NO142910B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMASOYTIC EFFECTIVE BENZISOCSAZOL COMPOUNDS - Google Patents

Description

The present invention relates to an analog method

for the preparation of pharmaceutically active benzisoxazole compounds of the general formula

1 2 in which R and R are each hydrogen, - alkoxy or halogen or together form - alkylenedioxy, Alk is C2~ alkylene and A is a group of formula in which R 3 and R 4 are each - C- alkyl or together with the adjacent nitrogen atom constitutes a pyrrolidino, piperidino or morpholino group and R 5 is - alkyl or phenyl, as well as non-toxic salts thereof, and the peculiarity of the invention is that either a) an o-substituted nitrobenzene of the general formula

6 12

wherein R is C, -C alkyl and R , R , Alk and A have the above meaning, ring closure by means of treatment with a base

or acid, or

b) an o-substituted nitrobenzene of the general formula

wherein R , R , Alk and A have the above meaning, ring-1 2 is closed by treatment in a reducing system,

after which a prepared compound is, if desired, converted into a non-toxic salt, or a prepared salt is converted into the corresponding free base.

These features of the invention appear in the patent claim.

The benzisoxazole skeleton itself has been known for a long time, but only relatively few chemical works have dealt with benzisoxazole derivatives and only a few scientific publications have been published regarding the synthesis of this type of compounds.

The structure of the benzisoxazole compounds of formula (I)

is characterized by the aminoalkyl side chain in the 3-position of the benzisoxazole skeleton.

Among the benzisoxazole compounds of formula (I), compounds of the following formula wherein C^_2 is alkoxy, R^ and R^ are each C^_^ alkyl and Alk is & 2-3 alkylene are preferred because of their strong anti-platelet - aggregation effect.

The compounds with formula

wherein R 1 and R 2 are each hydrogen, C 2 - 2 alkoxy or halogen or together form C 2 - 2 alkylenedioxy, R 2 is C 2 - 2 alkyl or phenyl and Alk is 2-3 alkylene are also particularly preferred due to their depressant effect on the central nervous system.

The benzisoxazole compounds of formula (I) can form acid addition salts and examples of this are the hydrochloride, hydrobromide, acetate, oxalate, citrate, tartrate, succinate, fumarate, lactate, etc.

The benzisoxazole compounds of formula (I) and their non-toxic salts exhibit a wide range of different pharmacological properties and can consequently be used in medicine.

Certain benzisoxazole compounds all have some or most of a number of pharmacological effects such as central nervous system depressant, muscle relaxant, vasodilator, anti-asthmatic, spasmogenic, analgesic, anti-narcotic, anti-arrhythmic, local anesthetic and anti-platelet aggregation effects.

The compounds of formula (I) in which R, stands for a C 1-2 alkoxy group and R^■ and R^ are each a C 1-2 alkyl group, show e.g. furthermore, generally strong inhibitory properties on both ADP- and collagen-induced platelet aggregation in vitro. Since anti-platelet aggregation agents are considered to be beneficial anti-thrombosis agents, they may be used as such agents.

The benzisoxazole compounds of formula (I) and their pharmaceutically acceptable salts can be administered parenterally or orally (with dosage adapted to individual requirements) in the form of conventional pharmaceutical preparations. They can e.g. supplied in the form of conventional solid pharmaceutical preparations such as e.g. tablets or capsules, or in the form of ordinary liquid pharmaceutical preparations such as e.g. suspensions, emulsions or solutions.

The benzisoxazole compounds of formula (I) are prepared according to the present invention from the corresponding o-substituted nitrobenzenes of formula

wherein Z is or

(wherein Rg is C^_^ alkyl) and

R 1 , R 2 , alk and A have the previously indicated meaning, by

to subject the aforementioned o-substituted nitrobenzenes to ring closure.

The cyclization can be carried out by the o-substituted nitro-

benzene of formula (II) wherein Z is

where R, is 6

C1-4 alkyl, is fused by treatment with a base or an acid to give the benzisoxazole compound of formula (I).

As a base, the use of a strong base such as e.g. potassium hydroxide, sodium hydroxide, potassium t-butoxide, sodium ethoxide, potassium methoxide, lithium triphenylmethane, sodium triphenylmethane or sodium hydride. As an acid, any acid with a dehydrating effect can be used, such as e.g. sulfuric acid or polyphosphoric acid.

The treatment is usually carried out in the presence of an inert solvent, and examples of inert solvents are alcohols such as e.g. t-butanol, ethanol, methanol, ethers such as ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, hydrocarbons such as e.g. heptane, hexane, benzene, toluene, amides such as dimethylformamide, hexamethylene-phosphorus triamide, water etc. The conditions under which the treatment is carried out, such as e.g. temperature and time may vary depending on the o-substituted starting nitrobenzene of formula (II) and the base or acid used. The treatment can be carried out under heating or cooling depending on the course of the reaction, but the temperature is usually from -20 to 100°C. The booth can be used in a stoichiometric amount or more, while the acid is preferably used in an excess amount so that it is used as a reaction medium.

An o-substituted nitrobenzene of formula (II) wherein Z is

can be further cyclized in a suitable reducing system to give the benzisoxazole compound of formula (I).

The reducing system can be constituted by the combination of a metal or a metal compound (e.g. tin, zinc, stannous chloride) with an acid (e.g. hydrochloric acid, acetic acid), the combination of an alkali metal (e.g. sodium, lithium, potassium, amalgamated sodium) with an alcohol or liquid ammonia, a sulphide compound such as sodium sulphide, ammonium sulphide or the like.

Among these, the most preferred reducing agent is the combination of a metal or a metal compound with an acid. The treatment with this special reducing agent can be carried out in the presence or absence of an inert solvent such as e.g. water, alcohols such as methanol, ethanol, hydrocarbons such as benzene, toluene or ethers such as ethyl ether, tetrahydrofuran, dioxane. An excess amount of the acid can also be used as a solvent. The temperature for the treatment can vary from room temperature to the return temperature for the reduction system. Likewise, the treatment using any other reducing agent can be carried out in a known manner adapted to each reducing agent.

The reduction system can also be a system for catalytic reduction, i.e. that a hydrogenation catalyst is used. In this case, conventional standard methods can be used, but it is recommended to use mild conditions to avoid too strong a reduction. Thus, a temperature of approximately room temperature, an atmospheric pressure for hydrogen gas and a relatively weak catalyst such as e.g. Pd-BaSO^, Pd-BaCO^ or metal catalyst which is poisoned with konoline, dimethyl sulphide, diethyl sulphide etc.

The benzisoxazole compounds of formula (I) prepared in this way can be separated from the reaction mixture and purified by conventional methods.

The thus obtained benzisoxazole compounds of formula (I) can be converted to their acid addition salts in the usual way and renewed conversion from the acid addition salts to the original free bases can also be carried out by usual methods.

The following examples are given to illustrate the invention.

EXAMPLE 1

To a mixture of 36 ml of t-butanol and 18 ml of toluene is added 1.8 g of metallic potassium followed by heating to a solution. To this solution is added 12.6 g of 1-(2'-nitro-4',5'-dimethoxy-phenyl)-1-(21 -(4"-phenyl-piperazino)ethyl)propan-2-one under cooling with water, followed by stirring for 4 hours at room temperature.

The reaction mixture is poured onto ice-mixed water and extracted with chloroform. The chloroform layer is washed with water, dried and evaporated to dryness. The oily residue is dissolved in ethyl acetate and mixed with 10 g of silica gel. The whole mixture was stirred for 30 min. and filtered to remove the silica gel. The filtrate was evaporated to dryness and the residue was crystallized in methanol-ether to give 7.0 g of 3-(2'-(4"-phenyl-piperazino)-ethyl)-5,6-dimethoxy-benz-2,1-isoxazole with a melting point of 115 - 117°C.

EXAMPLE 2

To 20 ml of sulfuric acid is added 2 g of 1-(2'-nitro-4',5'-dimethoxy-phenyl)-1(2'-(4"-phenylpiperazino)-ethyl)propan-2-one, followed by stirring in 4 hours at room temperature.

The reaction mixture was poured into ice-cold 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. This product was identical to the compound obtained in Example 1 .

EXAMPLE 3

To a solution of 9.03 g of stannous chloride dihydrate in 72 g of concentrated hydrochloric acid is added a solution of 2.59 g of 1-(2'-nitrophenyl)-3-dimethyl-amino-propan-1-one hydrochloride in 18 g concentrated hydrochloric acid, followed by stirring for 3 hours at room temperature.

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 evaporated to dryness. The oily residue was dissolved in ethanol and mixed with 4.5 g of oxalic acid in ethanol.

The deposited precipitates were collected and recrystallized from ethanol to give 2.2 g of 3-(2'-dimethylaminoethyl)-benz-2,1-isoxazole-oxalate with a melting point of 145-146.5°C.

EXAMPLE 4

Using the same procedure as described in

example 3, but replacing 1-(2'-nitrophenyl)-3-dimethylamino-propan-1-one hydrochloride with 1-(2'-nitro-5'-methoxyphenyl)-3-dimethylaminopropan-1-one hydrochloride , 3-(2'-dimethylaminoethyl)-5-methoxy-benz-2,1-isoxazole-oxalate with a melting point of 159-160°C was obtained.

EXAMPLE 5

A mixture of 0.8 g of 1-(2'-nitrophenyl)-3-dimethylaminopropan-1-one hydrochloride and 4.5 g of sodium sulfide in 45 ml of methanol was heated under reflux for 10 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and washed with water, dried and concentrated to dryness. The residue was chromatographed on silica gel and mixed with oxalic acid to give 3-(2'-dimethylaminoethyl)-benz-2,1-isoxazole-oxalate. This product was identical to the compound obtained in Example 3.

EXAMPLE 6

0.8 g of 1-(2'-nitrophenyl)-3-dimethylaminopropan-1-one hydrochloride in 12 ml of acetic acid was hydrogenated over 120 mg of 5% palladium-barium sulfate. After 2 equivalents of hydrogen were absorbed, the reaction mixture was filtered and the concentrate evaporated to dryness. The residue was dissolved in chloroform and washed with 2% aqueous

sodium hydroxide and then with water, dried and concentrated to dryness. The residue was chromatographed on silica gel and treated with oxalic acid to give 3-(2'--dimethylaminoethyl)-benz-2,1-isoxazole-oxalate. This product was identical to the compound obtained in Example 3.

The following compounds were prepared in the same manner as in Examples 1 and 3.

3-(2'-diethylaminoethyl)-5,6-dimethoxy-benz-2,1-isoxazole-cksalate, melting point 160 - 162°C.

3-(2<1->piperidinoethyl)-5,6-dimethoxy-benz-2,1-isoxazole-oxalate, melting point 199 - 200°C.

3-(2'-morpholinoethyl)-5,6-dimethoxy-benz-2,1-isoxazole-oxalate, melting point 133 - 185°C.

3-(3'-dimethylaminopropyl)-5,6,-dimethoxy-benz-2,1-isoxazole-oxalate, melting point 145 - 147°C.

3-(21 -(4"-phenylpiperazino)ethyl-5,6-methylene-dioxy-benz-2,1-isoxazole, melting point 126 - 127°C.

3-(2'-piperidinoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole, melting point 9 7.5 - 9 9.5°C.

3-(2'-diethylaminoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole-oxalate, melting point 168.5 - 169.5°C.

3-(2<1->morpholinoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole, melting point 116.5 - 119°C.

3-(2'-(4"-phenylpiperazino)ethyl)-benz-2,1-isoxazole-oxalate, melting point 194 - 196°C.

3-(2'-morpholinoethyl)-benz-2,1-isoxazole-oxalate, melting point 174 - 175°C.

3-(2'-piperidinoethyl)-benz-2,1-isoxazole-oxalate, melting point 154 - 155°C.

3-(2<1->pyrrolidinoethyl)-benz-2,1-isoxazole-oxalate, melting point 152 - 153°C.

3-(2'-(4"-methylpiperazino)ethyl)-benz-2,1,-isoxazole-oxalate, melting point 229 - 232°C.

3-(2<1->morpholinoethyl)-5-methoxy-benz-2,1-isoxazole-oxalate, melting point 178 - 180°C.

3-(2'-Di-n-propylaminoethyl)-5-methoxy-benz-2,1-isoxazole-oxalate, melting point 146 - 148°C.

3-(2'-dimethylaminoethyl)-5-ethoxy-benz-2,1-isoxazole-oxalate, melting point 153 - 155°C.

3-(2'-dimethylaminoethyl)-6-fluoro-benz-2,1-isoxazole-oxalate, melting point 150 - 151°C. 3 - (2'-morpholinoethyl) - 6-fluoro-benz-2,1-isoxazole-oxalate, melting point 176 - 177°C.

3-(2<1->dimethylaminoethyl)-6-methoxy-benz-2,1-isoxazole-oxalate, melting point 172 - 174°C.

3-(2'-morpholinoethyl)-6-methoxy-benz-2,1-isoxazole-oxalate, melting point 147 - 148°C.

Claims (1)

Analogous process for the preparation of pharmaceutically active benzisoxazole compounds of the general formula 1 2 in which R and R are each hydrogen, - C2 alkoxy or halogen or together form C1 - alkylenedioxy, Alk is C2 - alkylene and A is a group of formula 3 4 in which R and R are each C, - C2 alkyl or together with an adjacent nitrogen atom constitute a pyrrolidino, piperidino or morpholino group and R 5 is - C_ alkyl or phenyl, as well as non-toxic salts thereof, characterized in that either a ) an o-substituted nitrobenzene of the general formula 6 12 in which R is - alkyl and R , R , Alk and A have the above meaning, ring closure by means of treatment with a base or acid, or b) an o-substituted nitrobenzene of the general formula in which R 1 , R 2 , Alk and A have the above meaning, ring closure by treatment in a reducing system, after which a prepared compound is, if desired, converted into a non-toxic salt, or a prepared salt is converted into the corresponding free base.