CS252325B1 - Substituted 5,7-dihydrodibenzo (c, e) thiepines and their salts - Google Patents

Abstract

The invention relates to substituted 5,7-dihydrodibenzo(c,e)-thiepines of the general formula in which X represents a CO or (CH2)a group, where ϊ is? 1, 2 or 3) R denotes the group OH, NHCH^ or N(CH^>2, R* 1 * * * V denotes a hydrogen atom or is identical with the residue -X-R, and α denotes 0, 1 or 2, and their salts and pharmaceutically acceptable inorganic or organic acids if the substances of formula I are basic in nature. The substances according to the invention of formula I, or their salts, show effects in pharmacological tests on animals that indicate thymoleptic, centrally depressant and anticonvulsant activity. The substances according to the invention are therefore suitable as neurotropic and psychotropic drugs in the indications of mental depression, psychomotor restlessness and epilepsy. The specific findings recorded for individual substances according to the invention are given below.

Description

The invention ae relates to substituted 5,7-dihydrodibenzo (c, e) -thiepines of the general formula in which X represents a group CO or (CH ₂ ) _a , where? 1, 2 or 3) R is OH, NHCH3 or N (CH3> ₂ , R ^{* 1 * * * V} is hydrogen or is identical to -XR, and α is 0, 1 or 2, and their salts with pharmaceutically acceptable inorganic or organic acids when the compounds of formula I are basic in nature.

The compounds according to the invention of the formula I, or their salts, show effects in animal pharmacological tests which indicate thymoleptic, centrally depressant and antispasmodic activity. Thus, the compounds according to the invention are suitable as neuroprophic and psychotropic drugs in the indications of mental depression, psychomotor restlessness and epilepsy.

The following are specific findings reported for each of the compounds of the present invention.

M, H-dimethyl-6,6-dioxido-5,7-dihydrodibenso (o, e) thiepine-5-ylmethyl ethyl adenine was tested in the form of hydrogen oxalate hemihydrate In a rotating mouse test, 250 mg / kg of oral ataxia induced ataxia in 30 % At oral dose of 100 mg / kg, it potentiates the toxicity of yohlmbin in 40% of mice.

K, N-dimethyl-2- (6,6-dioxido-5,7-dlhydrodibenzo (c, e) thiepin-5-yl) ethylamine was tested in the form of hydrogen maleate.

Acute toxicity in male mice, LD ₅₀ when administered orally is 364 mg / kg; when administered intravenously 54.5 mg / kg. At an oral dose of 50 mg / kg, it significantly affects locomotor activity of the erythrocytes observed by the beam method (centrally damped effect). At an oral dose of 10 mg / kg, ente * gonis significantly significantly serotonin-induced edda rat paws.

N, N-dlmethyl-3- (6,6-dioxido-5,7-dihydrodibenzo (e, e) thleplin-5-yl) propylamine was tested as the dibasic maleate. In oral dose. 30 mg / kg excreted statistically significant antagonism against reserpine ptosis in mice. At an oral dose of 50 mg / kg it potentiates toxicity; yohlmbin in 30% of mice.

N, N-dlmethyl-6,6-dioxido-5,7-dihydrodibeezo (e, e) thiepine-5-kerboxemide is very poor in oral mice; dose t g / kg elicits only 1 animal from the 10-member group. In the rotating rod test in ayea, an oral dose of 10 mg / kg induced ataxia in 20% of the animals. In the maximum electrolyte test in ary, oral doses of 10 and 20 mg / kg have an anticonvulsant effect in 50 and 70% of animals, respectively.

6,6-dloxldo-5,7-dlhydrodibenzo (c, e) thiepine-5,7-dicarboxylic acid at an oral dose of 100 mg / kg shows a mild anti-inflammatory effect in rats in two models of inflammation (carregesin swelling and adjuvant swelling).

Ν, Ν, Ν ', N'-tetraaethyl-6,6-dioxldo-5,7 * dihydrodibenao (e, e) thiepine-5,7-dicarboxamide is very toxic; oral doses of 0.5 e 1.0 g / kg do not have lethal effects in mice. In the maximum electro-eye test in mice, an oral dose of 10 mg / kg has a protective anti-seizure effect in 30% of the animals. In the mouse rotating rod test, it produces oral ataxia in 10 to 20 S animals at doses of 10 to 50 mg / kg.

The starting material for the preparation of the compounds according to the invention is 5,7-dihydrodibenzo (c, e) thiepla of formula II with (III whose preparation is described in the literature (Truce W.E., finrick RD, S.A. Chem. Soc. 2St 6). 130, 1956) This substance is used either as such or is first oxidized with hydrogen peroxide to form a 6-oxide (sulfoxide), the preparation of which is not described in the literature in the literature and is therefore Included in the examples, or up to 6,6-dioxide (sulfone), the preparation of which is carried out according to literature data (Truce W.E., Emrick D. D., quoted.) Introduction of substituents at position 5 or at positions 5 e 7 they can then be carried out more easily at the stage of these 6-oxidized derivatives.

The introduction of the substituents into said positions is initiated by the abstraction of the proton from position 5 or the two protons from positions 5 and 7 by the action of hard metallating agents, preferably n-butyllithium or sodium hydride. The resulting anion or dienion then acts as a nucleophilic agent, which can be used to prepare carboxylic acids by reaction with carbon dioxide, or to prepare dimethylaminoalkyl derivatives by reaction with 2-dimethylaminoethyl chloride or 3-dimethylaminopropyl chloride. The above applies only to sulfoxide and sulfone. Substance II itself reacts β α -butyllithium in an yesal fashion, so that the primarily formed carbanion rearranges very rapidly to a 9,10-dihydrophenenrenene-9-thiolate anion, which further reactions lead to phenanthcen derivatives. For the preparation of 5- (tertiaminoalkyl) derivatives of the compound II, it is necessary to use another procedure starting from the chlorination of the compound II with sulfuryl chloride (Paquette L.A.Am. Chem. Soc. 86, 4 085, 1964) to the corresponding 5-chloro derivative. This is then reacted, for example, with 3-dimethylaminopropylmagnesium chloride, resulting in the formation of the 5- (3-dimethylaminopropyl derivative of compound II). These amides can be reduced with other amines with hydride reagents.

Unless literature references are given, all of the compounds described in the examples are new. Their identity was assured by analyzes and spectra. The examples serve only to illustrate the possibilities for preparing the compounds of the invention.

Example 1

N, H-dimethyl-3- (5,7-dihydrodibenzo (c, e) thiepin-5-yl) propylamine (I, X = (CH 3) 2, R = N ¹ CH 2 R ¹ = Η, n = O)

To a stirred solution of 6.9 g of 5,7-dihydrodibenzo (c, e) thlepin (II) in 40 ml of carbon tetrachloride was added dropwise a solution of 5.5 g of euryl chloride in 20 ml of carbon tetrachloride over 10 min. The mixture is heated at 60 ° C for 1 h and the carbon tetrachloride is evaporated in vacuo, the yellow crystalline residue (8.5 g), which is crude 5-chloro-5,7-dihydrodibenzo (c, e) thiepine, is dissolved in ml of benzene and 20 ml of tetrahydrofuran, and this solution was added dropwise over 5 minutes to a stirred solution of the Grignard reagent, prepared beforehand by reacting 1.6 g of magnesium with 8.0 g of 3-dimethylaminopropyl chloride in 50 ml of tetrahydrofuran. The mixture was refluxed for 4 h, then diluted with ether and quenched by addition of 100 mL of 10% ammonium chloride solution. From the separated organic layer, the basic substances are extracted into dilute hydrochloric acid, the acidic aqueous solution obtained is basified with 20% sodium hydroxide solution and the bases are isolated by extraction with benzene. Workup of the extract yielded 8.9 g of an inhomogeneous oil which was chromatographed on a column of 200 g of silica gel. The first chloroform eluates are inhomogeneous and discarded. Further elution with chloroform followed by a mixture of chloroform and ethyl acetate gave 2.53 g (26%) of a homogeneous, desired, oily base. Her. neutralization with oxalic acid in an ethanol / ether mixture yielded 2.9 g of crystalline hydrogen oxalate which crystallized from ethanol and melted in the pure state at 174.5-177.5 ° C.

Example 2

H, N-dimethyl-2T (6-oxido-5,7-dihydrodibenzo (e, e) thiepin-5-yl) ethylamine (I, X = (0112) 2) »

R = N (CH _{3) 2,} R ¹ = Η, n = 1)

To a solution of 5.84 g of 5,7-dihydrodibenzo (c, e) thiepine-6-oxide in 120 ml of benzene is added

0.9 g of 80% sodium hydride slurry in oil was heated to reflux for 2.5 h.

After cooling, 8.6 g of 2-dimethyleminoethyl chloride in 20 ml of benzene are added over a period of 90 minutes, the mixture is then refluxed for 2 hours, hydrolyzed with water and cooled from the organic phase and cooled to dilute hydrochloric acid. Evaporation of the organic phase ae regenerates 5.25 g of the starting material (sulfoxide). The acidic aqueous solution was basified with aqueous ammonia and the base was isolated by extraction with benzene. It was obtained in a yield of 0.50 g (65% of the conversion as a colorless oil).

By neutralizing oxalic acid in acetone, a crystalline hydrogen oxalate is obtained which crystallizes from aqueous ecetone as a hemihydrate and melts in the pure state at 192-193 ° C.

The starting 5,7-dihydrodibenzo (c, e) thiepine-6-oxide used has not been properly described in the literature and therefore its preparation is described here:

To a solution of 5.8 g of 5,7-dihydrodibenzo (c, e) thiepine (II) in 100 ml of acetic acid was added 5.5 ml of 30% hydrogen peroxide and the mixture was allowed to stand at room temperature for 24 hours.

It is then diluted with water, extracted with chloroform, dried and evaporated. The residue is chromatographed on a column of 300 g of neutral alumina (activity II). By combining with benzene, 0.95 g (12%) of the corresponding sulfone (m.p. 208 DEG-210 DEG C. after crystallization from ethanol) was first removed. The chloroform then eluted with 6.30 g (86%) of the desired sulfoxide, which crystallized from ethanol and was also pure at 129-130 ° C.

Example 3

6.6- dioxido-5,7-dihydro-dibenzo (c, e) thiepin-5-carboxylic acid (I, XR = COOH, ^R1 = H, n = 2)

A solution of 3.4 g of 5,7-dihydrodibenzo (c, e) thiepine-6,6-dioxide (literature cited) in a mixture of 80 ml of benzene and 50 ml of ether is stirred under nitrogen and 30 ml of a 9% solution are added. n-butyllithium in hexane. The mixture was stirred for 3 h and then poured onto excess solid carbon dioxide. Stir 1 h and leave for 48 h. After quenching with water, the organic phases are washed with dilute sodium hydroxide solution and evaporated. The residue is 0.5 g of regenerated starting sulfone, m.p. 208.5-211 ° C (ethanol). The alkaline aqueous solution was acidified with dilute hydrochloric acid, extracted with chloroform, the extract was evaporated and the residue was crystallized by trituration with benzene. 2.4 g (55% per conversion) of the solvate of the desired acid with benzene are obtained in a ratio of 1: 1, m.p. 118 DEG-121 DEG C. (benzene-ethhenol).

Example 4

6.6-dioxido-5,7-dihydrodibenzo (c, e) thite (pin-5,7-dicarboxylic acid (I, X-R = COOH),

R ¹ = COOH, n = 2)

The preparation of the preceding compound in larger batches is carried out in a similar manner as in Example 3 from 23.0 g of 5,7-dihydrodibenzo (c, e) thiine-6,6-dioxide in a mixture of 500 ml of benzene, 100 ml. ether with 100 ml of tetrahydrofuran by treatment with 200 ml of a 9% solution of n-butyllithium in hexane and then with excess carbon dioxide. In a similar treatment, 1.4 g of the starting sulfone are recovered and 18.4 g (57%) of the benzene solvate of the monocarboxylic acid is obtained, m.p. 115-120 ° C (benzene). The acidic aqueous solution after extraction of the aforementioned monocarboxylic acid was allowed to stand for 48 h at room temperature. During this time, 2.8 g (10%) of crystalline, highly polar product precipitated which did not pass into the organic solvent during extraction. It is filtered off with suction and crystallized from a mixture of benzene and ethanol in pure form, m.p. 150-152 ° C. This product is the title dicarboxylic acid.

Example 5

N-methyl-6,6-dioxido-5,7-dihydrodibenzo (c, e) thiepine-5-carboxamide (I, X-R = CONHCH, r '= H, n = 2)

A mixture of 7.3 g of 6,6-dioxido-5,7-dihydrodibenzo (c, e) thiepine-5-carboxylic acid benzene solvate (see Example 3), 20 ml of thionyl chloride and 30 ml of benzene is refluxed for 3 hours. The volatile components are then completely evaporated in vacuo, the residue is dissolved in 80 ml of benzene and the solution is added dropwise over 20 min to a stirred and cooled solution (maximum +5 ° C) of 7.7 g of methylamine in 50 ml of benzene.

The mixture was stirred at room temperature for 2 h, left overnight and stirred with 50 ml of water. The benzene phase of the filtrate was evaporated in vacuo and the residue crystallized from methanol. 4.45 g (67%) of the desired methylamide are obtained, which melts in a pure state at 242-244 ° C. Crystallization from benzene gave the 3H solvate with benzene melting at 235-240 ° C.

Example 6

K, N'-dimethyl-6,6-dloxido-5,7-dihydrodibenzo (c, e) thiepine-5,7-dicarboxamide (I, XR = r '= CONHCH ₃ , n = 2)

As in the previous example, 7.3 g of 6,6-dioxido-5,7-dihydrodibenzo (c, e) thiepine-5-carboxylic acid (benzene solvate, see Example 3) containing dicarboxylic acid (see Example 4) are treated. ). After decomposition of the reaction with 50 ml of water, a solid precipitated, which was filtered and purified by crystallization from a mixture of 100 ml of chloroform and 30 ml of ethanol. The title compound (0.72 g) is obtained, m.p. 280 DEG-283 DEG C. (chloroform).

Example 7

N, N-dimethyl-6,6-dioxide-5,7-dihydro-dibenzo (c, e) thiepin-5-carboxamide (I, XR = CON (CH _{3) 2,}

Η R ¹ = n = 2)

A mixture of the predominant amount of monocarboxylic acid (Example 3) and dicarboxylic acid (Example 4) (18.1 g) was refluxed for 4 h with a mixture of 75 ml of benzene and 50 ml of thionyl chloride, the volatiles were completely evaporated in vacuo. in 80 ml of benzene and the solution is added dropwise with stirring to a cooled solution of 45 g of dimethylamine in 100 ml of benzene. Stir 2 h at room temperature, leave overnight, dilute with 300 mL benzene, wash with water, dry and evaporate under reduced pressure. The residue was dissolved in benzene and chromatographed on a column of 300 g of silica gel. The less polar contaminants were removed by benzene elution and 9.86 g of the desired compound were eluted with chloroform, m.p. 229.5-230.5 ° C (benzene).

Example 8

N, M, N ^a, N'-Teti * and methyl 6,6-dioxide-5,7-dihydro-dibenzo (c, e) thiepin-5,7-dicarboxamide (I XR = R ¹ = COM _(CH3 ) ₂ , n = 2

A mixture (7.3 g) of the monocarboxylic acid (Example 3) and a predominant amount of dicarboxylic acid (Example 4) is converted, as in the previous example, with 20 ml of thionyl chloride in 30 ml of benzene into a mixture of acid chlorides which is treated with 15 g of dimethylamine in 90 ml benzene. The mixture was stirred at room temperature for 2 h, allowed to stand overnight and then shaken with 100 mL of water. The precipitate was filtered off with suction and crystallized from ethanol / chloroform to give 2.65 g of the title bis (dimethylamide); t. t.

275 DEG-278.5 DEG C. (ethanol-chloroform).

Example 9

5-dinethylaminomethyl-5,7-dihydro-dibenzo (c, e) thienyl (> yn-6,6-dioxide (I, X = CH, R = H (CH _{3) 2,}

Η R ¹ = n = 2)

To a solution of 3.65 g of H, N-dimethyl-6,6-dioxide-5,7-dihydrodibenzo (c, e) thiepine-5-carboxamide (Example 7) in 100 ml of tetmahydrofuran, which was stirred under a nitrogen atmosphere, Sodium borohydride (3.9 g) was added first and then 12 ml of borontrifluor etherate was added dropwise from cooling (max. 40 ° C). The mixture was stirred at room temperature for 1 h, then heated at reflux for 8 h, allowed to stand for one week, quenched by the addition of 50 ml of 15% hydrochloric acid, basified with aqueous ammonia and extracted with benzene. Workup of the extract gave the crude product which was chromatographed on 100 g of silica gel. The benzene and chloroform mixtures were separated in the first fractions of a little polar impurities and then 2.45 g (70%) of the desired base was eluted with the same mixture and chloroform alone, m.p. 199.5 - 201 ° C (benzene-petroleum ether). Neutralization with oxalic acid in aaetone gives a crystalline hydrogen oxalate which crystallizes as a hemihydrate, mp 203-204 ° C (aqueous acetone).

Example 10

5- (2-dimethylaminoethyl) -5,7-dihydro-dibenzo (c, e) thiepin-6,6-dioxide (I, X = (CH _{2) 2,} S = N (CH _{3) 2,} n = 2)

A solution of 3.4 g of 5,7-dihydrodibenzo (c, e) thiepine-6,6-dioxide in 30 ml of dimethylformamide is stirred under a nitrogen atmosphere, 0.7 g of 80% sodium hydride auspenae in oil is added and the mixture is stirred for 1 hour. , 5 h at room temperature. 8.3 g of 2-dimethylaminoethyl chloride are then added, stirred for 6 hours at room temperature and left to stand overnight. It is then quenched by the addition of 50 ml of water and extracted with a mixture of benzene and ether. The extract was washed with excess dilute hydrochloric acid and water, washed and evaporated. 2.3 g of the starting sulfone are thus recovered, m.p. 207.5-210.5 ° C. The acidic aqueous solution was basified with aqueous ammonia and the bases were isolated by extraction with benzene; 1.27 g (89 * per conversion), mp 134-136.5 ° C (methanol). Neutrification with maleic acid gives crystalline hydrogen maleate, m.p. 206-209 ° C (ethanol).

Example 1,

5- (3-dimethylaminopropyl) -5,7-dihydrodibenzo (c, e) thiepine-6,6-dloxide (I, X = (CH ₃ ) ₂ , H = =, H (CH ₃ ) _2> β ¹ = Η , n «2)

To a solution of 5.6 g of 5,7-dihydrodibenzo (c, e) thiepine-6,6-dloxide in 100 ml of benzene under stirring under nitrogen was added 40 ml of a 9% solution of n-butyllithium in hexane over 10 min.

The mixture was stirred at room temperature for 3 h, then 15 g of 3-dimethylaminopropyl chloride was added over 10 min, the mixture was stirred for 3 h and left to stand overnight. It is hydrolyzed with water, the organic phase is washed with excess dilute hydrochloric acid, dried and evaporated, resulting in the recovery of 2.55 g of the starting sulfone, m.p. 209 DEG-211 DEG C. (ethanol). The acidic aqueous solution was basified with aqueous ammonia and the base was extracted with benzene. Working up the extract yielded 5.2 g of crude product which was chromatographed on 200 g of silica gel. 4.11 g (100% per conversion) of the desired base was eluted with a mixture of ethyl acetate and ethanol and then ethanol alone, which crystallized and melted at 139-142 ° C. Neutralizing maleic acid provides a crystalline hydrogen maleate that crystallizes from a mixture of acetone and ether and also at 177-178 ° C.

Example 12

5,7-bis (3-dimethyl8minopropyl) -5,7-dihydro-dibenzo (c, e) _thiepin-6> 6-dioxide (I, R ¹ = XR = (CH _{2) 3} N _{(CH3) 2,} n = 2)

A solution of 2.8 g of 5,7-dihydrodibenzo (c, e) thlepin-6,6-dioxide in 50 ml of benzene is treated similarly with 20 ml of a 15% solution of n-butyllithium in hexane and after stirring for 3 h with 10 g of 3- dimethylaminopropyl chloride. The mixture is stirred under a nitrogen atmosphere for 3 h, hydrolysed with 100 ml of water, the organic phase is washed with 50 ml of 3M-HCl and water, dried and evaporated. 1.25 g of the starting sulfone are thus recovered. The acidic aqueous solution was basified with aqueous ammonia and the bases were extracted with benzene. Working up of the extract yielded 2.20 g of crude product which was chromatographed over 60 g of alumina (neutral, activity II). The benzene was eluted with 0.74 g (35% per conversion) of the monoalkylated product described in the previous example. Elution with chloroform gave 1.06 g (40% per conversion) of the title base which crystallized from cyclohexane and melted at 118-121 ° C.

Claims (1)

SUBJECT OF THE INVENTION Substituted 5,7-dihydredibenzo (c, e) thiepines of formula I, R ¹ (O) _n X-R (I) wherein X is CO or (CH3). where a is 1, 2 or 3> R is OK, NHCH 3 or NCCH 3, R is hydrogen or is identical to -XR, and R is 0, 1 or 2, and salts thereof g with pharmaceutically acceptable inorganic or organic acids when the compounds of formula I are basic in nature.