CS210532B1 - S-fluoro-5-/4-fluprophenyl/-2,3,4,5-tetrahydro-1h-1-benzazepine - Google Patents

Abstract

The invention relates to novel 1- (aminoacetyl) - and 1- (2-aminoethyl) -8-fluoro-5- (4-fluorophenyl) - -2,3,4,5-tetrahydro-1H-1-benzazepines and their salts with pharmaceutically acceptable inorganic salts or organic acids. Aminogroups in these substances it is either a residue saturated aliphatic or heterocyclic secondary amine with 2-5 carbon atoms or is a 4-substituted a piperazine residue in which the 4-substituent is methyl, 2-hydroxyethyl or 2-acyloxyethyl. The substances according to the invention are characterized a variety of pharmacodynamic effects makes them potentially neurotropic, circulatory and anti-inflammatory drugs. I prepare the known 8-fluoro-5- (4-fluorophenyl) - -2,3,4,5-tetrahydro-1-1-benzazepine, which is first reacted with chloroacetyl chloride converted to the 1-chloroacetyl derivative. With that make substitution reactions with excess secondary amines and the resulting 1- (aminoacetyl) derivatives are reduced with lithium aluminum hydride to the corresponding 1- (2-aminoethyl) derlvates. Substances with free primary alcoholic group in a branched chain (substituted Piperazinoethanol) Acidates Acid Chlorides to the respective esters. All basic the products provide neutralization with acids the corresponding salts (especially hydrochlorides, oxalates).

Description

The invention relates to 8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine derivatives of the general formula I,

wherein X is CO or CH 2 and B is a diethylamine or pyrrolidine residue or a substituted piperazine residue of formula / S-N NCH, -R wherein R represents a hydrogen atom, hydroxymethyl or acyloxymethyl, wherein acyl is a propionic or o-chlorobenzoic acid residue, and pharmaceutically acceptable salts with inorganic or organic acids.

The compounds of formula I and their salts are characterized by a number of pharmacodynamic effects which make them potential neurotrophic, circulating and anti-inflammatory drugs.

In particular, the following properties have been found in animal tests for each substance:

Substance I, X = CO, B = NCCgH, γg, exhibits acute toxicity in mice by oral administration, LD50 = 400 mg / kg. At a dose of 0 mg / kg, the compound elicits a slight central excitation in mice, i.e., increases their motility by 50% compared to the control group. At a dose of 80 mg / kg, the substance has a hypothermic effect in rats (decreasing the rectal temperature of rats by 1.0 ° C). At the same dose, it acts counteract in the electroshock test in mice (protecting 50% of the mice against hind limb convulsions induced by electric shock).

Compound I, X = CO, B = pyrrolidino, exhibits acute toxicity in mice LD50 = 400 mg / kg when administered orally. It has an anticonvulsant effect against pentetrazole in mice; an oral dose of 2.5-5 mg / kg significantly prolongs the latency of pentetrazole seizures. At a dose of 80 mg / kg, it also antagonizes the convulsive effect of electric shock in mice. At a dose of 25 mg / kg, the anti-inflammatory effect in the edema test induced by subplantar administration of 0.1 ml of a 1096 kaolin suspension in the rat (has a three-fold greater effect than phenylbutazone). At a dose of 80 mg / kg, the blood pressure of normotensive rats is reduced by 12% within 24 hours after administration.

Substance I, X = CHg, B = ¢ 1 (02 ^) 2: acute toxicity in mice by intravenous administration,

LD50 = 60 mg / kg. At an intraperitoneal dose of 12 mg / kg, it has an antireserpine effect in mice (significantly abolishing reserpine-induced ptosis). At a concentration of 10 µg / ml, it reduces the contraction of the isolated rat duodenum induced by both acetylcholine and barium chloride to 50%.

At an i. V. Dose of 12 mg / kg, the blood pressure of normotensive rats is reduced by 20% for at least 10 minutes.

Compound I, X = CO, B = 4-methylpiperazino: acute toxicity in mice by oral administration, LD50 = 1000 mg / kg. At an oral dose of 200 mg / kg, the compound has an anticonvulsant effect against electroshock in mice.

Compound I, X = CO, B = 4- (2-hydroxyethyl) piperazino: acute iv toxicity in mice, LD50 = 100 mg / kg. At 196 concentrations, it has a local anesthetic effect in guinea pigs in an infiltration anesthesia test equal to that of procaine. At a concentration of 50 µg / ml, it increases the inotropy of the isolated rabbit atrium by 25% and at the same time decreases the frequency by 25 56. At an iv dose of 20 mg / kg, it reduces the blood pressure of normotensive rats by 20-30 56 for several minutes; at the same dose, it reduces the adrenaline presoric response in rats by 50%. Substance I, X * CO, B = 4- (2-propionoxyethylpiperazino; acute toxicity in mice by iv administration, LD ₅₀ = 50 mg / kg, IV iv dose of 10 mg / kg induces a short and deep fall in blood pressure in normotensive rats.

Compound I, X CHg, B 4-methylpiperazino; acute oral toxicity in mice, LD 50 ⁼ 335 mg / kg. At an oral dose of 50 mg / kg, it reduces the locomotor activity of the mice by 50%.

At the same dose, it prolongs the duration of thiopental sleep in mice to twice the control value. At the same dose, it has an anticonvulsant effect against electroSok in mice (protecting 50% of the mice).

The exemplary embodiments describe in detail methods for preparing the compounds of the invention. These include several synthetic methods. The common starting material is the known 8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine of formula II (M. Rajšner et al., Collect. Czech. Chem. Commun. 43, 1760 (1978). which, by treatment with chloroacetyl chloride in chloroform in the presence of potassium carbonate, affords the novel chloroacetyl derivative of formula 111.

Substitution reactions of compound III with excess diethylamine, pyrrolidine, 1-methylpiperazine and 1- (2-hydroxyethyl) piperazine in benzene gave compounds I, X = CO and B = residues of said secondary amines. Reduction of these products with lithium aluminum hydride in an ether / benzene mixture resulted in compounds I with X = CHg and B = again the residues of said secondary amines. Compounds of formula I with X = CO or CH2 and B = 4- (2-hydroxyethyl) piperazino can be converted by acylation with the appropriate acyl halides in chloroform in the presence of potassium carbonate to the corresponding esters. All prepared compounds are basic in nature and provide neutralization with inorganic or organic acids to provide the appropriate salts, many of which crystallize well. Salts with the pharmaceutically acceptable acids included in the present invention are more preferred than the free bases for performing pharmacological tests and for preparing appropriate dosage forms.

Examples

1. 8-Fluoro-5- (4-fluorophenyl) -1- (4-methylpiperazinoacetyl) -2,3,4,5-tetrahydro-1 H -1-benzazepine

A mixture of 20.0 g of 8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine, 14.0 g of potassium carbonate and 50 ml of chloroform is stirred while stirring for 20 minutes. A solution of 12.0 g of chloroacetyl chloride in 50 ml of chloroform was added dropwise. The mixture was refluxed for 1 h, allowed to stand overnight at room temperature, then quenched with 120 mL of water and stirred for 20 min. The organic layer was then separated, dried over sodium sulfate and evaporated under reduced pressure. The residual oil crystallizes upon mixing with a little hexane. Extraction gave 21.0 g (79%) of crude 1- (chloroacetyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1 H -1-benzazepine (XII) with mp 130-132 ° C. Crystallization from a mixture of benzene and hexane gave the pure product, m.p. 133-134 ° C.

A mixture of 10.1 g of 1- (chloroacetyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine, 7.5 g of 1-methylpiperazine and 70 ml of benzene The mixture was refluxed for 9 h and then allowed to stand overnight at room temperature. The suspension is then quenched with dilute aqueous ammonia and extracted with benzene. The extract was washed with water, dried and evaporated. 11.0 g (92%) of the crude desired base are obtained, which crystallizes on standing, m.p. 163-165 ° C. Crystallization from ethanol gave the pure base, mp 164-165 ° C. Neutralization with hydrogen chloride in ethanol gives a crystalline dihydro chloride which melts at 244-245 ° C (aqueous ethenol).

2. 1- (Die tylaminolation tyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1 H -1-benzazepine

Deer 10.1 g of 1- (chloroacetyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 1), 5.5 g of anhydrous diethylamine and 70 ml of benzene was refluxed for 9 h and then treated in a similar manner to that described in Example 1. 8.8 g (79%) of the crystalline base were obtained, mp 104-105 ° C (cyclohexane). Neutralization with oxalic acid in a mixture of ethanol and ether gives a crystalline hydrogen oxalate of m.p. 206-207 ° C (ethanol-ether).

3. 8-Fluoro-5- (4-fluorophenyl) -1- (pyrrolidinoacetyl) -2,3,4,5-tetrahydro-1H-1-benzazepine

A mixture of 10.1 g of 1- (chloroacetyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 1), 5.3 g of pyrrolidine and 70 g ml of benzene is refluxed for 7 h and then treated in a similar manner as described in Example 1. The crude oil base is obtained in a theoretical yield of 11.0 g. It crystallizes from cyclohexane as a solvate with 1/3 of the solvent molecule and melts. at 97-98 ° C. Neutralization provides hydrogen oxalate, mp 211-212 ° C (ethanol-ether).

4. 8-Fluoro-5- (4-fluorophenyl) -1- [4- (2-hydroxyethyl) piperazino] acetyl-2,3,4,5-tetrahydro-1 H -1-benzazepine

A mixture of 20.2 g of 1- (chloroacetyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 1), 19.0 g of 1- ( Of 2-hydroxyethyl) -piperazine and 40 ml of benzene are refluxed for 7 h and then treated in a similar manner as described in Example 1. 17.5 g (68%) of the crystalline base are obtained with mp 150-151. ° C (benzenhexane). Neutralization with hydrogen chloride and ethanol / ether and crystallization from aqueous ethanol / ether gave crystalline dihydro chloride as a hemihydrate, mp 226-227 ° C.

5. 8-Fluoro-5- (4-fluorophenyl) -1- (2-pyrrolidinoethyl) -2,3,4,5-tetrahydro-1H-1-benzazepine

A solution of 5.0 g of 8-fluoro-5- (4-fluorophenyl) -1- (pyrrolidinoacetyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 3) in 70 ml of benzene is added dropwise to the stirred a suspension of 2.5 g lithium aluminum hydride in 70 ml of ether and refluxed for 7 h. After cooling, it is slowly quenched by the addition of 10 ml of 20% sodium hydroxide solution, stirred for 30 min, the solid is filtered off, washed with benzene and the filtrate is evaporated. 4.9 g (100%) of an oily base are obtained. Neutralization with anhydrous hydrogen chloride in ethanol / ether gives the sesquihydrochloride, which crystallizes from a mixture of aqueous ethanol and ether as a hemihydrate and melts at 195-196 ° C. The oxalate crystallizes from a mixture of ethanol and ether and melts at 99-200 ° C.

6. 1- (2-Diethylaminoethyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1 H -1-benzazepine

A solution of 4.1 g of 1- (diethylaminoacetyl) -8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 2) in 50 ml of benzene is reduced in a similar manner to in Example 5 using 2.5 g of lithium aluminum hydride in 70 ml of ether. The theoretical yield is an oily base which, by neutralization with hydrogen chloride in ether, gives crystalline monohydrochloride in a yield of 4.1 g (86%), m.p. 196-197 ° C (ethanol-ether).

7. 8-Fluoro-5- (4-fluorophenyl) -1- [2- (4-ethylpiperazino) ethyl] -2,3,4,5-tetrahydro-, 1H-1-benzazepine

A solution of 5.1 g of 8-fluoro-5- (4-fluorophenyl) -1- (4-methylpiperazinoacetyl) -2,3,4,5-tetrahydro-1H-benzazepine (Example 1) in 80 ml of benzene was reduced. similar to Example 5 with 2 > 5 g of lithium aluminum hydride in 70 ml of ether. The theoretical yield was an oily base which, by neutralization with hydrogen chloride in ether, gave 6.2 g (98%) of the dihydrochloride, m.p. 239-240 ° C (aqueous ethanol).

8-Fluoro-5- (4-fluorophenyl) -1- (2- / 4- (2-hydroxyethyl) piperazino / ethyl) -2,3,4,5-tetrahydro-1 H -1-benzazepine

A solution of 16.5 g of 8-fluoro-5- (4-fluorophenyl) -1- [4- (2-hydroxyethyl) piperazino] acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (Example 4) in 150 ml of benzene was reduced, as in Example 5, with 6.0 g of lithium aluminum hydride in 120 ml of ether. The theoretical yield (16.0 grams) gave an oily base which, as in the previous cases, gave a crystalline dihydrochloride, m.p. 225-226 ° C (aqueous ethanol-ether).

9. 8-Fluoro-5- (4-fluorophenyl) -1- (2- / 4- (2-propionoxyethyl) piperazino / ethyl) -2,3,4,5-tetrahydro-1H-1-benzazepine

A mixture of 5.0 g of 8-fluoro-5- (4-fluorophenyl) -1- (2- / 4- (2-hydroxyethyl) piperazino / ethyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 8), 2.0 g of anhydrous potassium carbonate and 20 ml of chloroform are stirred and a solution of 1.52 g of propionyl chloride in 15 ml of chloroform is added dropwise over 30 minutes. The mixture was refluxed for 1 h, cooled, quenched with 50 mL of water and extracted with chloroform. The extract was washed with 10% sodium carbonate solution and water, dried over sodium sulfate and evaporated. An oily base is obtained in a theoretical yield of 5.67 g. It gives the dihydrochloride melting at 91-192 ° C (95% ethanol-ether).

10,8-Fluoro-5- (4-fluorophenyl) -1- [4- (2-propionoxyethyl) piperazino] acetyl-2,3,4,5-tetrahydro-1 H -1-benzazepine

Acylation 4.5 g of 8-fluoro-5- (4-fluorophenyl) -1- [4- (2-hydroxyethyl) piperazino] acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (Example 4) is carried out with 1.32 g of propionyl chloride in 30 ml of boiling chloroform in the presence of 1.7 g of anhydrous potassium carbonate, similarly as described for the analogous example in Example 9. In the theoretical yield (5.2 g), an oily base is obtained. which, as in the previous cases, gives crystalline dihydrochloride, mp 190-19 ° C (ethanol-ether).

11. 8-Fluoro-5- (4-fluorophenyl) -1- (2- / 4- (2-o-chlorobenzoyloxyethyl) piperazino / ethyl) -2,3,4,5-tetrahydro-1 H -1-benzazepine

Acylation 5.0 g of 8-fluoro-5- (4-fluorophenyl) -1- (2- / 4- (2-hydroxyethyl) piperazino / ethyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (Example 8) is carried out with 2.45 g of o-chlorobenzoyl chloride in 35 ml of boiling chloroform in the presence of 4.0 g of anhydrous potassium carbonate similarly as described for the analogous example of Example 9. 6.0 g (90%) are obtained. An oily base which, as in the previous cases, gives a crystalline dihydrochloride, mp 199-200 ° C (95% ethanol-ether).

Claims (1)

SUBJECT OF THE INVENTION 8-Fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-1-benzazepine derivatives of formula I wherein X is CO or 0 'and B is diethylamine or pyrrolidine or substituted piperazine. -N_NCH formula -R ₂ wherein R is hydrogen, hydroxymethyl or acyloxymethyl wherein the acyl is the residue of propionic acid or o-chlorobenzoic acid, and the pharmaceutically acceptable salts thereof with inorganic or organic acids.