JPS6379874A - Isoindole derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H,lower alkyl, aryl, aralkyl, etc.; X is H or halogen; Y is carboxyl, tetrazolyl, etc.; n is 1-6). EXAMPLE:Ethyl [(7-chloro-2,3-dihydro-1-oxo-2-phenyl-1H-isoindol-5-yl)oxy]acetate. USE:Remedy for hypertension, etc., having diuretic and hypotensive activities accompanying salt-excreting action. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II (R<2> and R<3> are lower alkyl) with a halogenation reagent such as N-bromosuccinimide in the presence of a radical generator such as perbenzoic acid, etc., and reacting the reaction product with a primary amine of formula R<1>NH2. The reaction is carried out in a nonpolar organic solvent such as carbon tetrachloride at room temperature - 120 deg.C.

Description

Detailed Description of the Invention The present invention relates to the general formula (I) (wherein R1 represents a hydrogen atom, a lower alkyl group, a cyclic alkyl group, an aryl group, or an aralkyl group, and the cyclic alkyl group, aryl group and The aralkyl group may have one or more substituents. ) and its salts.

<Industrial Application Field> The compound of the present invention has a diuretic effect accompanied by salt excretion, and is useful as a therapeutic agent for hypertension and the like.

<Prior Art> As diuretic antihypertensive agents, thiazide drugs, spironolactone, furosemide, and the like are conventionally known. However, none of these drugs have an isoindole skeleton.

<Structure of the invention> The present invention relates to compounds of formula (1) and salts thereof.

Examples of the lower alkyl group in formula (I) include methyl, ethyl, propyl, isopropyl, lobutyl, and tertiary butyl. Cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl. As an aryl group,
Examples include phenyl, naphthyl, and biphenyl. Examples of the alkyl group include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, naphthylethyl, biphenylmethyl, and the like. Examples of substituents that the cyclic alkyl group, aryl group, and aralkyl group may have include a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxyl group, and a trifluoromethyl group.

When the above-mentioned cyclic alkyl group, aryl group and aralkyl group have two or more substituents, these substituents may be the same or different. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. can give.

When Y is a carboxyl group or a tetrazolyl group, salts of the compound of formula (1) include inorganic salts such as alkali metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, alkaline earth metal salts, and ammonium salts. Examples include salts with bases and salts with organic bases such as N-methylglucamine salt and ethanolamine salt.

The compound of the present invention can be produced by various production methods, examples of which are shown below.

a) (In the formula, R2 and R3 each represent a lower alkyl group, and X, R' and n are the same as above) A compound of formula (11) is converted to N-promosuccinimide in the presence of a radical generator such as perbenzoic acid. After reacting with a halogenating reagent such as
The compound of formula (Ia) can be produced by reacting with a primary amine represented by III). As the solvent, non-polar organic solvents can be used, preferably carbon tetrachloride, etc. The amount of the -class amine is usually determined by the formula (I
The reaction temperature, which may be about 2 to 20 times that of the compound represented by I), is usually appropriately selected from room temperature to about 120°C.

b) (wherein X, R', R3 and n are the same as above,
A represents a halogen atom) A compound represented by formula (rV) is converted to formula (V) in an inert solvent.
By reacting with a compound of formula (I) in the presence of a base, the compound of formula (I
The compound of a) can be produced. Examples of the inert solvent include dimethylformamide and acetone. The base is preferably an alkali metal carbonate, and specific examples include potassium carbonate and sodium carbonate. The reaction temperature is appropriately selected between room temperature and about 100°C.

CIA) (II)) (wherein, X
, R', R' and n are the same as above) The compound of formula (Ia) is mixed with water, methanol, ethanol, dioxane,
A compound represented by formula (Ib) can be produced by reacting with a base such as an alkali metal or alkaline earth metal hydroxide in a mixed solvent of an organic solvent such as dimethylformamide and water.

The raw material compound of formula (It) above can be produced by the method shown below.

(■) (m) (■) (■)
(Correct) (In the formula, X, R
', and R3 are the same as above) That is, the compound of formula (mV) is reacted with a normal esterification reaction, for example, with thionyl chloride, and then reacted with a lower alcohol to form the compound of formula (■). Can be done. Next, the compound of formula (■) can be obtained by dissolving the compound of formula (■) in an inert organic solvent such as ethyl acetate and subjecting it to catalytic reduction in the presence of palladium and carbon. Then the formula (
The compound of formula (IX) is reacted with sodium nitrite under sulfuric acid acidity, diazotized, and then hydrolyzed.
can be obtained. A compound of formula (IX) is dissolved in dimethylformamide or acetone and mixed with an alkali metal carbonate such as potassium carbonate at room temperature to 10
By reacting at a temperature of 0'e, a compound of formula (II) can be obtained. The compound of formula (Vl) can be prepared by a known method (J, Med, chem, 241337-
1342 (1981)).

Further, the raw material compound of formula (■) can be produced by the method shown below.

(In the formula, X, R', and R2 are the same as above) That is, the formula (
Compounds of formula (X) can be prepared by reacting compounds of formula (IX) with iodomethyl in the presence of anhydrous potassium carbonate in an inert organic solvent such as acetone or dimethylformamide. Subsequently, the compound of formula (X) is dissolved in carbon tetrachloride, reacted with N-promosuccinimide in the presence of perbenzoic acid, brominated, and then treated with a primary amine represented by formula (III) from room temperature to 120°C. Compounds of formula (XI) can be obtained by reacting the compounds of formula (XI) at a temperature of By adding and refluxing, a compound of formula (mV) can be produced.

<Effects of the Invention> The compound of the present invention has excellent diuretic and antihypertensive effects accompanied by salt excretion, and is a useful compound as a medicine.

The pharmacological effects of the compounds of the present invention are specifically shown below.

Diuretic and salt excretion effects Male rats (body weight 150 ~ zso) were fasted from the day before the experiment.
g) Oral loading of physiological saline (25 m
A/kg), and then the test compound suspended in O9 packed carboxymethyl cellulose was orally administered. Administration 5
After a period of time, urine volume and urinary sodium excretion were measured. Animals in the control group received 0.5*carboxymethylcellulose alone orally.

The results are shown in Table 1.

Table 1 * p < o, os, umbrella * p < 0.01.
VS control group The urine volume and urinary Na content in Table 1 were calculated using the following formula.

Urine volume = (Urine volume of test compound group) - (Urine volume of control group) Urinary Na content = (Urine Na content of test compound administration group) - (Urine Na content of control group) It is clear from Table 1 As shown, the compound of the present invention exhibited superior diuretic and salt excretion effects compared to the control compound, chenilic acid.

Compounds a-c are shown below.

Compound a [(7-chloro-2,3-dihydro-1-oxy) The present invention will be further explained with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Step 1 Methyl 2-chloro-6-methyl-4-nitrobenzoate 2-chloro-6-methyl-4-nitrobenzoic acid 19.5
g was dissolved in 180 mfL of thionyl chloride and fast-flowed for 2 hours. After distilling off excess thionyl chloride under reduced pressure, the obtained oil was dissolved in 200 mλ of methanol,
The 0 reaction solution, which was rapidly flowed for 4.5 hours, was concentrated to obtain needle-shaped crystals.

Recrystallization from methanol gave 17.9 g of the title compound as white needle-like crystals. Melting point 90-92℃ Step 2 Methyl 4
-Amino-2-chloro-6-methylbenzoate 31.4 g of the compound obtained in Step 1 was dissolved in 500 mL of ethyl acetate, and 0.8 g of platinum oxide was added thereto for catalytic reduction. After absorbing the theoretical amount of hydrogen, the catalyst was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of ether, and insoluble materials were filtered.

The ether in the filtrate was distilled off to obtain 26.6 g of the title compound as pale yellow crystals. Melting point 74-77℃ 98g of the compound obtained in step 2 was added to 2.5 grams of 1-K sulfuric acid at 60-70℃.
It was dissolved while heating. At the same temperature, a sodium nitrite aqueous solution (sodium nitrite 37.3 g, water 3
00 mfL) was added dropwise little by little, and after the completion of the addition, the mixture was further stirred for 1 hour. After cooling, benzene was added to the reaction mixture for extraction.

After drying the benzene layer with Glauber's salt, the benzene was distilled off, and the residue was subjected to silica gel column chromatography to obtain 77 g of the title compound as yellow crystals.

16.3 g of the compound obtained in step 3 was dissolved in 340 ml of dimethylformamide, and 16.8 g of anhydrous potassium carbonate.

Add 20.3g of ethyl bromoacetate and 60-70℃
The reaction was continued for 5 hours while heating. After completion of the reaction, dimethylformamide was distilled off under reduced pressure, ice water was added to the resulting residue, and then ether was added for extraction. The ether layer was then washed with water, dried over sodium sulfate, and the ether was distilled off under reduced pressure.

The obtained residue was purified by silica gel column chromatography to obtain 19.9 g of the title compound.

Reference Example 2 17.0 g of the compound obtained in Step 3 of Reference Example 1 was dissolved in 200 t+l of acetone, and 12.9 g of anhydrous potassium carbonate was dissolved.
.

13.3 g of methyl iodide was added and the mixture was heated under reflux for 4 hours.

After cooling and filtering off insoluble materials, the filtrate was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 14.0 g of the title compound as a pale yellow oil.

12.0 g of the compound obtained in Dole step 1 was added to 250 nI of benzene.
10.7 g of N-promosuccinimide dissolved in L
, 0.5 g of benzoyl peroxide was added, and the mixture was heated under reflux for 3 hours. After cooling, the precipitated crystals were filtered off, 12 g of orthotoluidine was added to the filtrate, and the mixture was heated under reflux for 6 hours. After cooling, the reaction solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. After drying the organic layer over Glauber's salt, the solvent was distilled off, and the resulting residue was recrystallized from ethanol to obtain 7.1 g of the title compound.

Melting point: 171.5-172.5℃
Add 6.5 g of anhydrous aluminum chloride,
Refluxed for an hour. After that, the solvent was distilled off under reduced pressure, diluted hydrochloric acid was added to the residue, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, thoroughly washed with hot water, and then dried to obtain 8.8 g of the title compound.

Melting point: 272-273°C Compounds of Reference Examples 3 to 6 below were obtained in the same manner as Reference Example 2.

Example 1 19.3g of the compound obtained in Reference Example 1 was heated with 500v of carbon tetrachloride.
Dissolved in aiL, N-promosuccinimide 12.3
g.

100 mg of benzoyl peroxide was added and the mixture was refluxed for 6 hours.

After cooling, insoluble matter was filtered, and 64.3 g of aniline was found in the filtrate.
was added, stirred at room temperature for 1 hour, and then stirred at a temperature of 90 to 100°C for 2 hours.
Time reacted. After the reaction solution was allowed to cool, excess aniline was removed by adding 4N hydrochloric acid and washing. The organic layer was washed with water, dried over Glauber's salt, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography and then recrystallized from ethanol to obtain 4.3 g of the title compound. Melting point: 150-152°C Similar to Example 1, the following Example 2
-6 compounds were obtained.

Example 7 6.8g of the compound obtained in Reference Example 2 was added to 200ml of acetone.
λ, 3.8 g of potassium carbonate and 4.57 g of ethyl bromoacetate were added, and the mixture was refluxed for 2 hours. After cooling, the reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a yield of 7.8%.
I got g. Melting point: 98-100°C In the same manner as in Example 7, the following compounds of Examples 8 to 11 were obtained.

Example 12 4.2 g of the compound obtained in Example 1 was dissolved under heating in 40 mfL of dimethylformamide. Add to this solution a sodium hydroxide aqueous solution (sodium hydroxide 1.46 g, water 1
5IIIA) was added little by little. After stirring at room temperature for 1 hour, the reaction solution was poured into 350 mjl of water, then made acidic by adding concentrated hydrochloric acid, and the precipitate was collected by filtration to obtain the title compound.
I got 2g. Melting point 207-209℃ NMR δppm (DM
SO-da, TMS) 4.82 (2H, S) 4.87 (2H, s) 7.0 to 7.15 (2H) 7.15 to 7.77 (5H, m) Same as Example 12 The following compounds of Examples 13 to 22 were obtained.

Procedural amendment

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 represents a hydrogen atom, a lower alkyl group, a cyclic alkyl group, an aryl group, or an aralkyl group; The group, aryl group and aralkyl group may have one or more substituents. X represents a hydrogen atom or a halogen atom. Y represents a carboxyl group, a lower alkoxycarbonyl group or a tetrazolyl group. n is (indicates an integer from 1 to 6) and its salts