JPS6220189B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (However, R is a hydrogen atom or a lower alkyl group,
represents a hydroxyl group, a lower alkoxy group, a benzyloxy group, or a halogen atom) or a pharmaceutically acceptable acid addition salt thereof, and a method for producing the same.

The compounds [ ] of the present invention are all new compounds and are useful pharmaceutical compounds having excellent hypoglycemic and platelet aggregation inhibiting effects. For example, α−
(3,4-methylenedioxyphenethylaminomethyl)-2-hydroxybenzyl alcohol, α
-(3,4-methylenedioxyphenethylaminomethyl)-2-methoxybenzyl alcohol, α
-(3,4-methylenedioxyphenethylaminomethyl)-2-chlorobenzyl alcohol, α-
[(α-Methyl-3,4-methylenedioxyphenethylamino)methyl]-2-methoxybenzyl alcohol, α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]- 2-chlorobenzyl alcohol and the like have a hypoglycemic effect about 100 times more than that of phenformin, a commercially available hypoglycemic agent.

As the compound [ ] of the present invention, for example, the symbol R
The group represented by is a hydrogen atom, a methyl group, an ethyl group,
n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, and the group represented by the symbol X is a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, butoxy group,
Examples include compounds having a benzyloxy group, a chlorine atom, a bromine atom, and the like. Among these compounds,
Preferred compounds include α-(3,4-methylenedioxyphenethylaminomethyl)-2-hydroxybenzyl alcohol, α-(3,4-methylenedioxyphenethylaminomethyl)-2-ethoxybenzyl alcohol , α-(3,4-methylenedioxyphenethylaminomethyl)-2-
n-butoxybenzyl alcohol, α-(3.4
-methylenedioxyphenethylaminomethyl)-
2-chlorobenzyl alcohol, α-(3・4-
methylenedioxyphenethylaminomethyl)-2
-Methoxybenzyl alcohol, α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-methoxybenzyl alcohol, α-[(α-methyl-3,4-methylenedioxyphene) enethylamino)methyl]-2-chlorobenzyl alcohol, α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2
-Hydroxybenzyl alcohol, α- [(α-
n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol, α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2- Benzyloxybenzyl alcohol, α-[(α-n・
Butyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol, α-(3,4-methylenedioxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol, etc. .

When the group R is a lower alkyl group, the compound [ ] of the present invention has two asymmetric carbon atoms in the molecule, and therefore has two types of diastereoisomers, and each of these isomers has two types of optical Although active forms exist, the present invention includes the compounds of either.

The compound [ ] of the present invention can be produced by the method shown in the following reaction formula.

(However, X' represents a lower alkoxy group, a benzyloxy group, or a halogen atom, and R has the same meaning as above.) That is, 2-substituted phenylglyoxal [] or its hydrate ['] and 3,4- Methylenedioxyphenethylamine compounds []
and subjected to a condensation reaction to obtain an α-substituted imino-2-substituted-acetophenone derivative [ ], and the carbonyl group and carbon-nitrogen double bond of this compound were reduced to a hydroxymethylene group and a carbon-nitrogen single bond, respectively. to prepare α-(3,4-methylenedioxyphenethylaminomethyl)-2-substituted-benzyl alcohol [-a], and then compound [-a]
Compound [-b] can be produced by subjecting (X'=OCH ₂ C ₆ H ₅ ) to debenzylation by subjecting it to a catalytic reduction reaction. In addition, compounds [-a] and [-
b], when the group R is a lower alkyl group, there are two asymmetric carbon atoms in each molecule, so two types of diastereoisomers exist, and these can be separated by, for example, recrystallization. death,
It can also be isolated.

The condensation reaction between compound [] or ['] and compound [] can be carried out in an appropriate solvent in the presence or absence of a catalyst. Examples of the catalyst include tosylic acid. The reaction proceeds smoothly even at room temperature, and the compound [] is obtained in good yield. The compound [] obtained here can be isolated and purified, but since it is generally unstable, it is convenient to use it in its crude form as a raw material for the next step.

The reaction of reducing the carbonyl group and carbon-nitrogen double bond of the compound [] thus obtained is carried out using a reducing agent commonly used in this type of reduction reaction, such as sodium borohydride, in an appropriate solvent. It is preferable to carry out. In addition to the above-mentioned reducing agents, lithium aluminum hydride, alane, diborane, etc. can also be used. This reaction also proceeds smoothly at room temperature, and compound [-a] can be produced in good yield.

The compound [-a] obtained here can be separated and purified into each diastereoisomer by recrystallization using a suitable recrystallization solvent such as methanol, ethanol, aqueous acetone, etc.

The compound [-a] obtained as described above can be easily obtained by dissolving the free base or acid addition salt thereof in a suitable solvent and stirring in a hydrogen gas stream in the presence of a catalyst according to a conventional method of catalytic reduction. It can be debenzylated to As the catalyst, platinum-based or palladium-based catalysts such as platinum, platinum oxide, palladium black, palladium on carbon, etc. can be used. As a starting material for this step, for example, a theastereoisomer of compound [-a] or a mixture thereof may be used.
The reaction proceeds smoothly at room temperature and pressure, and the corresponding diastereoisomers of compound [-b] or mixtures thereof can be obtained in good yields.

When the compound [-b] obtained here is a mixture of diastereoisomers, it can be separated and purified into each diastereoisomer by recrystallizing with a suitable recrystallization solvent, such as aqueous methanol.

When the compound of the present invention thus prepared is used as a medicine, the appropriate dosage for adults is 1 μg to 10 mg/Kg of free base per day, particularly preferably about 4 μg to 2 mg/Kg.
In addition, the compound of the present invention [] may be an inorganic acid such as hydrochloric acid or sulfuric acid, or succinic acid, citric acid, fumaric acid, etc.
It can also be used as an acid addition salt with an organic acid such as maleic acid. Examples of dosage forms include powders, tablets, capsules, liquids, emulsions, suspensions,
Both injections and the like can be used.

Production example of raw material amine A mixed solution of 12.7 g of piperonal, 14.9 g of 1-nitro-n.pentane, 0.7 ml of acetic acid, 0.6 ml of n.butylamine and 50 ml of toluene is refluxed for 21 hours. Furthermore, 2.1 g of 1-nitro-n pentane was added, and 18
Reflux for an hour. After cooling, the reaction solution was washed with an acidic sodium sulfite aqueous solution and water, and after drying, the solvent was distilled off to obtain 1-
12.6g of (3,4-methylenedioxyphenyl)-2-nitro-n-hexene-1 as brown oil
get. Yield 60%.

IRν ^lig _nax (cm ^-1 ): 1685, 1645, 1617, 1600 Massm/e: 249 (M ⁺ ) 11.5 g of this product (hereinafter referred to as
50 ml of THF solution was added dropwise to a solution of 5.6 g of lithium aluminum hydride in 50 ml of THF under ice cooling for 30 minutes, and then the mixture was refluxed for 3 hours. to the reaction solution
After adding 100 ml of THF, 5 ml of water, 5 ml of a 40% caustic soda aqueous solution, and 5 ml of water were sequentially added dropwise under ice cooling, and after further stirring at room temperature for 1 hour, insoluble matter was filtered off. After drying the filtrate, the solvent is distilled off and the residue is distilled.
7.2 g of α-n.butyl-3,4-methylenedioxyphenethylamine are obtained as a colorless oil.
bp.163-165℃/9mmHg, yield 71%.

IRν ^lig _nax (cm ^-1 ): 3620, 3360, 1600 Massm/e: 222 (M ⁺ +1) NMR (CDCl ₃ ) δ: 0.7-1.6 (m, 11H), 2.1-
3.1 (m, 3H), 5.90 (s, 2H), 6.68 (s,
3H, aromatic hydrogen) Example 1 (1) 2-benzyloxyphenylglyoxal hydrate (3 g of 2-benzyloxyacetophenone, 2.1 g of selenium dioxide, dioxane
dimethyl sulfoxide (hereinafter referred to as DMSO) 9.
ml, add 2.06 g of 3,4-methylenedioxyphenethylamine, and stir at room temperature for 30 minutes. A DMSO solution of α-(3,4-methylenedioxyphenethylimino)-2-benzyloxyacetophenone is obtained.

(2) Add 18 ml of ethanol to the solution obtained in (1), and add a small amount of 0.7 g of sodium polyhydride while cooling on ice. Thereafter, the reaction was completed by stirring at room temperature for 2 hours. Ethanol is distilled off from the reaction solution, the residue is dissolved in ethyl acetate, washed with water and dried, the solvent is distilled off, the resulting oily residue is converted into a hydrochloride salt, and recrystallized from ethanol to obtain α-( 3.
3.5 g of 4-methylenedioxyphenethyleraminomethyl)-2-benzyloxybenzyl alcohol hydrochloride was obtained.

mp.169-170℃, yield 65.5%.

Example 2 1.5 g of α-(3,4-methylenedioxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol (hydrochloride) obtained in Example 1, 0.45 g of 10% palladium on carbon and 90% water content Stir a mixture of 30 ml of ethanol at room temperature and pressure in a hydrogen stream. After absorbing the theoretical amount of hydrogen, the catalyst is filtered off,
The filtrate was concentrated and the residue was recrystallized from a mixture of ethanol and ether to obtain 1.1 g of α-(3,4-methylenedioxyphenethylaminomethyl)-2-hydroxybenzyl alcohol, hydrochloride.

mp.178-179℃, yield 93%.

Examples 3 to 6 In the same manner as in Example 1, the following compounds were prepared from the corresponding phenylglyoxal derivatives.

(3) α-(3,4-methylenedioxyphenethylaminomethyl)-2-methoxybenzyl alcohol hydrochloride, mp.173-174℃ (ethanol/
ether), yield 67%.

(4) α-(3,4-methylenedioxyphenethylaminomethyl)-2-ethoxybenzyl alcohol hydrochloride, mp, 189-190°C (methanol), yield 69%.

(5) α-(3,4-methylenedioxyphenethylaminomethyl)-2-n-butoxybenzyl alcohol hydrochloride, mp. 139-140°C (ethanol/ether), yield 68%.

(6) α-(3,4-methylenedioxyphenethylaminomethyl)-2-chlorobenzyl alcohol hydrochloride, mp. 145-147°C (ethanol/ether), yield 55%.

Example 7 (1) Crude 2-methoxyphenylglyoxal hydrate prepared from 4.5 g of 2-methoxyacetophenone was dissolved in 15 ml of DMSO, and 4.83 g of α-methyl-3,4-methylenedioxyphenethylamine was added to the solution. Add g and stir at room temperature for 30 minutes. A DMSO solution of α-(α-methyl-3,4-methylenedioxyphenethylimino)-2-methoxyacetophenone is obtained.

(2) Add 30 ml of ethanol to the solution obtained in (1), and add a small amount of 1.73 g of sodium borohydride while cooling on ice. After stirring at room temperature for 2 hours, (2) of Example 1
The crude α-[(α-methyl-
3,4-methylenedioxyphenethylamino)
methyl]-2-methoxybenzyl alcohol is obtained.

This product is converted into a hydrochloride salt and is repeatedly recrystallized from a mixture of ethanol, ether, or aqueous acetone.
Two hydrochloride salts are obtained.

Low melting point hydrochloride mp.152-153℃ (hydrated acetone), yield 54.5% High melting point hydrochloride mp.173-175℃ (ethanol/ether), yield 13.7% Example 8 (1) 2-chloroacetophene Crude 2-chlorophenylglyoxal hydrate prepared from 4.64 g of non-alcoholic acid was added to 15 ml of DMSO, and α-methyl-3.4
- Add 4.83 g of methylenedioxyphenethylamine and stir at room temperature for 30 minutes. α−
(α-methyl-3,4-methylenedioxyphenethylimino)-2-chloroacetophenone
Obtain a DMSO solution.

(2) Add 30 ml of ethanol to the solution obtained in (1), add 1.73 g of sodium borohydride in small portions under ice cooling, and stir at room temperature for 2 hours after addition. After the reaction, the crude α
-[(α-Methyl-3,4-methylenedioxyphenethylamino)methyl]-2-chlorobenzyl alcohol is obtained.

This product is converted into a hydrochloride salt and recrystallized repeatedly from ethanol or methanol to obtain two types of hydrochloride salts.

High melting point hydrochloride mp.202-203℃ (decomposition) (methanol), yield 50
%.

Low melting point hydrochloride mp.188-189℃ (decomposition) (ethanol), yield 17
%.

Example 9 (1) 3.45 g of α-methyl-3,4-methylenedioxyphenethylamine was added to 15 ml of DMSO solution of crude 2-benzyloxyphenylglyoxal hydrate prepared from 5.0 g of 2-benzyloxyacetophenone. Add and stir at room temperature for 30 minutes. A DMSO solution of α-(α-methyl-3,4-methylenedioxyphenethylimino)-2-benzyloxyacetophenone is obtained.

(2) Add 30 ml of ethanol to the solution obtained in (1), and add a small amount of 1.25 g of sodium borohydride while cooling on ice. Stir for an additional 2 hours at room temperature. After the reaction, the same post-treatment as in Example 1 (2) was carried out to obtain crude α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol. Obtained as an oil.

By converting this product into hydrochloride and recrystallizing it from ethanol (the recrystallized filtrate is called the mother liquor), α
-2.37 g of [(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol hydrochloride was obtained.
mp.185-187℃, yield 27%.

The free base of this product shows a mp. of 107.5-108°C (ethyl acetate/n-hexane), and the 1/2 fumar hydrochloride shows a mp. of 170-171°C (decomposition) (ethanol/ethyl acetate).

Meanwhile, the mother liquor was concentrated and the residue was used as the free base.
Next, this was made into a fumarate salt and recrystallized from methanol to form α-[(α-methyl-
3.02 g of 3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol, 1/2 fumarate was obtained. mp.169～
170℃ (decomposition), yield 33%.

The free base of this product exhibits a mp. of 78 to 79.5°C (ethyl acetate/n-hexane).

Example 10 α-[(α-methyl-3,4-
methylenedioxyphenethylamino)methyl]-
From 1.26 g of 2-benzyloxybenzyl alcohol hydrochloride (mp. 185-187℃), 0.3 g of 10% palladium on carbon, 2 ml of water and 40 ml of ethanol,
In the same manner as in Example 2, α-[(α-methyl-3.
0.99 g of 4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol hydrochloride is obtained. mp.171-172℃ (decomposition) (ethanol/ether), yield 92%.

1/2 oxalate of this product is mp.199-200℃ (decomposition)
(methanol).

Example 11 α-[(α-methyl-3,4-
methylenedioxyphenethylamino)methyl]-
2-benzyloxybenzyl alcohol (mp.78
~79.5℃) 140mg, oxalic acid 14mg, 10% palladium.
α-[(α-methyl-
3,4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol, 1/2
Obtain 102 mg of oxalate. mp.205-206℃ (decomposition) (methanol), yield 90%.

Example 12 (1) To 15 ml of DMSO solution of crude 2-benzyloxyphenylglyoxal hydrate prepared from 4.9 g of 2-benzyloxyacetophenone, α-n.butyl-3,4-methylenedioxyphenethylamine was added. Add 4.23g and stir at room temperature for 30 minutes. α-(α-n・Butyl-3・4
-methylenedioxyphenethylimino)-2-
Obtain a DMSO solution of benzyloxyacetophenone.

(2) Add 30 ml of ethanol to the solution obtained in (1), and add a small amount of 1.21 g of sodium borohydride under ice cooling. Stir occasionally for 2 hours at room temperature. After the reaction, the same post-treatment as in Example 1 (2) was carried out to obtain crude α-[(α-n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl. Get alcohol.

By using this product as oxalate and recrystallizing it from methanol (the recrystallized filtrate is called the mother liquor), α
-3.5 g of [(α-n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol 1/2 oxalate is obtained.
mp.169-171℃ (decomposition), yield 40%.

The hydrochloride of this product shows mp.148℃ (decomposition) (ethanol/ether).

Meanwhile, the mother liquor was concentrated and the residue was used as the free base.
Next, by converting it into a hydrochloride and recrystallizing it from ethanol, α-[(α-n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2
-Benzyloxybenzyl alcohol/hydrochloride
Obtain 2.09g. mp.180-182℃ (decomposition), yield 23
%.

Example 13 α-[(α-n・butyl-3・
4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol,
1/2 oxalate [mp.169-171℃ (decomposition)] 1.1g, oxalic acid 200mg, 10% palladium on carbon 200mg, water 5
ml and 60 ml of ethanol, α-[(α-n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol, 1/2 oxalic acid Obtain 760 mg of salt. mp.212-213℃ (decomposition) (methanol), yield
85%.

Example 14 α-[(α-n・butyl-3・
4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol
α-[(α-
420 mg of n.butyl-3.4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol hydrochloride was obtained. mp.198~190℃
(decomposition) (ethanol), yield 74%.

Claims (1)

[Claims] 1. General formula (However, R is a hydrogen atom or a lower alkyl group,
represents a hydroxyl group, a lower alkoxy group, a benzyloxy group, or a halogen atom) or a pharmacologically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein in the general formula [], R is a hydrogen atom. 3. The compound according to claim 1, wherein in the general formula [], R is a methyl group. 4. The compound according to claim 1, wherein in the general formula [], R is an ethyl group. 5. The compound according to claim 1, wherein in the general formula [], R is a propyl group which may be branched. 6. The compound according to claim 1, wherein in the general formula [], R is a butyl group which may be branched. 7. The compound according to claim 1, wherein in the general formula [], X is a hydroxyl group. 8. The compound according to claim 1, wherein in the general formula [], X is a lower alkoxy group. 9. The compound according to claim 1, wherein in the general formula [], X is a benzyloxy group. 10. The compound according to claim 1, wherein in the general formula [], X is a halogen atom. 11 In the general formula [], X is a methoxy group,
9. The compound according to claim 8, which is an ethoxy group or a butoxy group. 12. The compound according to claim 10, wherein in the general formula [], X is a chlorine atom. 13. The compound according to claim 1, which is α-(3,4-methylenedioxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol. 14. The compound according to claim 1, which is α-(3,4-methylenedioxyphenethylaminomethyl)-2-hydroxybenzyl alcohol. 15. The compound according to claim 1, which is α-(3,4-methylenedioxyphenethylaminomethyl)-2-ethoxybenzyl alcohol. 16. The compound according to claim 1, which is α-(3,4-methylenedioxyphenethylaminomethyl)-2-n-butoxybenzyl alcohol. 17. The compound according to claim 1, which is α-(3,4-methylenedioxyphenethylaminomethyl)-2-chlorobenzyl alcohol. 18. The compound according to claim 1, which is α-(3,4-methylenedioxyphenethylaminomethyl)-2-methoxybenzyl alcohol. 19. The compound according to claim 1, which is α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-methoxybenzyl alcohol. 20. The compound according to claim 1, which is α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-chlorobenzyl alcohol. 21 Claim 1 which is α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol
Compounds described in Section. 22. The compound according to claim 1, which is α-[(α-n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2-hydroxybenzyl alcohol. 23. The compound according to claim 1, which is α-[(α-methyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol. 24. The compound according to claim 1, which is α-[(α-n.butyl-3,4-methylenedioxyphenethylamino)methyl]-2-benzyloxybenzyl alcohol. 25 General formula (However, X′ represents a lower alkoxy group, a benzyloxy group, or a halogen atom.) A phenylglyoxal derivative or its hydrate represented by the general formula (However, R represents a hydrogen atom or a lower alkyl group) by condensation reaction with an amino compound represented by the general formula (However, R and X' have the same meanings as above.)
The α-substituted iminoacetophenone derivative represented by General formula characterized by subjecting to reduction reaction (However, X represents a hydroxyl group, a lower alkoxy group, a benzyloxy group, or a halogen atom, and R has the same meaning as above) or a pharmacologically acceptable acid addition thereof Salt manufacturing method.