost the same hypoglycemic effect as when oral administration of the benzyl alcohol derivative (dose: 10 mg/Kg), 100
mg/Kg of fenformin was required. Furthermore,
Benzyl alcohol derivative in the present invention []
also exhibit platelet aggregation inhibitory effects, such as dl-α-
When (2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol hydrochloride was orally administered to rats at a dose of 100 mg/Kg, platelet aggregation in plasma could be prevented by approximately 20%. did it. The benzyl alcohol derivatives of the present invention do not exhibit, for example, adrenergic β effects such as cardiac contractility (which is considered to be a side effect as a therapeutic agent for diabetes). It also has low acute toxicity, such as dl
The maximum tolerated dose of -α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol 1/2 oxalate was observed 48 hours after intraperitoneal injection into 4 mice per group. The result was over 300mg/Kg. When the benzyl alcohol derivative of the present invention [ ] is used as a drug, it can be used either as a racemate or an optically active form. or,
It can be used both as a free base and as a pharmacologically acceptable acid addition salt. Free bases and salts can be converted into each other using conventional conversion techniques.
Pharmaceutically acceptable salts include, for example, inorganic acid addition salts such as hydrochloride, phosphate, nitrate or sulfate, or acetate, lactate, tartrate, fumarate, maleate, oxalate. , organic acid addition salts such as succinate, methanesulfonate, and benzoate. The benzyl alcohol derivative [ ] can be administered orally or parenterally, and can also be mixed with an excipient suitable for oral or parenteral administration. The daily dosage of benzyl alcohol derivative [ ] is 5 μg/Kg to 10 mg/Kg, especially 20 μg/Kg when the purpose is to lower blood sugar.
~2mg/Kg is appropriate; on the other hand, if the purpose is to inhibit platelet aggregation, 500μg/Kg~200mg/Kg,
In particular, 1 mg/Kg to 100 mg/Kg is suitable. When the therapeutic agent for hyperglycemia of the present invention is administered orally, it can be administered in the form of tablets, powders, capsules, granules, etc., which may be supplemented with conventional excipients such as calcium carbonate, calcium phosphate, corn starch, It may contain potato starch, sugar, lactose, talc, magnesium stearate, etc. In addition, liquid preparations such as aqueous or oily suspensions, solution syrups, elixirs, etc. may also be used. In the case of parenteral administration, for example, an injection preparation or a suppository is given, and in the case of an injection preparation, it is given in the form of a solution or suspension. , corn oil, or a non-aqueous solvent, polyethylene glycol, polypropylene glycol, etc. Suppositories may contain well-known pharmaceutical carriers such as polyethylene glycols, lanolin, coconut oil, and the like. The benzyl alcohol derivative [] of the present invention has (i) 2,3,4-trimethoxyphenethylamine and the general formula (However, R represents a benzyl group) or a hydrate thereof is condensed with the general formula (However, R has the same meaning as above) α-(2,3,4-trimethoxyphenethylimino)acetophenone derivative (ii) Acetophenone derivative [] is reduced to form the general formula (However, R has the same meaning as above) α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol derivative; (iii) If necessary, Producing by optically resolving a 2-benzyloxybenzyl alcohol derivative [] to obtain its optically active form, and then (iv) catalytically reducing the racemic or optically active form of the 2-benzyloxybenzyl alcohol derivative []. I can do it. The starting material [ ] can be easily obtained, for example, by oxidizing 2-benzylacetophenone with selenium dioxide. [Chemical Abstracts, VOl.66, 46399C (1967);
Volume 72, 89963y (1970)] The condensation of 2,3,4-trimethoxyphenethylamine and phenylglyoxal derivatives or their hydrates is easily completed; for example, the compound [] prepared by mixing in the presence or absence of a catalyst. The reaction is between 0° and 50°C.
It is preferable to proceed at a temperature of . Preferred examples of reaction solvents include dimethyl sulfoxide and lower alkanols, and preferred examples of catalysts include P.
-Toluenesulfonic acid. The α-(2,3,4-trimethoxyphenethylimino)acetophenone derivative [] thus obtained can be used in the next step without being isolated from the reaction solution. The 2-benzyloxybenzyl alcohol derivative [] can be obtained by treating the compound [] with a reducing agent in a solvent. Examples of reducing agents include alkali metal borohydrides (sodium borohydride, potassium borohydride, lithium borohydride, etc.),
Mention may be made of lithium aluminum hydride, diborane or aluminum hydride. Examples of the reaction solvent include lower alkanols (methanol, ethanol, propanol, etc.), a mixture of water and lower alkanol, tetrahydrofuran, dioxane, and the like. Preferably, the reaction proceeds at a temperature of -10° to 50°C. Since the 2-benzyloxybenzyl alcohol derivative [] thus obtained is usually a racemate, it is optically resolved as necessary to obtain an optically active form. 2-
Benzyloxybenzyl alcohol derivative []
In optical resolution, a resolving agent in a solvent is reacted with a racemate to produce two types of diastereoisomer salts, and then the diastereoisomer salts are separated into their respective components by fractional crystallization. By the fractional crystallization, the poorly soluble diastereoisomer salt is obtained as crystals from the reaction mixture, and the easily soluble diastereoisomer salt is dissolved in the reaction mixture. Preferably, the fractional crystallization is carried out at a temperature of -20° to 25°C. Examples of the resolving agent include optically active tartaric acid derivatives (optically active d-camphorsulfonic acid, d-α-bromocamphorsulfonic acid, L-(-)-malic acid such as dibenzoyltartaric acid, diacetyltartaric acid, or monobenzoyltartaric acid). , l-mandelic acid, quinic acid, optically active amino acids or derivatives thereof (optically active forms such as N-acetylphenylalanine, N-carbobenzyloxyglutamic acid, glutamic acid)
Examples include. The solvent used in this separation step must have a significantly different solubility for the two diastereoisomers, and examples of solvents suitable for this purpose include water, lower alkanols (methanol, ethanol, etc.), ethyl acetate, Examples include chloroform, dimethylformamide, or a mixture thereof. Catalytic reduction of the racemic form of the 2-benzyloxybenzyl alcohol derivative [] or its optically active isomer proceeds in a solvent in a hydrogen stream in the presence of a catalyst. Preferred examples of the catalyst include platinum, platinum dioxide, palladium black, palladium on carbon, etc., and preferred examples of the solvent include lower alkanols (methanol, ethanol, etc.). Also, the reaction is
Preferably, the reaction is carried out at a temperature of 20 DEG to 50 DEG C. and a pressure of 1 to 5 atmospheres. A specific example of the synthesis of the compound of the present invention is shown below as a reference example. Reference example 1 (1) Dissolve 10 g of 2-benzyloxyacetophenone in 40 ml of dioxane, and add selenium dioxide to this.
Add a mixture of 6.4 g and 3 ml of water and reflux for 12 hours. After the reaction is completed, insoluble materials are removed by filtration and the filtrate is concentrated. The resulting residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, followed by an aqueous sodium bicarbonate solution and then with water. Thereafter, the solution is dried and the solvent is distilled off to obtain 10.5 g of 2-benzyloxyphenylglyoxal hydrate as a crude oil. (2) Dissolve 10.5 g of 2-benzyloxyphenylglyoxal hydrate (crude oil) in 30 ml of dimethyl sulfoxide, and add 9 g of 2,3,4-trimethoxyphenethylamine. The mixture was stirred at room temperature for 30 minutes and α-(2,
3,4-trimethoxyphenethylimino)-2
- Obtaining a solution of benzyloxyacetophenone in dimethyl sulfoxide. (3) Add 60 ml of ethanol to the α-(2,3,4-trimethoxyphenethylimino)-2-benzyloxyacetophenone solution obtained in (2).
After cooling on ice, 2.5 g of sodium borohydride was gradually added to the solution and stirred at room temperature for 2 hours. Then, ethanol is distilled off from the reaction mixture. The residue thus obtained is dissolved in ethyl acetate, washed with water, dried, and then the solvent is distilled off. The residue was dissolved in ethanol, made acidic with ethanolic hydrochloric acid, and then the solvent was distilled off. By recrystallizing the residue with a mixture of ethanol and ether, α-
13.1 g of (2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol hydrochloride are obtained. MP129°-130°C Yield 66% (total yield from 2-benzyloxyacetophenone) (4) α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol 5g hydrochloride and 10% palladium on carbon 1
A mixture of g and 50 ml of 90% aqueous methanol is shaken at room temperature and pressure in a hydrogen stream. After consuming the theoretical amount of hydrogen, insoluble matter is filtered off and the filtrate is concentrated.
By recrystallizing the residue thus obtained from a mixture of ethanol and ether, α-(2,
3.4 g of 3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol hydrochloride are obtained. MP133゜−134℃ Yield 85% Elemental analysis value C ₁₉ H ₂₅ O ₅ N・HCl Theoretical value C, 59.45: H, 6.83:
N, 3.65: Cl, 9.24 Actual value C, 59.29: H, 6.82:
N, 3.94: Cl, 9.55 1/2 oxalate: MP192°C (decomp) (recrystallized from ethanol) 1/2 succinate: MP157°-158°C (recrystallized from 80% aqueous ethanol) Reference example 2 ( 1) Free base obtained by neutralizing 6.8 g of α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol hydrochloride with 10% potassium carbonate and N-acetyl-L - Dissolve 3 g of phenylalanine in 15 ml of ethyl acetate, add 10 ml of ether, and let stand at room temperature for 96 hours. The precipitated crystals were collected by filtration and recrystallized from a mixture of ethyl acetate and ether to obtain l-α-(2,3,
4-trimethoxyphenethylaminomethyl)-
2-benzyloxybenzyl alcohol/N-
2.3 g of acetyl-L-phenylalanine salt is obtained. MP109° - 110°C [α] ²² _D -15.2° (C = 1.0, methanol) 2.3 g of the obtained salt is dissolved in methylene chloride and washed with a 10% aqueous potassium carbonate solution. Thereafter, the solution is dried and the solvent is distilled off. The crystals thus obtained are recrystallized from isopropyl ether to obtain 1.35 g of l-α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol. MP82゜-83℃ [α] ²² _D -43.4゜ (C = 1.0, methanol) Hydrochloride: MP142゜-144゜ (recrystallized from a mixture of ethanol and ether) [α] ²² _D -59.1゜ (C = 1.0, methanol) 1/2 oxalate: MP165° - 166°C (ethanol recrystallization) [α] ²² _D -56.8° (C = 0.5, methanol) (2) l-α-(2,3,4-trimethoxy A mixture of 0.2 g of 1/2 phenethylaminomethyl)-2-benzyloxybenzyl alcohol oxalate, 60 mg of 10% palladium carbon and 10 ml of 90% aqueous methanol was treated in the same manner as in Reference Example 1-(4) to obtain If the resulting crude crystals are recrystallized from 70% aqueous methanol,
110 mg of l-α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol 1/2 oxalate is obtained. MP193゜−194゜(decomp.) [α] ²² _D −35.4゜
(C=0.26 70% aqueous methanol). Experimental example 1 Hypoglycemic effect Mice (ddY strain, male, 6 weeks old, 4-5 mice per group)
After fasting overnight, the sample is dissolved in distilled water and administered orally (10 ml/Kg). Immediately after this, 10 ml/Kg (1 g/Kg of glucose) of 10% glucose solution (physiological saline) is injected subcutaneously. glucose administration 30
After a minute, blood was collected from the crotch vessel under ether anesthesia, and the blood was collected using the GOD method [H.
and E. Berndt: Methods of Enzymatic Analysis; E. Bergmeyer, E.D. (Academic Press, New York and London, 1963)
123] to measure blood glucose level. Maximum Tolerated Dose The drug was intraperitoneally injected into a group of 4 mice (ddY strain, male, 4 weeks old), and the maximum tolerated dose was determined based on the presence or absence of death 48 hours later. (Maximum tolerated dose: maximum dose without fatalities). These results are shown in Table 1, and show that the hypoglycemic effect of the dl form of the compound [ ] of the present invention is not only about 10 times more potent than that of phenformine, but also has a lower ratio of the effective dose to the maximum tolerated dose (therapeutic index). It was also confirmed that it was more than 30 times better than fenformin. Furthermore, it was found that the dl form of the compound [] of the present invention has almost the same hypoglycemic effect as the compound [A], but its therapeutic index is more than twice as good.

[Table] Experimental example 2 Platelet aggregation inhibitory effect (platelet aggregation measurement method) A sample dissolved or suspended in water was orally administered to rats (SD strain, male, 3 animals per group) that had been fasted for about 20 hours. One hour later, blood was collected from the abdominal aorta under ether anesthesia. Immediately after blood collection, 9 volumes of this blood and
Platelet-suspended plasma is prepared by mixing the blood with 1 volume of 3.8% trisodium citrate aqueous solution and centrifuging the blood (500 x g, 5 minutes). This plasma was adjusted to have a platelet count of 1.8×10 ⁶ platelets/mm ³ , and then added to 0.55 ml using the method of Holmsen et al.
Collagen suspension prepared using p. 254 (1969)]
Add 0.05ml to cause flocculation. This degree of cohesion
Measurement is performed using a Bryston aggregometer combined with a recorder at 37°C and 1100 rpm according to the method of Born [Nature, Vol. 194, p. 927 (1962)]. The measurement results are shown in Table 2, and it was found that the dl-form of the compound of the present invention [] has the same platelet aggregation inhibitory effect as aspirin, which is a control compound. In addition, compound [A] showed almost no platelet aggregation inhibitory effect.

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Claims (1)

[Scope of Claims] 1. A therapeutic agent for hyperglycemia comprising α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol or a salt thereof as an active ingredient. 2. The therapeutic agent for hyperglycemia according to claim 1, which is a l-type compound. 3. The therapeutic agent for hyperglycemia according to claim 1 or 2, wherein the salt is an inorganic acid salt. 4. The therapeutic agent for hyperglycemia according to claim 1 or 2, wherein the salt is an organic acid salt. 5. The therapeutic agent for hyperglycemia according to claim 1 or 2, which is in a dosage form suitable for oral administration. 6. The therapeutic agent for hyperglycemia according to claim 1 or 2, which is in a dosage form suitable for injection. 7. A hypoglycemic agent containing α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol or a salt thereof as an active ingredient. 8. A platelet aggregation inhibitor comprising α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol or a salt thereof as an active ingredient.