JPS6058919B2 - Phthalidyl-isoquinoline derivatives, their production methods and pharmaceuticals containing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to phthalidyl-isoquinoline derivatives, processes for their production and their pharmaceutical uses, particularly in the treatment of allergic episodes.

NOSCAPINE is well known in the art and is an alkaloid commonly used for its antitussive properties.

A derivative structurally similar to the compound, namely tritoqualin (
TritOquaInel French Patent No. 1295309
) is known to have anti-allergic effects [HAH Netal, Ar'Z. FORSCH. ? 1
490 (1970)].

It has been found that new compounds belonging to the above type have excellent pharmacological activity and are useful for this type of therapeutic use. The compounds according to the present invention are phthalidyl-isoquinoline derivatives represented by the following general formula (1), diastereomers thereof, and pharmacologically acceptable acid addition salts thereof.

[In the formula, R1, R2, R4, R5 and R6 are each a lower alkoxy group, R3 is a hydrogen atom or a lower alkoxy group, and R
7 each represents a lower alkyl group.

] In the above, the terms lower alkyl and lower alkoxy refer to groups having up to 4 carbon atoms, in particular methyl and ethyl groups and methoxy and ethoxy groups.

The compound of the present invention represented by the above general formula (1) is produced by reducing the corresponding nitro derivative represented by the general formula [in the above formula, R1 to R7 are the same as those in the general formula (1)].

The nitro derivative represented by the above general formula (■) has the general formula [wherein R1 to R3 and R7 are the same as those in the general formula (1)].

Xθ is 0H-, CI-, Br-, I- or CH3SO4
and the ammonium salt of substituted dihydro-isoquinoline represented by the general formula [indicating R4 to R6
are obtained by a condensation reaction with a trialkoxy-phthalide represented by the same formula as those in general formula (1).

The reaction is carried out in a basic solvent and preferably in a lower alcohol at a temperature below the boiling point of the solvent.
The compound represented by the above general formula (■) is a known compound [see French Patent No. 12953].

The ammonium salt of substituted dihydro-7 isoquinoline represented by the above general formula (■) is partially known and can be obtained by adding the compound represented by R71X to the compound represented by the above general formula (■) according to a conventional method. can. The compound represented by the above general formula (■) is produced by formalizing substituted phenylethylamine and then cyclizing it according to the following reaction scheme. [In each of the above formulas, R1 to R3 are the same as above] The formalization reaction is carried out using formic acid and acetic anhydride in a temperature range of 25 to 80°C according to a conventional method.

Further, the cyclization reaction can be carried out using phosphorus oxychloride at a temperature of 50 to 100°C. Intermediates and production examples for producing the compounds of the present invention are listed below in Example A, and production examples of the compounds of the present invention are listed in Examples 1 and 2.

Example A 2-methyl-6●7●8-trimethoxy3,4-dihydroisoquinolinium iodide (ammonium salt of the compound represented by general formula (■); R1=R2=R3=0
CH3, R7=CH3 and X=I) (a) 2-formyl-3●4●5-trimethoxy, phenylethylamine 3,4,5-trimethoxyphenylethylamine1.
422 kg were slowly added into a mixture of 2.185 k9 of 98% formic acid and 1.728 k9 of acetic anhydride, and the temperature was reduced to approximately 5 k9.
Hold at 0'C.

After maintaining the reaction bath at the above temperature for about 32 hours, the formic acid monoacetic acid mixture and excess anhydride are distilled off. The formylated product 1.734k9 thus obtained is subjected to the subsequent reaction in an unpurified state. (b) 6 ◆ 7 The mixture is maintained at the above temperature for about 2 hours.

The reaction mixture was then mixed with 503. After cooling to below ℃, add water 5.
1e and 1.8 kg of crushed ice. The acidic aqueous layer is separated, made alkaline using 40% aqueous sodium hydroxide solution, and extracted with toluene. Distill toluene under reduced pressure to remove 6.
7●8-trimethoxy3●4-dihydro4t soquinoline is obtained. This is subjected to the next reaction unpurified.
(c) 2-methyl-6●7,8-trimethoxy3●4
-Dihydroisoquinolinium iodide 6, 7, 8-
Trimethoxy 3,4-dihydroisoquinoline 1.9
K9 and acetone 7e are placed in a reaction vessel and then 2.1 kg of methyl iodide is added while maintaining the temperature below 50°C.

The reaction mixture is heated under reflux for 30 minutes, an additional 200y of methyl iodide is added and the mixture is refluxed for a further approximately 1 hour. The reaction mixture was cooled to below 20°C, the iodomethylate was dried by suction, washed with a small amount of acetone, and 2.3
Obtain objective 00k9.

Example 1 2-methyl-6●7,8-trimethoxy1-[4,5
・6-triethoxy7-amino-3-phthalidyl]-
1,2,3,4-tetrahydroisoquinoline (code number 458L) (a) 2-methyl-6●7,8-trimethoxy1-[4,5,6-triethoxy7-nitro-3-phthalidyl]-1,2・3●4-Tetrahydroisoquinoline 2-methyl-6,7,8-trimethoxy 3,4-dihydroisoquinolinium iodide (J.
Chem. SOc. l95l, 1150) 235V (0
．． 647 mol), 201.4 V of 4,5,6-triethoxy-7-nitrophthalide and 1079 V of potassium carbonate are added in 1.240' of methanol.

After stirring for two hours at a temperature below the boiling point of the solvent, 730 ml of water is added to crystallize the reaction solution. The crystals are separated in a furnace, washed with water and dried to obtain C27H34OlON227Oy. Melting point 116
~140NC]) 2-Methyl-6●7,8-trimethoxy1-[4
・5●6-triethoxy7-amino-3-phthalidyl]1●2●3,4-tetrahydroisoquinoline (
The nitro derivative 270y obtained in a) was added to ethanol 1.5701? in an autoclave. and Rane Nickel 21
Add to f.

Hydrogen gas is introduced under w atm and the reaction is heated to 65° C. with stirring. After 1 hour and 4 hours, the theoretical amount of hydrogen is absorbed.

The solution is filtered after cooling. Ethanol was distilled off under reduced pressure, the residue was dissolved in methanol 0.6e, and potassium hydroxide tablets 60
y is added and the mixture is heated to reflux with stirring for 1 hour. The mixture is cooled to precipitate crystals. 2-methyl-6●7●8
-trimethoxy 1-(4, 5, 6-triethoxy 7
-Amino-3-phthalidyl)-1,2,3●4-tetrahydroisoquinoline (194.5 da) (yield 76%) was obtained.

It has a white crystalline form and a melting point of 144°C, and shows a single spot on thin layer chromatography. Example 2 2-Methyl-6●7-dimethoxy1-[4.5.6-
Triethoxy7-amino-3-phthalidyl]-1,2
・3,4-tetrahydroisoquinoline (a) 2-methyl-6,7-dimethoxy1-[4●5,6-triethoxy7-nitro-3-phthalidyl]-1,2,3,4
- 200y (0
．． 6 mol), 4●186 y of 5.6-triethoxy-7-nitrophthalide and 100 y of potassium carbonate are added to 1.5 f of methanol with stirring.

The reaction mixture is stirred for 24 hours at a temperature below the boiling point of the solvent, then allowed to cool, and 900 ml of water is added to precipitate crystals. The solution is filtered and the filtered material is washed with methanol and then water.
After drying, cream-colored crystals 247y with C=H32O9N2 are obtained. (b) 2-methyl-6●7-dimethoxy1-[4,5,6-triethoxy7-amino-3
-phthalidyl]-1●2●3●4-Tetrahydroisoquinoline First, a Zn-Cu conjugate is prepared.

That is, 350 V of zinc powder was mixed with 50 V of 1% sodium hydroxide aqueous solution.
The solution is then separated by decantation and the solid is then washed twice with water and the water is decanted after each wash. Next, copper sulfate 17q
Then, 700 ml of a solution prepared by dissolving 7 ml of concentrated sulfuric acid in 700 mL of water is added to the water-washed powder. The mixture is shaken once and the supernatant liquid is decanted.
Next, 500ml of water was added to the Zn-Cu bond prepared above.
Then, a solution prepared by dissolving the nitro derivative 167y obtained in (a) above in acetic acid 1e is gradually added thereto.

All operations are performed under stirring. Stirring is continued at 20-25°C for an hour. Separate the conjugate, partially concentrate the solution under vacuum, and add 2.5 e of water. The resulting solution is extracted three times with chloroform. The chloroform extracts are combined and washed with aqueous sodium bicarbonate and then water.

The extract is dried by shaking with anhydrous sodium sulfate and concentrated in vacuo. The residue is dissolved in 500 ml of methanol, 50 y of potassium hydroxide tablets are added and the reaction mixture is heated under reflux for 1 hour while stirring.

It is then cooled and crystallized. Thus 2-methyl-6
-7-dimethoxy-1-[4,5,6-triethoxy-7-amino-3-phthalidyl]-1●2●3●4-tetrahydroisoquinoline 115y is isolated in the form of white crystals with a melting point of 143°C. Various pharmacological tests were conducted on the compounds of the present invention as described below.

The compounds of the present invention were well tolerated by the test animals at their therapeutic doses.

Toxicity was determined according to conventional methods.

Compound 458L of the present invention upon oral administration to mice
The LD5O of the compound was approximately 6 da 1k9, and chronic toxicity tests on mice showed that the compound was well tolerated. The compound of the present invention, 458L, was found to have a particularly inhibitory effect on the action of histidine decarboxylase enzyme in vivo, and to block the in-vivo formation of histamine, which is well known to have pathological effects on animals and humans. .

The activity of the compound of the present invention, 458L, was compared with that of tritoqualin.

Tritoqualin is the only known substance pharmacologically utilized for this purpose. As a technique for measuring histidine decarboxylase activity in the kidneys of Mo.
B. KOsmickietal) [J.
PharmaOl. Parisl97 table foot, 3, 33
1-342].

Claims (1)

[Claims] 1 General formula (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R
_1, R_2, R_4, R_5 and R_6 each represent a lower alkoxy group, R_3 represents a hydrogen atom or a lower alkoxy group, and R_7 represents a lower alkyl group. Phthalidyl-isoquinoline derivatives represented by the above, diastereomers thereof, and pharmacologically acceptable acid addition salts thereof. 2 R_1, R_2, R_3, R_4, R_
The compound according to claim 1, wherein the alkoxy group represented by 5 and R_6 is a methoxy group or an ethoxy group. 3. The compound according to claim 1 or 2, wherein R_7 is a methyl group. 4 2-Methyl-6,7,8-trimethoxy-1-[4
The compound according to claim 1, which is 5,6-triethoxy-7-amino-3-phthalidyl]-1,2,3,4-tetrahydroisoquinoline. 5 2-methyl-6,7-dimethoxy-1-[4,5,
6-triethoxy-7-amino-3-phthalidyl]-1
- The compound according to claim 1, which is 2,3,4-tetrahydroisoquinoline. 6 General formula (6) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [R_ in the formula
1 and R_2 are lower alkoxy groups, R_3 is a hydrogen atom or lower alkoxy group, R_7 is a lower alkyl group and X^
- is OH^-, Cl^-, Br^-, I^- or CH_
3SO_4^-] Ammonium salt of substituted dihydroisoquinolines and general formula ▲ Numerical formula, chemical formula,
There are tables, etc. ▼ (IV) [In the formula, R_4, R_5 and R_
6 represents a lower alkoxy group] and the resulting general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R_1, R_2, R_3, R_4, R_5, R_6 and R_7 are the same as above] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R_1, R_2, R_3, R_
4, R_5, R_6 and R_7 are the same as defined above], diastereomers thereof, and pharmaceutically acceptable acid addition salts thereof. 7 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R
_1, R_2, R_4, R_5 and R_6 each represent a lower alkoxy group, R_3 represents a hydrogen atom or a lower alkoxy group, and R_7 represents a lower alkyl group. An anti-allergic drug containing as an active ingredient at least one selected from phthalidyl-isoquinoline derivatives represented by the following, diastereomers thereof, and pharmacologically acceptable acid addition salts thereof. 8 2-methyl-6, 7, 8
-trimethoxy-1-[4,5,6-triethoxy-7
-amino-3-phthalidyl]-1,2,3,4-tetrahydroisoquinoline as an active ingredient.