JPS5936669A - 1-(1,2-benzisoxazol-3-yl)-1-cycloalkanecarboxylic acid ester, its acid addition salt and quaternary ammonium salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R1 is H, halogen, OH, lower alkyl, CF3 or lower alkoxy; Y is group of formula II or III [R2 is H or lower alkyl; R3 and R4 are lower alkyl or together with N form a heterocyclic group; R5 is lower alkyl or group of formula IV (R6 and R7 are lower alkyl, phenyl, or together form a 4-6C straight-chain alkylene); m and n are 0, 1, 2 or 3; q and r are 1, 2 or 3]; a is 4, 5 or 6}, its physiologically permissible acid addition salt and quaternary ammonium salt. EXAMPLE:1-Methyl-4-piperidyl 1-(1,2-benzisoxazol-3-yl)-1-cyclohexane-carboxylate oxalic acid salt. USE:Antispasmodic agent. PROCESS:The compound of formula I can be prepared by reacting the compound of formula V (novel substance) or its reactive derivative with the compound of formula Z-Y (Z is OH or reactive ester residue of alcohol).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel and useful 1-(1
,2-benzisoxazole-3-i/l/ ) -1
-Relating to cycloalkane carboxylic acid esters. More specifically, general formula (I) [wherein R1 means a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a trifluoromethyl group, or a lower alkoxy group, Y means and R2 means a hydrogen atom or lower alkyl group, R3
and R4 are the same or different and mean a lower alkyl group, or together with the adjacent nitrogen atoms form a heterocyclic group, R5 is lower, and R6 and R7 are the same or different and mean a lower alkyl group or a phenyl group. mean or R6
and R7 together mean a linear alkylene group having 4 to 6 carbon atoms, a means an integer of 4 to 6, m and n
each means an integer from 0 to 3, but the sum is from 1 to 4
q and r each represent an integer of 1 to 3, and the sum thereof represents an integer of 3 to 5. ] The present invention relates to a compound represented by the above, and its physiologically acceptable acid addition salts and quaternary ammonium salts.

Physiologically acceptable quaternary ammonium salts of compounds of formula (I) are represented by the general formula (I'), where C means a physiologically acceptable anion, R1, R2, R3 , R+, Rs.

a, m, n, q and r have the same meanings as above. ] It is expressed as

The compound of formula (I), its acid addition salt and quaternary ammonium salt may have one or more asymmetric carbon atoms in some cases, and may also exhibit geometric isomerism, so they may have several types of stereoisomerism. A body may be present. The present invention includes these stereoisomers, mixtures and racemates thereof.

Terms used in this specification will be explained below.

Halogen atoms mean fluorine, chlorine, bromine, and iodine. Lower alkyl group means a straight chain or branched chain having 1 to 4 carbon atoms, such as methyl, ethyl,
Examples include propyl, isopropyl and butyl, with methyl and ethyl being preferred. The lower alkoxy group means a linear or branched group having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, and isopropoxy, with methoxy being preferred. The heterocyclic group formed by R5 and R6 together with the adjacent nitrogen atom further includes 1
5 to 7 which may have 5 to 7 oxygen atoms or sulfur atoms
It means a membered heterocyclic group, such as 1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino, and thiomorpholino. A physiologically acceptable anion represented by C means an anion formed by removing a proton from a strong inorganic or organic physiologically acceptable acid, such as a halide ion (eg chloride, bromide).

iosito ion), lower alkyl sulfate ion (
Examples include methyl sulfate, ethyl sulfate ion), lower alkyl sulfonate ions (e.g. methanesulfonate ion), substituted or unsubstituted benzenesulfonate ions (e.g. benzenesulfonate, p-toluenesulfonate ion), and nidrade ion.
Particularly preferred are bromide and iositoion.

The compound of formula (I) is, for example, a compound of general formula (Ir) [wherein
R1 and a have the same meanings as defined above. ] Carboxylic acids or reactive derivatives thereof represented by the general formula (II) Z -Y (III) [wherein Z means a hydroxy group or a reactive ester residue of alcohol, and Y is the same as above. mean something ] It is obtained by reacting with a compound represented by these.

Reactive derivatives of carboxylic acids (I) include, for example, metal salts, especially alkali metal salts such as sodium salts and potassium salts, carboxylic acid halides, mixed acid anhydrides, and active esters. Examples of the reactive ester residue of alcohol represented by Z include halogen atoms such as chlorine, bromine, and iodine, and benzenesulfonyloxy.

Examples include organic sulfonyloxy groups such as p-toluenesulfonyloxy and methanesulfonyloxy.

Metal salts of carboxylic acids (IT) are reacted with compounds in which Z in formula (III) is a reactive ester residue of an alcohol, and carboxylic acids (II) or other reactive derivatives are reacted with compounds in which Z in formula (III) is a reactive ester residue of an alcohol. Reacts with compounds where is a hydroxy group. These reactions can be carried out under normal esterification reaction conditions.

For example, metal salts of carboxylic acids (II) and formula (III)
The reaction with a compound in which Z is a reactive ester residue of alcohol is usually carried out in a solvent, and specific examples of solvents include lower alcohols such as isopropyl alcohol and 5ec-butyl alcohol, tetrahydrofuran, and dioxane. Examples include ethers such as
Isopropyl alcohol is preferred. The reaction temperature and reaction time vary depending on the type of raw material compound, etc., but usually the reaction may be carried out at room temperature to about 100'C for about 1 to 24 hours.

The reaction between the carboxylic acid (IT) and the compound in formula (III) in which Z is a hydroxy group is carried out without a solvent or in a solvent in the presence of a strong acid. Examples of solvents include benzene, toluene, xylene, dichloroethane, tetrahydrofuran, and dioxane. Examples of strong acids include sulfuric acid, hydrogen chloride, boron trifluoride, and p-toluenesulfonic acid. Reaction temperature is usually about 50℃
-150°C, reaction time is usually about 30 minutes to 20 hours.

The halide of carboxylic acid (II) can be produced by reacting carboxylic acid (II) with a halogenating agent such as thionyl chloride or phosphorus oxychloride according to a conventional method. The reaction between this halide and the compound in formula (III) in which Z is a hydroxy group is carried out without a solvent or in a solvent, if necessary in the presence of a base (eg, tertiary amine, alkali carbonate).

Specific examples of solvents include benzene and toluene.

Examples include aromatic hydrocarbons such as xylene, ethers such as dioxane, and halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane. The reaction temperature is usually about -20°C to 150°C, and the reaction time is usually about 1 to 24 hours.

Mixed acid anhydrides of carboxylic acids (11) can be produced by reacting carboxylic acids (formerly) with trifluoroacetic anhydride, benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, etc. according to a conventional method. The carboxylic acids (H) were converted to p-nitrophenol according to a conventional method.

It can be produced by reacting with N-hydroxysuccinimide or the like. The reaction between this mixed acid anhydride or active ester and a compound in which Z is a hydroxy group in formula (In) is usually carried out in a solvent, if necessary, in the presence of a base (e.g., tertiary amine, alkali carbonate). . Specific examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as dioxane, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethylformamide, and pyridine. Can be mentioned. The reaction temperature is usually about -20
°C to 150 °C, and the reaction time is usually about 1 to 24 hours.

The compound of formula (I) is isolated and purified by conventional methods. Compound (I) can be obtained in free form or in the form of an acid addition salt depending on the type 1 reaction of the starting compound and the processing conditions. Acid addition salts can be prepared using conventional methods, such as alkali carbonates.

It can be converted to the free state by treatment with a base such as ammonia. On the other hand, free bases can be converted into acid addition salts by treatment with various physiologically acceptable inorganic or organic acids using conventional methods. Inorganic acids used for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid, nitric acid, sulfuric acid, and organic acids include, for example, citric acid, oxalic acid, fumaric acid, maleic acid, Examples include lactic acid, succinic acid, malic acid, tartaric acid, and methanesulfonic acid.

The compounds of formula (I) optionally contain one or more asymmetric carbon atoms and may therefore be obtained in the form of racemates or mixtures of stereoisomers. These racemates and mixtures of stereoisomers can be separated into each stereoisomer by conventional methods.

The quaternary ammonium salt represented by formula (1') is represented by formula (T
) and the compound of the general formula (■) R8-X (■) [wherein R8 means the same as mentioned above, and X means an anion component. It can be obtained by reacting with a compound represented by

This reaction can be carried out according to a conventional method for producing a quaternary ammonium salt, and is carried out by reacting both compounds without a solvent or in a solvent. Specific examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diisopropyl ether, tetrahydrofuran, and dioxane, dialkyl ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, methanol, and ethanol. , lower alcohols such as isopropyl alcohol, acetonitrile, dimethylformamide, or mixtures thereof. The reaction temperature is for compound (■) and compound (■).

Although it varies depending on the type of reaction solvent, it is usually about 10°C to 130°C.
℃, and the reaction time is usually about 10 minutes to 72 hours.

When the compound is reacted with a compound of formula (IV) in which R8 is a group different from R5, two types of quaternary ammonium salts are produced in a ratio of about 1:1.

The quaternary ammonium salt represented by the formula (I') can also be combined with the compound represented by the formula (n) or its reactive derivative and the general formula (■) HO-T (D [wherein T is as defined above) It can also be obtained by reacting with a compound represented by the following.

X- in formula (■') can be converted into another anion by a conventional method. For example, a compound of formula (■') in which X is
By treating with a compound represented by LL (W) [wherein M means an alkali metal atom and X'' means an anion component different from X'], can lead to a compound where is X''. This reaction is carried out in a solvent, and the solvent is preferably one that dissolves both compounds, such as water and lower alcohols (eg, methanol).

ethanol) or mixtures thereof.

The reaction temperature is usually room temperature to about 100°C.

Physiologically acceptable acid addition salts and quaternary ammonium salts of compounds of formula (I) are optionally isolated in the form of hydrates or solvates.

The raw material compound represented by formula (n) is a new substance, and can be produced, for example, by the following method.

(■) (■) (■) (■) [In the formula, R1 and a mean the same as mentioned above, R means a lower alkyl group, Hal and Ha I' are the same -
Alternatively, it means a halogen atom such as chlorine, bromine, or iodine. ] The reaction between the compound of formula (W) and the compound of formula (■) is carried out in an aprotic solvent under anhydrous conditions in the presence of 2 mol of base per 1 mol of compound (Vr). Specific examples of the base include alkali metal alcoholades, alkali metal amides, alkali metal hydrides, etc., and specific examples of the solvent include dimethylformamide, dimethyl sulfoxide, and the like. The reaction temperature is usually about 0°C to 100°
C1 reaction time is usually about 30 minutes to 8 hours.

A compound of formula (n) is obtained by hydrolyzing the compound of formula (■) according to a conventional method.

The compound of formula (I) and its physiologically acceptable acid addition salts and quaternary ammonium salts have strong anti-acetylcholine and antispasmodic effects, as well as mydriasis, suppression of saliva secretion, and
Since side effects such as tachycardia are weak, it is useful as a medicine such as an antispasmodic agent.

Below, the results of pharmacological tests on representative compounds of the present invention are shown.

Antispasmodic effect W, D, M using ileum pieces removed from guinea pigs.

Paton's method [Br, J, Pharmaco
J, 12.119 (1957)]. Transmural stimulation (0.1m5ec, 20V.

The concentration of the test compound that inhibited contraction by 50% (IC5o) at 5 Hz, 12 sec was calculated. The test results are shown in Table 1.

(Margin below) Table 1 Antispasmodic effect *Means the compound of Example 1 (the same applies below).

The compound of formula (I) and its physiologically acceptable acid addition salts and quaternary ammonium salts are usually administered orally, parenterally, or rectally in the form of a preparation prepared by mixing with a pharmaceutical carrier. be done.

These formulations may also contain other ingredients of therapeutic value. As a specific example of the formulation, the agent is prepared by a conventional method.

The clinical dosage of the compound of formula (I) and its physiologically acceptable acid addition salts and quaternary ammonium salts varies depending on the type of compound, administration method, patient's symptoms and age, etc. ~40 mg/KgZ day, preferably 0.
1-20 mg/Kg/day.

The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention is not limited to these Examples. The compounds were identified using elemental analysis values, mass spectra, IR spectra, NMR spectra, etc.

Reference example 1 1-(1,2-benzisoxazole-3-y1,2-
Benzisoxazole-;l-acetic acid methyl ester 15
g was dissolved in 120 ml of dimethyl sulfoxide, 6.9 g of 60% sodium hydride was added under water cooling, and the mixture was stirred at room temperature for 30 minutes.
．． Add 6 g and stir at room temperature for 4 hours. Add 400 ml of toluene, 8 ml of concentrated hydrochloric acid, and 100 ml of water to the reaction solution and shake. The organic solvent layer is washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. 30 g of the oily residue was subjected to column chromatography on silica gel and developed with toluene. The unreacted 1,5-dibromopenkune and the subsequent flow-out fractions were collected, and toluene was distilled off under reduced pressure to obtain oily 1-(1,2-benzisoxazol-3-yl)-1.
-15 g of cyclohexanecarboxylic acid methyl ester were obtained.

This methyl ester was mixed with 2.3 g of sodium hydroxide, 8 ml of water, and 110 ml of ethanol at 60°C for 40 min.
After heating for a minute, the ethanol is distilled off. The residue is partitioned between water and toluene, the aqueous layer is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated to dryness to obtain 9.63 g of the solid target product. A portion was recrystallized from toluene/hexane, melting point 116~
Colorless crystals at 118°C were obtained.

Reference Example 2 Using 20.4 g of 1,4-dibromobutane instead of 1,5-dibromobutane in Reference Example 1, Reference Example 1
The reaction and treatment were carried out in the same manner as above to obtain 1-(1,2-benzisoxazol-3-yl)-1-cyclopentanecarboxylic acid methyl ester.

This was subjected to alkaline hydrolysis in the same manner as in Reference Example 1 to obtain 13.8 g of crystals of the desired product. A portion was recrystallized from ethyl acetate/hexane to give colorless crystals with a melting point of 124-126°C.

Reference Example 3 10 g of l-(5-chloro-1,2-benzisoxacic acid 5-chloro-1,2-benzisoxazole-3-acetic acid methyl ester and 10 g of 1,5-dibromopentane)
．． Using 5 g, it is reacted in 80 ml of dimethylformamide in the same manner as in Reference Example 1. Thereafter, the same operation as in Reference Example 1 was performed to obtain 5.6 g of crystals of the target product. A portion was recrystallized from diethyl ether/hexane, melting point 195-1.
Colorless crystals at 97°C were obtained.

Example 1 l-(1,2-benzisoxazol-3-yl)-1
-8.0g of cyclohexanecarboxylic acid to 60g of toluene
ml, add 8 ml of thionyl chloride, and heat at 100°C.
Heat for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and to the residue were added 60 ml of toluene, 10 ml of to-21-ethylamine, and then 6.4 g of 1-methyl-4-hydroxypiperidine, followed by heating at 100° C. for 1 hour. The reaction solution was diluted with toluene, washed successively with 5% sodium carbonate and water, and then extracted with 5% hydrochloric acid. The aqueous layer is made alkaline with ammonia and extracted with toluene. The toluene extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily substance. This was dissolved in 50 ml of ethanol, 2.62 g of oxalic acid was added, and after the oxalic acid was dissolved, the ethanol was distilled off. The residue was recrystallized from ethanol/diethyl ether to obtain 6.49 g of the desired product. Melting point: 126-130°C Examples 2-20 Reaction was carried out in the same manner as in Example 1 using the corresponding 1-(1,2-benzisoxazol-3-yl)-1-cycloalkanecarboxylic acids and amino alcohols. The compounds shown in Table 2 were obtained by treatment and then generation of acid addition salts by conventional methods. Note that the recrystallization solvent was ethanol/diethyl ether for all compounds.

99- Example 21 Promide 1-methyl-4-piperidyl 2.5 g of 1-(1,2-benzisoxazol-3-yl)-1-cyclohexanecarboxylate was dissolved in 20 ml of acetone, and 3.5 g of ethyl bromide was dissolved. Add 9g and leave at room temperature for 2 days. The precipitated crystals were collected and recrystallized from ethanol/diethyl ether to obtain 2.0 g of the desired product. Melting point 214-224°C
Examples 22-31 Corresponding 1-(1,2-benzisoxazol-3-yl)-1-cycloalkanecarboxylic acid esters and Table 3
The reaction was carried out in the same manner as in Example 21 using the compound R8X shown in
After treatment, the compounds shown in Table 3 were obtained.

× A: Ethanol, AC acetone, E, diethyl ether, M, methanol.

Continued from page 1 211100 7138-4C317
1008214-4C 261100) 7330-4CO Inventor Yasuyuki Mizuta 6-6-50 Koshien Seven-cho, Nishinomiya-shi No. 4-0 Inventor Toshiaki Kadokawa 4-3-0 Okanami-cho, Hirakata-shi Inventor Katsura Kawashima Suma-ku, Kobe City Eirakucho 3-7-21-492-

Claims (1)

[Claims] In the formula, R1 means a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a trifluoromethyl group, or a lower alkoxy group, Y means, and R2 means a hydrogen atom or means a lower alkyl group, R3 and R4 are the same or different and mean a lower 1-alkyl group, or together with adjacent nitrogen atoms form a heterocyclic group, R5 is lower, R6 and R7 are the same -
or differently means a lower alkyl group or a phenyl group, or R6 and R7 together have 4 to 4 carbon atoms.
6 means a linear alkylene group, a means an integer of 4 to 6, m and n each mean an integer of 0 to 3, the sum of which means an integer of 1 to 4, q and r each mean an integer from 1 to 3, and the sum thereof means an integer from 3 to 5. ] and its physiologically acceptable acid addition salts and quaternary ammonium salts.