CS233436B1 - 2-bromo-4- (2-chlorophenyl) -9-piperazino--H-thieno (3,2-f) -1,2,4-triazolo- (4,3-a) -1,4-diazepines and their methyl sulfonates - Google Patents

Abstract

The invention falls within the field of synthetic methanesulfonic acids. Siv. Its subject is 2-bromo-4-(2-chlorophenyl)-9-piperazine-6H-thieno(3,2-f)-1,2,4- -triazolo(4,3-a)-1,4-diazepines of the general formula I, in which R denotes methoxy, ethoxide, phenoxy, methylthio or phenylthio group and n denotes 2 or 3, and their methanesulfonates. The substances according to the invention have neurotropic effects, in particular sedative, centrally depressant and anticonvulsant and are suitable for therapy as tranquilizers in neurotics, as hypnotics in people suffering from insomnia and as anticonvulsants in epileptics. Two methods can be used for their preparation, the first of which consists in the substitution reaction of 2,9-dibromo-4-(2-chlorophenyl)-6H-thieno(3,2-f)-1,2,4-triazolo(4,3-a)-1,4-diazepine with the corresponding N-monosubstituted piperazinyl, in which the N-substituent is (CH2)nH (Ran is the same as in formula I). The second method consists in the alkylation of 2-bromo-4-(2-chlorophenyl)-9-piperazino-6H-thieno(3,2-f)-1,2,4-triazolo(4,3-a)-1,4-diazepine with substituted alkyl bromides RCCHOinQr, where R and n are again the same as in formula I. The obtained bases of formula I are converted into methanesulfonates by neutralization of acid.

Description

The invention relates to novel 2-bromo-4- (2-chlorophenyl) -9-piperazino-6H-thieno (3,2-f) -1,2,4-triazolo (4,3-a) -1,4- diazepines of formula I,

wherein R is aethoxy, ethoxy, phenoxy, methylthio or phenylthio and n is 2 or 3, and their methanesulfonates.

The literature (DOS 2,732,921; 2,732,943; Belg. 869,136) discloses 2-thromo-4- (2-chlorophenyl) -9-plperoino-6H-thieno (3,2-phenoxy) for some N-substituent derivatives. 1, 2,4-triesolo (4,3-e) -1,4-palzepine has significant neurotrophic effects, in particular hypnotic, anxiolytic, antispasmodic and sedative effects. It has now been shown that the new compounds of the formula I according to the invention have similar effects at very low toxicity. The properties of at least a few of them that have been found in animal fermecological tests may be mentioned. All of the compounds were tested in the form of methanesulfonates by oral administration, and the reported doses are calculated on a base basis.

2-Bromo-4- (2-chlorophenyl) -9- [4- (2-methoxyethyl) piperezino] -6H-thleno (3,2-f) -, 2,4-triazolo (4,3-a) -1,4-dlazepine shows a mean lethal dose in mice (LD 50) of approximately 300 mg / kg. The substance is highly effective in the anti-seizure test against electro-eye tt mice; its mean protective dose is 0.22 mg / kg. Furthermore, the substance is intensely palcoordinately effective in a rotating rod test in mice; the median effective dose inducing ataxia (BD 50) is about 1 mg / kg.

2-Bromo-4- (2-chlorophenyl) -9- [4- (2-ethoxyethyl) piperazino] -6H-thieno (3,2-f) -1,2,4-triezolo (4,3-a) -1,4-dlazepln exhibit acute toxicity in myěí LD ^ _Q also about 300 mg / kg.

In the mouse electro-eyed anti-seizure test, its ED is 0.98 mg / kg.

The other compounds of the invention described in the examples are even less toxic (their LD 50 is between 0.6 and 1.0 g / kg) and their mean protective doses are somewhat in the mouse electro-eye anticoagulant test. greater than 1 mg / kg. The same dose induces ataxia in 30-40% of mice in the rotating rod test. In summary, the compounds of formula (I) according to the invention are well-suited for use in therapy as trenquillizers in neurotics, as hypnotics in people suffering from insomnia, and as antlconvulsants in epileptics.

The compounds of the formula I according to the invention can be prepared by several methods, of which at least the most important two are illustrated in the examples. The first is the substitution reactions of the known 2,9-dibromo-4- (2-chlorophenyl) -6H-thieno (3,2-f) -1,2,4-trlazolo (4,3-e) -1,4- diazepine (Weber K.-H. et al., Lleblgs Ann. Chem. 1978. 1,257) with piper and sine derivatives of formula II.

R (CH ₂ ) "ΙθΙΗ _(II) in which Ran denotes the same as in formula I, using a 100-12058 excess (serving simultaneously as a cleaved hydrocarbon scavenger) for these plperinone derivatives and carrying out the reactions at temperatures of 60 to 65 ° C; ^e C in yields of 60 to 70 * ee obtained crystalline base of formula I which are converted by neutralization-acid methanesulphonate methaneulfonovnu not crystalline, which are part of this invention.

A second process for the preparation of the compounds of the formula I according to the invention consists in the alkylation reactions of my known 2-taro-4- (2-chlorophenyl) -9-piperazino-6H-thieno (3,2-f) -1,2,4-trlazelo ( 4, (I) -1,4-palzepine (DOS 2,732,943; Belg. 869,136) by means of substituted alkyl bromides of formula III,

R <CH ₂ ) "- Br (ΙΠ) in which Ran denotes again the same as in formula I. These alkylations are preferably carried out in an inert solvent, β preferably in boiling chloroform, in the presence of potassium carbonate · Base I are recovered in high yields and neutralization reactions were converted to methanesulfonates.

The identity of all the novel compounds according to the invention, i.e. the base of the formula I 1 of their methanesulfonates, was determined analytically and further by spectral methods, i.e. by ultraviolet, infrared, NMR and mass spectra.

Example 1

2-Aromo-4- (2-chlorophenyl) -9- [4- (2-methoxyethyl) plperezino] -6H-thieno (3,2-f) -1,2,4-triazolo (4,3- e) -1,4-diazepine

A mixture of 7.7 g of 2,9-dibromo-4- (2-chlorophenyl) -6H-thieno (3,2-f) -1,2,4-triazolo (4,3-e) -1,4-podzepine and 7.3 g of 1- (2-methoxyethyl) piparazine (Berrett PA et al., J. Chem. Soc. 1961).

404) was stirred and heated at 160-165 ° C under nitrogen for 2 h. After cooling, the mixture is dissolved in 100 l of dichloromethane, the solution is washed with 5% aqueous ammonia and water, the base is shaken with 58 aqueous hydrochloric acid, the separated aqueous solution is made alkaline with aqueous ammonia and the base is extracted with dichloromethane. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue (11.9 g) was chromatographed over a 50 g silica gel column. Elution with chloroform and chloroform containing 18% methanol yielded 5.55 g (63%) of the desired homogeneous base, mp 204-206 ° C, in the first fractions.

Crystallization from ethanol yields a pure substance, m.p. 205-207 ° C. Neutralization with methanesulfonic acid in ethanol yields a crystalline methanesulfonate which crystallizes from ethanol and melts at 238-240 ° C.

Example 2

2-Bromo-4- (2-chlorophenyl) -9- [4- (3-methoxypropyl) piperazino] -6H-thieno (3,2-f) -1,2,4-triezolo (4,3-a) -1,4-diazepine.

A mixture of 8.9 g of 2,9-dibroB-4- (2-chlorophenyl) -6H-thieno (3,2-f) -1,2,4-triazolo (4,3-a) -1,4-dlazepine and 9.2 g of 1- (3-methoxypropyl) piperazine were treated similarly to the previous example.

The crude product (11.9 g) was dissolved in 50 ml of chloroform and the solution was decolorized and filtered off through a 50 g silica gel column. The column is washed with 250 ml of chloroform and 750 ml of chloroform containing 28 methanol. The combined filtrates were evaporated in vacuo and the crystalline residue was purified by crystallization from 120 l of ethanol. 6.1 g (59%) of pure base melting at 214-216 ° C are obtained. Neutralization with methanesulfonic acid in a mixture of ethanol and ether affords crystalline methanesulfonate melting in pure state at 227-229 ° C (ethanol ether). Crystallization from 988 ethanol gave the monohydrate melting at 210-215 ° C.

The starting, - (3-methoxypropyl) piperazine is a substance which has not been described in the literature. The following procedure is suitable for its preparation:

A mixture of 110 g of 1-ethoxycarbonylplperazine, 96.1 g of potassium carbonate, 400 ml of dioxane and 106.4 g of 3-aethoxypropyl bromide (Smlth LI, Sprung JA, J. Amer. Chem. Soc. 65, 1276, 1943) is stirred for 5 minutes. , 5 h at 90 ° C. After standing overnight, the inorganic salts were filtered off and washed with dloxene. The filtrate was evaporated under reduced pressure, the residue basified with aqueous ammonia and extracted with dichloromethane. The extract was dried over potassium carbonate, evaporated and the residue distilled. 118.5 g (74%) of crude 1-ethoxycarbonyl-4- (3-methoxypropyl) plperazine are obtained.

233436 - 4 boiling at 99 to 111 ° C / 27 Pa. the pure substance is obtained by redistillation, m.p. 104 ° C / 20 Pa. Crystalline hydrochloride melting at 144.5-145 ° C (chloroform-ether) is suitable for characterization.

A mixture of 124.5 g of the previous carbaate, 152 g of potassium hydroxide and 150 µl of ethanol and stirred and refluxed for 4 h (internal temperature 95 ° C, bath temperature, 10 ° C). After partial cooling in the snow, it is diluted with 500 [mu] l of warm water, ethanol aa is evaporated off under reduced pressure and the cooled residue aa is extracted with chloroform. Treatment of the extract ae afforded 66.8 g (78%) of 1- (3-methoxypropyl) pI-rBS boiling at 94-98 ° C / 50 mbar. Redistillation of aa gives a completely pure substance, m.p. 95-96 ° C / 1.6 kPa. For characterization, the crystalline dlhydrochloride obtained, which crystallizes with a mixture of acetone and ethanol and melts at 210-212 ° C, is suitable for neutralization.

Example 3

2-Eromo-4- (2-chlorophenyl) -9- [4- (2-ethoxyethyl) piperazino] -6H-thleno (3,2-f) -1,2,4-triazolo (4,3-a) -1,4-palzapln

Mix 6.9 g of 2,9-dibromo-4- (2-chlorophenyl) -6H-thleno (3,2-f) -1,2,4-trlezolo (4,3-a) -1,4-palsepline and 7.1 g of 1- (2-ethoxyethyl) plperasin (Tkaczynakl T., Acte Polon. Fharm. 23, 355, 1966) and worked up similar to the preceding examples. 5.3 g (66%) of crude base melting at 183-187 ° C are obtained. Completely pure is obtained by crystallization from ethanol, m.p. 188-190 ° C. Neutralization with methanesulfonic acid in ethanol gave crystalline dlmethanesulfonate, m.p. 213-2.6 ° C (ethanol).

He attaches

Ek * 2-bromo-4 (2-chlorfanyl) -9- / 4- _(2-net! Hylthloathyl) piparaBlno / 6H-thlano (3,2-f) -1,2,4-triazol (4, 3-a) -1,4-diazapine

Mix 6.9 g of 2,9-dibromo-4- (2-chlorophanyl) -6H-thleno (3 ₎ -2-f -1,2,4-trlazolo (4,3-a) -1,4-palzepine and 7.2 g of 1- (2-methylthloethyl) plperazine (Stack EA, Org. Prep. Proced. Int. 7 (1), 1, 19751 Cham. Abetr. 83, 31, 547, 1975) were treated similar to those described in OVERVIEW OF EXAMPLES. The crude basic product (9.8 g) was chromatographed over a column of 50 g elllkegel. The fractions obtained by eluting with chloroform and chloroform containing 1'-methanol were combined (6.4 g) and purified by crystallization from smal, 20 ml of ethanol and 30 ml of chloroform. 5.6 g (69%) of the desired base melting at 240-242 ° C are obtained. Crystallization of ee amBal with ethanol and chloroform affords a pure product, mp 245-248 ° C. By neutralization with methanesulfonic acid in ethanol / ether ee, a crystalline methanesulfonate is obtained which crystallizes from said emission as a solvate and 1 molecule of ethanol, mp 248-250 ° C.

Example 5

2-Bromo-4- (2-chlorophenyl) -9- [4- (2-phenoxyethyl) piperazino] -6H-thleno (3,2-f) -, 2,4-trlazolo (4,3-a) - 4-dl azepl n

Mix 3.4 g of 2-bromo-4- (2-chlorophenyl) -9-plperazino-6H-thieno (3,2-f) -1,2,4-triazolo (4,3-a) -1 4-diazepine, 2.6 g of 2-phenoxyethyl bromide (Narval CS, Tanenbaum AL, Org. Syn., Coll. Vol. 1, 435, 1932). 2.5 g of potassium carbonate and 10 ml of chloroform are stirred and refluxed under nitrogen for 15 hours. After standing overnight, it is poured into 100 ml of water and extracted with chloroform. The extract was washed with water, dried over potassium carbonate and evaporated in vacuo. The residue is chromatographed on a 150 g elllkegel column. Elution with benzene and chloroform ee removes less polar material and then elutes 3.5 g (83%) of the homogeneous desired base, mp 204-206 ° C, with chloroform containing 1-3% methanol. Crystallization from ethanol-chloroform aa gives pure substance melting at 206-208 ° C. Neutralization with methanesulfonic acid in an ethanol / ether mixture yields crystalline methanesulfonate,

Tuesday crystallized from the emission of 9ΘΛ ethanol and ethers as a monohydrate, m.p. 213.5 and 215.5 ° C.

Example6

2-Bromo-4- (2-chlorophenyl) -9- [4- (2-phenylthioethyl) piperazino] -6H-thieno, (3,2-f) -1,2,4-triazolo (4 3-a) -1,4-diazepine

Mix 3.5 g of 2-taro-4- (2-chlorophenyl) -9-plperezino-6H-thieno (3,2-f) -1,2,4-triezolo (4,3-a) -1,4 -diazepine, 2.9 g of phenylthioethyl bromide (Scherlin SM, Jekubowltaeh A1, J. Prakt. Chem. / NF / 138, 23, 1933). 2.6 g of potassium carbonate and 10 ml of chloroform were treated as in the previous example. The crude product (5.1 g) was chromatographed on 150 g allikegel. After removing the less polar constituents of the alcohols with a mixture of bansane and chloroform and chloroform alone, the desired product is eluted with chloroform containing 1.5% methanol. The base is thus obtained in a yield of 3.5 g (77%) and melts at 201.5-204 ° C. The pure substances were crystallized from a mixture of ethanol and dichloromethane and melted at 202-203.5 ° C. Neutralization with methanesulfonic acid in ethanol and ether aa gives a crystalline aethanesulfonate melting at 258-261 ° C.

Claims (1)

2-Bromo-4- (2-chlorophenyl) -9-plperezino-6B-thleno (3,2-f) -1,2,4-triazolo (4,3-e) -1,4-diazepenes of Formula I (I) wherein R is methoxy, ethoxy, phenoxy, methylthio or phenylthio and n is 2 or 3, and their methanesulfonates.