DE1643265C3 - Nuclear-substituted 2-aminomethylbenzhydrols, processes for their preparation and pharmaceuticals based on these compounds - Google Patents

Description

15th

in the

Ri is hydrogen or an alkyl radical with 1-4

Carbon atoms,
R ^{2 is} a halogen atom or the trifluoromethyl group

and
R ³ denotes hydrogen or a chlorine atom and their acid addition salts.

2. 2-Methy! Aminomethyl-4'-chloro-benzhydrol and its acid addition salts.

3. 2-methylaminomethyl-4'-fluoro-benzhydrol and its acid addition salts.

4. Process for the preparation of the compounds according to claim 1, characterized in that one each in a manner known per se j <> a) a phthalide of the general formula H

(M)

in the

R ² and R ^{3 have} the meaning given in claim 1

possess, with an amine of the general formula III

H ₂ NR ¹ (III)

in the

R ¹ denotes hydrogen or an alkyl radical having 1-4 carbon atoms, and the compound of the formula IV thus obtained

Il

C-NH-R ¹

Have meaning, reduced to the end product,

or that one

b) an indoline of the general formula V.

NR ¹

in which R ¹ , R ² and R ^{3 have} the meaning given in claim 1, with a carboxylic acid anhydride into a compound of the general formula Vl

(IV)

CH-OH

R ²

and R 'indicated in claim 1

(Vl)

-R ¹

in which R ¹ , R ² and R ^{3 have} the meaning given in claim 1 and Ac is an acyl group, converts, deacylates this compound and, for the preparation of compounds according to claim 1, the corresponding aminomethylbenzhydrols in which R ^{1 is} a hydrogen atom, N- alkylated, and that the end product thus obtained is optionally converted into a physiologically acceptable acid addition salt

5. Pharmaceutical preparations containing as active ingredient one of several compounds of the Formula 1 or their physiologically harmless acid addition salts in a dosage of 10-100 mg per dose.

The compounds according to the invention have a pronounced appetite-suppressing effect; the unwanted, with the known appetite suppressants, however, meisi has a very strong stimulating effect on the The central nervous system is only weakly developed in the compounds obtainable according to the invention.

Two processes have proven to be particularly advantageous for the production of the new compounds:

In the case of the ring opening according to variant a) according to claim 4, a phthalide of the general type is initially used Formula II in an inert solvent, for example an alcohol, benzene, toluene or xylene dissolved and with an amine of the general formula III offset. If the amine of the formula III is a liquid, the reaction can also be carried out without additional solvent can be carried out. In some cases, the reaction already takes place Room temperature, but in general it is

more advantageous at higher temperatures, optionally at the reflux temperature of the one used Solvent to work.

In this way, the corresponding aminocarbonyl compounds of the formula IV are obtained; whose Carbonyl group in the usual way, for example with complex hydrides such as lithium aluminum hydride for CH2 group is reduced.

In the event that R ^{1 is} a hydrogen atom, the N-alkyl compound is produced by customary methods, for example by reaction with a corresponding alkyl halide or dialkyl sulfate

In the ring opening according to variant b) according to claim 4, a compound of the general Formula V in the relevant anhydride or i> together with the anhydride in a solvent dissolved and preferably heated under reflux. The reaction time depends on the particular one used Reaction components and can fluctuate between a few minutes and several days. To When the reaction is terminated, the diacylated compound of the formula VI is isolated; to make the not acylated end products of formula I is the compound of formula VI in a suitable inert Solvent dissolved and heated after adding a strong >> base, preferably an alkali hydroxide. To At the end of the deacylation, the benzhydrol of the general formula I is isolated by customary methods

The compounds of the formula I obtained in the deacylation, in which R ^{1 is} hydrogen, are likewise alkylated as indicated under a)

The end products of the general formula I obtained by one of the processes mentioned can if desired, can be converted into their acid addition salts in the customary manner. Suitable for salt formation Acids are, for example, inorganic acids such as hydrohalic acids, sulfuric, nitric, phosphoric or perchloric acid; also organic acids such as ant, vinegar, propionic, oxalic, amber, tartaric, Lemon, maleic, ascorbic, salicylic, methanesulfone κι or toluenesulfonic acid.

According to the method explained in more detail above, z. B. the following end products - preferably in the form of their salts with the abovementioned acids - are obtained: 4 ^r >

2-methylaminomethyl-4'-fluoro-benzhydrol,

2-methylaminomethyl-2'-chlorobenzhydrol,

2-methylaminomethyl-3'-chlorobenzhydrol,

2-methylaminomethyl-4'-chlorobenzhydrol,

2-methylaminomethyl-4'-bromobenzhydrol, '"

2-methylaminomethyl-4'-iodo-benzhydrol,

2-methylaminomethyl-3'-trifluoromethyl-

benzhydrol,
2-methylaminomethyl-3'-trifluoromethyl-4'-chloro-

benzhydrol, ''

2-ethylaminomethyl-4'-chlorobenzhydrol,
2-n-butylaminomethyl-4'-chloro-benzhydroI,
2-isobutylaminomethyl-4'-chloro-benzhydrol.

The compounds used as starting materials wi of the general formula II can be obtained by processes known per se, for example by treating an O-acylbenzoic acid with zinc dust in acetic acid with heating.

Isoindolines of the general formula V are produced, for example, by Grignardation of a phthalimide with a compound Z - Mg - Hal and subsequent reduction of the 1-hydroxy-3-oxoisoindoline formed (Z is a through the radicals R ² and R ^J substituted phenyl radical).

The acid addition salts of the new compounds are preferred for use in therapy with common pharmaceutical fillers or carriers, stretching, disintegrating, binding, sliding, thickening or diluents, solvents or solubilizers or agents for achieving one Depot effect mixed which allow enteral or parenteral use. As pharmaceutical preparation forms come z. B. tablets, coated tablets, pills, capsules, solutions, suspensions or emulsions in Question, in addition to the new active ingredients, e.g. B. still preservatives or stabilizers, emulsifiers and buffer substances can be added. The pharmaceutical preparations should in general 10-100 mg, preferably 20-50 mg of active substance per Dose included.

The following examples serve to explain the invention in more detail:

example 1
2-methylaminomethyl-4'-chlorobenzhydrol · HCl

12.3 g (0.05 mol) of 3- (4-chlorophenyl) phthalide was dissolved in 500 ml of benzene saturated with methylamine. The mixture was left in a flask fitted with a calcium chloride tube for 48 hours at room temperature and then evaporated to dryness under a water jet. The remaining 2-methylaminocarbonyl-4'-chlorobenzhydrol was recrystallized from ethanol / petroleum ether.
Mp 150-152 ° C, yield 3.2 g (97%).

A solution of 13.2 g (0.048 mol) of the 2-methylaminocarbonyl compound in 100 ml of tetrahydrofuran and 50 ml of ether became a refluxing one Suspension of 3.8 g (0.1 mol) of lithium aluminum hydride in 200 ml of ether was added. The mixture was 3 hours heated to reflux. After cooling, the excess lithium aluminum hydride was mixed with excess Potassium hydroxide solution destroyed. The solid components were removed by filtration through the ether phase dried over magnesium sulfate and then filtered. The ether was drawn off in a water jet vacuum. Of the The residue was dissolved in ethanol and hydrogen chloride with cooling until a weakly acidic reaction initiated. The material crystallized on addition of ether.

The 2-methylaminomethyl-4'-chlorobenzhydrol hydrochloride was recrystallized from ethanol / ether.
Mp 224-227 ° C; Yield 93g (71%).

Example! 2
2-methylaminomethyl-4'-bromobenzhydrol · HCl

a) 17 g of 3- (4-bromophenyl) phthalide were dissolved in 500 ml of benzene Methylamine IV initiated for 2 hours at 10 ° C. The mixture was left for 3 days at room temperature left. Most of the solvent was removed in vacuo and the residue off Ether / petroleum ether recrystallized. 2-Methylaminocarbonyl-4'-bromobenzhydrol was obtained from Mp. 144-145 ° C in a yield of 18.5 g (98%).

b) A solution of 18.5 g of the 2-methylaminocarbonyl compound in 100 ml of tetrahydrofuran and 50 ml of ether became a refluxing one Suspension of 3.8 g of lithium aluminum hydride in

200 ml of ether added. The mixture was refluxed for 3 hours after cooling was the excess lithium aluminum hydride with excess potassium hydroxide solution destroyed The solid constituents were separated off by filtration, the ether phase over magnesium sulfate dried and filtered. The ether was stripped off in vacuo. The residue was taken up in ethanol and hydrogen chloride initiated until the weakly acidic reaction with ι ο cooling. After recrystallization 2-MethylaminomethyW-bromobenzhydrol hydrochloride was obtained from methanol / ether of melting point 206-207 ° C. in a yield of 12.7 g (65%).

15th

Example 3

2-methylaminomethyl-3'-trifluoromethylbenzhydrol · HCl

15.3 g of 3-trifluoromethylphthalide were in with> « Dissolved methylamine saturated ethyl alcohol and left for one hour at 20 "C. The mixture was then evaporated to dryness and the residue recrystallized from benzene / petroleum ether. You got that 2-methylaminocarbonyl-3'-tΓifluoromethyl-benzhydrol of melting point 99-100 ° C. in a yield of 15 g (90%).

14.3 g of 2-methylaminocarbonyl-3'-fluoromethylbenzhydrol were dissolved in 100 ml of tetrahydrofuran and this solution was cooled and stirred Solution of 3.5 g of lithium aluminum hydride in 100 ml of jo added dropwise to dry tetrahydrofuran. The mixture was stirred while refluxing for 3 hours and then cooled. The excess lithium aluminum hydride was removed by adding dropwise Water destroys and the inorganic precipitate J5 removed by filtration. The filtrate was dried over magnesium sulfate and in vacuo to Evaporated to dryness The residue was converted into the hydrochloride by addition of ethereal hydrochloric acid transferred and recrystallized from ethanol / ether / petroleum ether The 2-methylaminomethyl-3'-trifluoromethylbenzhydrol hydrochloride of melting point was obtained. -162 ° C in a yield of 8.0 g (53%).

Example 4

2-methylaminomethyl-4'-chlorobenzhydrol ■ HCl

a) 66 g of l- (4-ChIorphenyl) -N-methylisoindoline were dissolved in 700 ml of acetic anhydride and heated under reflux for 24 hours, the major part of the acetic anhydride is then evaporated in vacuo and the concentrated solution maintained at 0 ⁰ C. That crystallized out

2- (N-Methyl-N-acetyl) -aminomethyl-4'-chloro-O-acetyl-benzhydrol was filtered off, washed with ether and dried. Mp 135 ° C, yield 17.5 g (81.6%).

b) 187 g of 2- (N-MethyI-N-acetyI) -aminomethyl-4'-chloro-O-acetylbenzhydrol and 500 ml of 50% strength aqueous potassium hydroxide solution in 1200 ml of ethylene glycol were refluxed for 8 hours. After cooling, 3000 g of ice were added to the solution and the mixture was extracted 5 times with 500 ml of methyl acetate each time. The combined ethyl acetate extracts were washed with sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was taken up in ethanol and the hydrochloride was precipitated by adding ethereal hydrochloric acid. After recrystallization from ethanol, the hydrochloride had a melting point of 226-227 ° C.
Yield 135g (84%).

Example 5
2-methylaminomethyl-4'-fluoro-benzhydrol · HCl

a) 50 g of 1- (4-fluorophenyl) -N-methylisoindoline were dissolved in 500 ml of acetic anhydride and refluxed for 16 hours. The main part of the acetic anhydride was drawn off in vacuo and the concentrated solution was ^{left to stand at 0 °} C. for crystallization. The 2- (N-methyl-N-acetyl) -aminomethyl-4'-fluoro-O-acetyl-benzhydroI was filtered off with suction, washed with ether and dried

Yield 51.7 g (71.5%); M.p. 106 ° C.

b) 50 g of 2- (N-methyl-N-acetyl) aminomethyl-4'-fluoro-O-acetyl-benzhydrol and 125 ml of 50% aqueous potassium hydroxide solution were refluxed for one hour in 1250 ml of ethylene glycol Solution was diluted with 1000 g of ice and extracted 5 times with 200 ml of ether each time. The combined ether extracts were washed with sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in ethanol and the hydrochloride was precipitated with ethereal hydrochloric acid.
After recrystallization from ethanol, the hydrochloride had a melting point of 231 ° C.
Yield 31.2g (73%).

Example 6
2-methylaminomethyl-2'-chlorobenzhydrol ■ HCI

12 g of 1- (2-chlorophenyI) -2-methylisoindoiine and 100 ml of acetic anhydride were refluxed for 5 days heated. The acetic anhydride was then removed in vacuo and the residue with dilute Treated aqueous ammonia and extracted 5 times with 50 ml of ether each time. The combined ether extracts were successively with dilute hydrochloric acid, water and saturated sodium carbonate solution washed, dried and evaporated to dryness.

The residue consisting of 15 g of a dark oil was dissolved in 70 ml of ethylene glycol and 35 ml of 50% strength aqueous potassium hydroxide solution and heated under reflux for 2 hours. The mixture was then diluted with 200 g of ice and extracted 3 times with 100 ml of ether each time. The combined ether extracts were washed with water, dried and evaporated to dryness. The residue was dissolved in ethanol and neutralized with ethereal hydrochloric acid. The precipitate was recrystallized from ether / petroleum ether.
Yield 9 g (61%), m.p. 205 ° C.

Following the procedure of Example 6, from 70 g of 1- (3-chlorophenyl) -2-methylisoindoline, 25 g (29%) of 2-Me-

ethylaminomethyl-S'-chlorobenzhydrol · hydrochloride
obtained of m.p. 174 ° C.

Example 7
2-n-Butylaminomethyl-4'-chlorobenzhydrol · HCl

g of 1- (4-chlorophenyl) -2-n-butylisoindoline and 100 ml of acetic anhydride were refluxed for 30 hours heated. The acetic anhydride was then removed in vacuo and the residue washed with water and diluted

Treated with ammonia.

The organic substance was extracted 3 times with 100 ml of ether each time. The combined ether extracts were washed with dilute hydrochloric acid, water and saturated sodium carbonate solution, dried and evaporated to dryness. The dark brown oily residue was chromatographed on silica gel in the usual manner using a chloroform-methanol-ammonia mixture (97: 3: 0.5% by volume) as the eluent. The main fraction consisted of 6 g of an ι ο light yellow oil, which was used as such for the following reaction. 6 g of the oil obtained by the above process, 30 ml of ethylene glycol and 15 ml of 50% strength aqueous potassium hydroxide solution were refluxed for 6 hours, cooled to room temperature and diluted with 100 ml of water. The mixture was extracted 3 times with 50 ml of ether each time, and the combined Ether extracts washed with water, dried and evaporated to dryness. The residue was converted into the hydrochloride by neutralization with ethereal hydrochloric acid and the crystalline precipitate was recrystallized from ether / ethanol
Yield 3.2 g (27 ° / o), mp. 102- 105 ⁰ C.

Example 8
2-Isobutylaminomethyl-4'-chloro-benzhydrol · HCl

25th

18 g of l- (4-chlorophenyl) -2-isobutylisoindoline were in 180 ml of acetic anhydride heated under reflux for 15 hours. The solution was concentrated to a volume of about 50 ml by evaporation under reduced pressure and then poured onto ice / ammonia. The diacetyl compound was extracted with ether, the combined ether extracts washed with acid, water and saturated sodium carbonate solution, over Magnesium sulfate dried and finally evaporated to dryness. The obtained 17 g of the dark oil were dissolved in 90 ml of ethylene glycol and after the addition of 45 ml of 50% aqueous potassium hydroxide solution 10 Heated under reflux for hours. After dilution with g of ice, the mixture was extracted 3 times with 200 ml of ether each time combined ether extracts washed with 100 ml of water, dried and evaporated. The residue was on 600 g of silica gel using a mixture of 90 parts of benzene and 10 parts of methanol chromatography as eluent. The purified material was dissolved in ether and with ethereal Hydrochloric acid precipitated. After recrystallization from ethanol / ether, 6 g (28%) of the hydrochloride were obtained from m.p. 154 ° C.

Example 9

2-methylaminomethyl-3'-trifluoromethyl-4'-chlorobenzhydrol ■ HCI

a) 10 g of 1- (3-trifluoromethyl-4-chlorophenyl) -2-methylisoindoline and 100 ml of acetic anhydride were 1 Refluxed week. Most of the acetic anhydride was removed in vacuo, the Treated residue with ice and ammonia and extracted with ether. The ethereal solution was washed with Water, dilute hydrochloric acid and sodium carbonate solution and washed over magnesium sulfate dried. After the solvent had been stripped off in vacuo, 12.5 g of 2- (N-methyl-N-acetyl) -aminomethyl-S'-trifluoromethyM'-chloro-O-acetylbenzhydrol were obtained as a dark colored oil.

b) 12.5 g of the oily 2- (n-methyl-N-acetyl) aminomethyl-S'-trifluoromethyl ^ '- chloro-O-acetyl-benzhydrols, 40 ml of 50% potassium hydroxide solution and 120 ml of ethylene glycol were 2 hours The mixture was then diluted with 200 ml of water and acidified with concentrated hydrochloric acid. The hydrochloride which had crystallized out was recrystallized twice from ethanol / ether
Yield 7 g (69%), m.p. 253 ^° C.

Claims (1)

Patent claims: 1. Nuclear-substituted 2-aminomethyl-benzhydrols the general formula NH-R ¹ (D lü