FI59586C - FRAMEWORK FOR THE PHARMACOLOGICAL PROPERTIES OF VARIABLE BENS-1,2-ISOXAZOLFOERENINGAR - Google Patents

Description

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Patent and Register Office Antöktn utUjd och utl.ikrifttn publtcand 29.05.81 (32) (33) (31) Requested stuolksut — Bsgird prtarltet 01.07.7 * + 31-07.7 * + Japan-Japan (JP) 755 * + * + / ? * +, 88556/7 * + (71) Sumitomo Chemical Company, Limited, no. 15, Kitahama 5-chome,

Higashi-ku, Osaka-shi, Japan-JapanJP) (72) Junki Katsube, Osaka-fu, Tsuyoshi Kobayashi, Niigata-ken, Katsumi Tamoto, Hyogo-ken, Yoahiaki Takebayashi, Hyogo-ken, Kikuo Sasajima, Osaka-fu , Shigeho Inaba, Hyogo-ken, Hisao Yamamoto, Hyogo-ken, Japan-Japan (JP) (7 * 0 Leitzinger Oy ('5 * +) Method for the preparation of pharmacologically valuable benz-1,2-isoxazole compounds - Förfarande för framställning from pharmacological equivalents of benz-1,2-isoxazole derivatives

The invention relates to a process for the preparation of pharmacologically valuable benz-1,2-isoxazole compounds of the formula R 2, wherein R 1 and R 2 are each methoxy or together form a methylenedioxy group, and their non-toxic salts.

The process according to the invention is characterized in that a) o-substituted nitrobenzene of the formula r ~ \ (ch2) 2-n ^ _n -y is treated

R1'sr'Y'CHCO3R3 "R2 ^ S ^ ^ XNO2 2 59586 wherein and R ^ is as defined above and R ^ is lower alkyl, with a base or an acid, or b) reducing o-substituted nitrobenzene of formula I '-' m

R

wherein R 1 and R 2 are as defined above,

Christensen et al. (J.Am.Chem. Soc., 67, 2001 (1945)) have reported that benz-2,1-isoxazole derivatives can be prepared in part by reduction of substituted o-nitroacetophenones to the corresponding o- (hydroxyamino) acetophenones, followed immediately by dehydration which results in cyclization of the compound. However, no information on the pharmacological properties of the compounds can be found in said publication.

To prepare pharmacologically active benz-2,1-isoxazoles, several substituted benz-2,1-isoxazoles have been synthesized according to Christensen et al. by methods analogous to the method and the compounds prepared have been tested pharmacologically. As a result, it has now been found that some of the new benz-2,1-isoxazole derivatives have remarkable pharmacological properties. These new benz-2,1-isoxazole derivatives are characterized by a nitrogen-containing group at the 3-position. Such derivatives have not been previously described in the literature.

In process variant a) potassium hydroxide, sodium hydroxide, potassium t-butoxide, sodium ethoxide, sodium methoxide, lithium triphenylmethane, sodium triphenylmethane or sodium hydride can be used as the base. As the acid, any acid having a dehydrating effect can be used, such as concentrated sulfuric acid or polyphosphoric acid.

3,59586 The treatment is usually carried out in the presence of an inert solvent. Examples of inert solvents are alcohols (e.g. t-butanol, ethanol, methanol), ethers (e.g. ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane), hydrocarbons (e.g. heptane, hexane, benzene, toluene), amides (e.g. dimethylformamides, hexamethylidene), hexamethylenethylene etc. The conditions under which the treatment is carried out, such as temperature and time, may vary depending on the o-substituted nitrobenzene (II) used as a starting material and the base or acid used.

The treatment can be carried out by heating or cooling depending on the intensity of the reaction, but the temperature is usually about -20 to 100 ° C. A stoichiometric amount or more of base may be used, while it is best to use an excess of acid so that it is used as the same medium.

Process variant b) uses as a reducing agent e.g. a combination of a metal or its compound (e.g. tin, zinc, stannous chloride) with an acid (e.g. hydrochloric acid, acetic acid), an alkali metal (e.g. sodium, lithium, potassium, amalgamated sodium) in combination with an alcohol or liquid ammonia (sulphide compound) for example sodium sulfide, ammonium sulfide) or the like.

One of the most preferred reducing agents is the combination of a metal or a compound thereof with an acid. Treatment with this particular reducing agent can be performed in the presence or absence of an inert solvent; such inert solvents are, for example, water, alcohols (e.g. methanol, ethanol), hydrocarbons (e.g. benzene, toluene) or ethers (e.g. ethyl ether, tetrahydrofuran, dioxane). Excess acid can also be used as a solvent. The treatment temperature can range from room temperature to the reflux temperature of the reduction system. The treatment with any other reducing agent can be carried out in the same manner in a manner known per se, established for each reducing agent.

The reduction system may also be catalytic, i. a hydrogenation catalyst is used. In this case, conventional standard methods can be applied, but it is recommended to use mild conditions to avoid over-reduction. Thus, a temperature close to room temperature, atmospheric pressure as hydrogen gas pressure and a relatively mild catalyst such as Pd-BaSO 4, 4,59586 are best used.

Pd-BaCO 2 or a metal catalyst poisoned with quinoline, dimethyl sulfide, diethyl sulfide or the like.

The benzisoxazole compounds (I) thus prepared can be separated from the reaction mixture and purified by conventional methods.

The benzisoxazole compounds (I) thus obtained can be converted into their addition salts in the usual manner, and the conversion from the addition salts back to the original free bases can also be carried out in the usual manner. Examples of addition salts include hydrochloride, hydrobromide, acetate, oxalate, citrate, tartrate, succinate, fumarate, lactate, and the like.

The benz-2,1-isoxazole compounds of the formula I and their non-toxic salts have central nervous system, muscle relaxant and neuroleptic properties. They are also vasodilatory and anti-asthmatic compounds. For example, 3- [2 '- (4 "-phenylpiperazino),? when mice are used as experimental animals.

Said compound (20 mg) has a similar muscle relaxant effect as 25 mg of chlorodiazepoxide. * Thus, the compound prepared according to the invention is a more effective compound for slowing motion and relaxing muscles than the known chloride diazepoxide. Also 3- [2 '- (4 "-phenylpyrazino) ethyl] -5,6-methylenedioxy-benz-2,1-isoxazole, its 90 mg dose has the same motion retardant effect as the 105 mg dose of chlorothiazepoxide.

The following examples illustrate the invention.

Example 1 (Process variant a)) 3- [21- (4 "-phenylpiperazino) -ethyl] -5,6-dimethoxy-benzo-2,1-isoxazole.

To a mixture of 36 ml of t-butanol and 18 ml of toluene was added 1.8 g of metallic potassium, and then the solution was heated.

To this solution was added 12.6 g of 1- (2'-nitro-4 ', 5'-dimethoxyphenyl) -1- [2' - (4 "-phenylpiperazino) ethyl / propan-2-one under cooling with water, followed by stirring. hours at room temperature.

5,59586

The reaction mixture was poured into ice water and extracted with chloroform. The chloroform layer was washed with water, dried and evaporated to dryness, the oily residue was soaked in ethyl acetate and mixed with 10 g of silica gel. The whole mixture was stirred for 30 minutes and filtered to remove silica gel. The filtrate was concentrated to dryness, and the residue was crystallized from methanol-ether to give 7.0 g of 3- [2 '- (4 "-phenylpiperazino) -ethyl] -5,6-dimethoxy-benz-2,1-isoxazole, m.p. 117 ° C.

Example 2 (Process variant b)) 3- [2 '- (4 "-phenylpiperazino) -ethyl] -5,6-dimethoxy-benz-2,1-isoxazole.

To 20 ml of sulfuric acid was added 2 g of 1- (2'-nitro-4 ', 5'-dimethoxyphenyl) -1- [2' - (4 "-phenylpiperazino) ethyl] propan-2-one and then stirred for 4 hours at room temperature. .

The reaction mixture was poured into ice water, neutralized with aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water, dried, treated with charcoal and evaporated to dryness, the oily residue was crystallized from methanol-ether to give 3- [2 '- (4 "-phenylpiperazino) ethyl] -5,6-dimethoxy-benz-2,1-isoxazole. the product was identified as the compound obtained in Example 1.

Example 3 (Process variant a)) 3- [21- (4 "-phenylpiperazino) ethyl 47-5,6-methylenedioxybenz-2,1-isoxazole.

As in Examples 1 and 2, 1- (2'-nitro-4 ', 5'-methylenedioxyphenyl) -1- [2' - (4 "-phenylpiperazino) ethyl / propan-2-one was treated with potassium t-butoxide in sulfuric acid to give the title compound with a melting point of 126-127.5 ° C was obtained.

Example 4 (Process variant b)) 3- [2 '- (4 "-phenylpiperazino) ethyl] -5,6-dimethoxy-benz-2,1-isoxazole.

To a solution of 90 g of stannous chloride dihydrate and 72 g of concentrated hydrochloric acid was added 4.0 g of 1- (2'-nitro-4 ', 5'-dimethoxyphenyl) -3- (4'-phenylpiperazino) propane-1- and the mixture was stirred for 3 hours at room temperature.

6 59586

The reaction mixture was diluted with water and stirred for several minutes, basified with aqueous sodium hydroxide while cooling, and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated to dryness. The residue was recrystallized from a mixture of methanol and ethanol to give 2.9 g of 3- (2 '- (4 "-phenylpiperazino) ethyl] -5,6-dimethoxybenz-2,1-isoxazole, m.p. 115-117 ° C. .

Example 5 (Process variant b)) 3- [5 '- (4 "-phenylpiperazino) ethyl] -5,6-methylenedioxy-benz-2,1-isoxazole.

In the same manner as in Example 4, 1- (21-nitro-4 ', 5'-methylenedioxyphenyl) -3- (4'-phenyl-piperazino) propan-1-one was treated with stannous chloride to give 3 - [? - (4 ") hydrochloric acid. -phenylpiperazino) ethyl-5- (6-methylenedioxy-benz-2,1-isoxazole), m.p. 126-127.5 ° C.

Claims (2)

A process for the preparation of pharmacologically valuable benz-1,2-isoxazole compounds of the formula 7 59586. ) for o-substituted nitrobenzene of formula (CH,) - 1 / NV V | 2 2 V- / R = / R1 ns ^ ^ Vs ^, chcor3 R211 wherein R1 and R2 are as defined above and R1 is lower alkyl, with a base or an acid, or b) reducing o-substituted nitrobenzene of formula (CH2) n- ^ R, ^ CO TT 111 wherein R1 and R2 are as defined above.