JPS5826350B2 - 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline luino seizouhou - Google Patents

Description

Detailed Description of the Invention] (In the formula, one of R1 and R2 is a hydroxy group protected with an alkyl group or a benzyl group, and the other is a hydroxy group protected with a hydroxy group or an alkyl group or a benzyl group, and R3 is a lower Pyrimidinyl group, triazolyl group, chenyl group, thiadiazolyl group, pyridyl group, tetrazolyl group, which may be substituted with an alkyl group,
A 1,2,3,4-tetrahydroisoquinoline derivative represented by a benzothiazolyl group or a 2-oxotetrahydrofuryl group (X means 10- or -8-, respectively) or a salt thereof is subjected to a hydrolysis reaction of a protecting group. to obtain a 6,7-hydroxy-1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof having the general formula (wherein R3 and X have the same meanings as before)・2・3・4-
This invention relates to a method for producing tetrahydroisoquinolines.

The 1,2,3,4-tetrahydroisoquinoline derivative (1) and its salts used as raw materials in this invention are new compounds, such as 1-(1-methyl-LH-tetrazol-5-yl)thiomethyl -6・7
-Dibenzyloxy-1,2,3,4-tetrahydroisoquinoline is obtained by reacting 3,4-dibenzyloxyphenethylamine with (1-methyl IH-tetrazol-5-yl)thioacetic acid chloride, then obtaining the N-(2 −
(3,4-dibenzyloxyphenyl)ethyl>2-(
(1-Methyl LH-tetrazol-5-yl)thio]acetic acid amide is treated with a dehydration condensation agent, and the resulting 1-
It can be produced by reducing (1-methyl-IH-tetrazol-5-yl)thiomethyl-6,7-dibenzyloxy-3,4-dihydroisoquinoline,
Other compounds can also be produced in the same manner.

The reaction of this invention is carried out by subjecting the 1,2,3,4-tetrahydroisoquinoline derivative (I) or its salt to a hydrolysis reaction of a protecting group.

Here, the 1,2,3,4-tetrahydroisoquinoline derivative is represented by the above general formula (1), has a hydroxy group protected with an alkyl group or a benzyl group as one of R1 and R2, and has a hydroxy group or A hydroxy group protected by an alkyl group or a benzyl group is R1
and R3 has a pyrimidinyl group, triazolyl group, chenyl group, thiadiazolyl group, pyridyl group, tetrazolyl group, benzothiazolyl group or 2-oxotetrahydrofuryl group which may be substituted with a lower alkyl group as the other of R2. , -〇- or -S as X.

Here, examples of the alkyl group in the hydroxy group protected by an alkyl group include methyl ethyl, propyl, isopropyl, and the like.

In addition, pyrimidinyl group, triazolyl group, chenyl group, thiadiazolyl group, pyridyl group, tetrazolyl group, benzothiazolyl group and 2-
The oxotetrahydrofuryl group may be substituted with lower alkyl groups such as methyl, ethyl, propyl, inpropyl, butyl, inbutyl, tertiary butyl, pentyl, hexyl and the like.

In addition, as the hydrochloric acid of ■.2.3.4-tetrahydroisoquinoline derivative (■), inorganic acid salts such as hydrochloride, sulfate, hydrobromide, acetate, picrate, oxalate,
Examples include organic acid salts such as tartrates.

1,2,3,4-tetrahydroisoquinoline derivative (1
) or its salts, hydrochloric acid, hydrobromic acid, boron trichloride, boron tribromide, aluminum chloride, pyridine hydrochloride, pyridine hydrobromide, etc. Pyridine-hydrogenide, lithium iodide,
Examples include a method of using tertiary butyl thiolithium alone or in combination. Among these, when using a liquid type, no particular solvent is required, but when a solvent is used, dichloromethane is the solvent. Although commonly used, any other solvent that does not adversely affect this reaction can be used.

The temperature of this reaction is not particularly limited, and is appropriately selected depending on the type of hydroxy protecting group, the type of hydrolysis method, etc.

The target substance (II) obtained in this way can be prepared using conventional methods as required, including inorganic acid salts such as hydrochloride, sulfate, and hydrobromide, and organic acids such as acetate, tartrate, and picrate. It may also be introduced into salts such as salt.

The object substance (II) of this invention and its salts are new substances, and have, for example, antispasmodic effects, vasodilatory effects, etc.
It is useful as a medicine.

Furthermore, the target substance of this invention (Kama Tokuko Publication No. 43-151)
It has far superior pharmacological action compared to the known compound described in Publication No. 93.

This indicates that the object substance (II) of this invention and the
This is supported by the following pharmacological test results comparing the antispasmodic effect with the known compound described in Example 1 (hereinafter referred to as known compound) described as a particularly preferred compound in Publication No. 3-15193.

In other words, the test results below demonstrate that the target substance of the present invention (... has a far superior pharmacological effect even compared to the known compound described in Japanese Patent Publication No. 15193-1982, which has the best pharmacological effect). It shows that there is.

Test method Mongrel dogs weighing 8 to 16 kg, which had been fasted for 24 hours, were treated with urethane (1.5 P/kg) and morphine (15 m
9/kg).

Insert a balloon into the jejunum, 10c'rILH20
, and connected it to a tension meter.

Changes in movement were mainly observed by changes in movement amplitude, but the number of movements was also taken into consideration in the evaluation.

Select the highest value among the changes over time, calculate the rate of change, and
The % inhibition amount (ED50) (mcg/ky) was determined.

Next, the present invention will be explained with reference to examples.

Example 1 ■-(1-Methyl-IH-tetrasol-5yl)thiomethyl-6,7-dibenzyloxyto 2,3,4-tetrahydroisoquinoline 300 m 9.99% ethanol/
A mixture of L/rnl and 3rrLl of concentrated hydrochloric acid is heated to reflux for 3 hours.

After the reaction, the solvent is distilled off from the reaction solution, ethanol is added to the residue, and the mixture is dried under reduced pressure.

After adding acetone to the residue and crystallizing it, the crystals were recrystallized from a mixture of ethanol and ether, resulting in mp 21.
220 ml of 1-(1-methyl-IH-tetrazol-5-yl)thiomethyl-6,7-cyhydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride at 5 DEG to 216 DEG C. (decomposition) are obtained.

Example 2 l-(1-Methyl-IH-tetrasol-5-yl)thiomethyl-6,7-simethoxy 1,2,3,4-tetrahydroisoquinoline 05'? anhydrous dichlormeth：/
Dissolve in 10 ml and add 3 to this solution while cooling to -60°C.
A solution of 2.41 boron bromide dissolved in 5 ml of anhydrous dichloromethane is added dropwise, and then the temperature of the reaction solution is raised to room temperature overnight.

Add 5 ml of methanol to the reaction solution under ice-water cooling, and add excess 3.
After decomposing boron bromide, it is concentrated under reduced pressure.

Ethanol is added to the residual oil to crystallize it, and when it is poured into a door car, 1-(1-methyl-IH-tetrazol-5-yl)thiomethyl-6,7-cyhydroxy-i,2,3,4
-Tetrahydroisoquinoline hydrobromide 0.25P is obtained.

The hydrochloride salt was converted into the hydrochloride salt by a conventional method and recrystallized from ethanol/ether to give colorless crystals of 1-(1-methyl-IHtetrazol-5-yl)thiomethyl-6,7-dihydrochloride, mp 215-216°C (decomposition). Seat 2, 3, 4
- Tetrahydroisoquinoline hydrochloride is obtained.

The following compound is obtained in the same manner.

(111-(2-pyrimidinyl)thiomethyl-6,7-
Dihydroxyate 2,3,4-tetrahydroisoquinoline hydrochloride, mp 204-205°C (decomposition).

(2) l-(5-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-6,7-dihydroxyate 2,3,4-tetrahydroisoquinoline hydrochloride, mp
229-231'C(3)1-(2-chenyl)thiomethyl-6,7dihydroxy-1.2,3,4-tetrahydroisoquinoline hydrochloride, mp 177-178°C.

(4) 1-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-6,7-dihydroxyate 2
・3,4-tetrahydroisoquinoline dihydrochloride, mp
199-201'C (decomposition).

(5) 1-(4-pyridyl)oxymethyl-6,7 dihydroxyate 2,3,4-tetrahydroisoquinoline dihydrochloride, mp 250-255°C (decomposition).

(6) 1-(1,2,5-thiadiazol-3-yl)
Oxymethyl-6,7-sihydrox7-1,2,3,4
-Tetrahydroisoquinoline hydrochloride, mp 252°C (decomposed).

(7J1-(1,3,4-thiadiazol-2-yl)
Thiomethyl-6,7-dihydroxyte 2,3,4-tetrahydroisoquinoline hydrochloride, mp 234°C (2 decompositions).

(8) 1-(2-benzothiazolyl)thiomethyl 6,7
-Sihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, mp 170-172°C.

(9) 1-(2-oxotetrahydrofuran-3-yl)thiomethyl-6,7-dihydroxyate 2,3,4-
Tetrahydroisoquinoline hydrochloride, mp236-239
°C (decomposition).

Claims (1)

[Scope of Claims] 1 General formula (wherein R1 and R2 are a hydroxy group protected with an alkyl group or a benzyl group, and the other is a hydroxy group protected with a hydroxy group or an alkyl group or a benzyl group, R3 is a pyrimidinyl group, triazolyl group, chenyl group, thiadiazolyl group, pyridyl group, tetrazolyl group, benzothiazolyl group or 2-oxotetrahydrofuryl group, which may be substituted with a lower alkyl group, and X is 〇- or -8-, respectively. A 1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof represented by the following formula is subjected to a hydrolysis reaction of the protecting group to form 6 represented by the general formula (wherein R3 and X have the same meanings as before).・7-cyhydroxyl 1 ・2・3・4-
6,7-hydroxyl-1,2,3-, which is characterized by obtaining a tetrahydroisoquinoline derivative or a salt thereof.
Method for producing 4-tetrahydroisoquinolines.