CS219786B1 - 11-/aminoalkyl/derivatives of the 11h-dibenzo/b,e/-1,4-dithiepin a 11h-dibenz-/b,f/-1,4-oxathiepine and method of preparation of the same - Google Patents

Description

The invention relates to 11- (aminoalkyl) derivatives of 11H-dibenzo (b, e) -1,4-dithiepines and HH-dibenz (b, f) -1,4-O'xathiepines of formula I

wherein X is oxygen or sulfur, R is dimethylamino, N (CH3) 2 or methylamino NHCH 3, R ¹ is hydrogen or chlorine and n is 1, 2 or 3, their salts, are pharmaceutically acceptable organic or inorganic acids and methods for their preparation.

The compounds of the invention exhibit therapeutically useful antidepressant and tranquilizing activity at acceptable to moderate toxicity. In particular, the properties of a number of typical substances according to the invention are described as evidence of their effects. Unless otherwise indicated, all agents were administered orally, and dosages are recalculated on a base basis. In particular, the following pharmacological methods were used in the evaluation, which have been described in the literature.

Acute toxicity was determined in mice, female, in groups of ten. Death was monitored within 7 days after oral administration. Results are reported as mean lethal doses of LD50 in mg / kg.

The incoordination effect as a central depressant criterion was studied in mice in a rotating rod test (J. Metyšová et al., Arzneim-Forsch. 13, 1039, 1963 J. Mean effective ataxia-inducing doses (ED50J) were determined at the time of optimal effect of test substances.

Inhibitory effect on locomotor activity of mice - also as a criterion (P. B. Dews, Brit. J. Pharmacol. 8, 46, 1952). A dose reducing the mean control value of spontaneous locomotor activity of 0 '50% was determined (D50 J.

The inhibitory effect on the mobility of mice was further monitored in the observation test of Ther (L. Ther, Deut. Apoth. Ztg. 93, 292, 1953 J. Doses) producing an effect corresponding to 50% of the average control value are reported.

Bird antagonism in mice induced a depressive effect (J. Metysova and J. Metys, Int. J. Neuropharmacol. 4, 111, 1965 J. Doses that statistically significantly antagonize reserpine ptosis are statistically significant.

Antagonism of hypothermia in mice is another indicator of antidepressant efficacy (J. Metyšová and J. Metyš, cited). Doses of substances and the number of ° C by which body temperature is increased compared to the control reserpine group are reported.

Antagonization of the ulcerogenic effect of reserpine in rats has also been used to identify possible antidepressant effects (J. Metyšová and J. Metyš, cited). Doses that significantly anitagonize the ulcerogenic effects of reserpine are reported.

In order to allow comparison, the results achieved in the most important tests with several standards are listed first:

Acute toxicity, LD50 values in mg / kg: chlorpromazine, 198; imipramine, 370; amitriptiline, 2.25; dosulepin, 320.

Incoordination effect (ataxia), ED 50 values in mg / kg: chlorpromazine, 8.2.

Dews locomotor activity inhibition, Djo value in mg / kg: chlorpromazine, 4.8.

Inhibition of mobility by Ther, D50 values in mig / kg: chlorpromazine, 4.8.

The hypothermic effect of reserpine: an oral dose of 10 mg / kg imipramine increases body temperature by 2.97 ° C compared to the control reserpine group: a dose of 10 mg / kg amitriptyline increases body temperature by 2.51 ° C.

Antagonizing the ulcerogenic effect of reserpine, ED dose in mg / kg having a significant effect: imipramine, 25; dosulepin, 50.

Now formacological data for individual substances according to the invention:

11- (2-dimethylamino-ethyl) -1H-dibenzo (b, e) -1,4-dithiepine (tested as hydrogen oxalate, substance 14019): Toxicity, LD50 between 200 (non-toxic dose) and 500 mg / kg (induces mortality 60% of animals). Incoordination effect, ED50 = 143 mg / kg. Inhibition of locomotor activity (Ther), D 50 = 17 mg / kg Intensely antagonizes the hypothermic efficacy of reserpine, a dose of 10 mg / kg raises the temperature against the reserpine control group by 4.22 ° C. This is a significantly higher effect than imipramine or amitriptyline. may be described as an antidepressant with a very mild central depressant activity.

11- (3-idimethylaminopropyl) -1H-dibenzo (ib, e) -1,4-dithiepine (tested as · hydrogen oxalate, substance 1420): Toxicity, LD50 between 200 (nontoxic dose) and 500 mg / kg (causes death 60 % of animals). Incoordination effect, ED50 = 143 mg / kg. Mobility Inhibition (Ther), D50 = 20 mg / kg. Intensely antagonizes the hypothermic efficacy of reserpine, a dose of 10 mg / kg raises the temperature against the reserpine control group by 3.80 ° C, a higher effect than imipramine or amitriptyline. The substance is an antidepressant with low central depressant efficacy.

11- (2-dimethylaminoethyl) -1H-dibenz (b, f) -1,4-oxathiepine (tested as hydrogen oxalate, 14091J: Toxicity, LD50 = 227 mg / kg. Incoordination effect, ED50 = = 57.5 mg The substance is a mild tranquilizer.

11- (3-dimethylaminopropyl) -1H-dibenzo (b, f) -1,4-oxathiepine (tested as hydrogen oxalate, 14090): Toxicity, LD 50 = 373 mg / kg. Incoordinating effect, ED50 =

61.9 mg / kg. Inhibition of locomotor activity (DewsJ occurs from a dose of 50 mg / kg. The substance is a mild tranquillizer,

2-chloro-11- (3-dimethylaminopropyl) -1H-dibenz '(b, f) -1,4-oxathiepine (tested as hydrogenoxalpha, substance 14016): Toxicity, LD50 between 200 (non-toxic dose) and 500 mg / kg (causes 80% of the deaths). Incoordination effect, ED50 = 84.9 mg / kg. Mobility Inhibition (Ther), D50 = 10 mg / kg. Antireserpine effect against hypothermia, dose of 10 mg / kg raises the temperature against the control reserpine group by 1.42 ° C. The substance is an antidepressant with mild central depressant activity.

11- (2-methylaminoethyl) -HH-dibenz (b, f) -1,4-oxathiepine (tested as hydrogen oxalate, 14092): Toxicity, LD 50 = 250 mg / kg. Incoordination effect, ED50 = 60.2 mg / kg. Mobility Inhibition (Ther), D50 = 50 mg / kg. Antireserpine effect against ptose, ED = 10 mg / kg. Antireserpine effect against ulcerogenic effect, ED = 50 mg / kg. The substance is an antidepressant of considerable intensity with a mild central depressant component.

11- (3-methylaminopropyl) -1H-diben, z (b, f) -1,4-oxathiepine (tested as hydrogen oxalate, 14093 J: Toxicity, LD50 = = 284 mg / kg. For iv administration LD50 = 30 mg / / kg Incoordinating effect, ED50 = 79.5 mg / / kg Antireserpine effect on ptose, ED equals 150 mg / kg, when administered ED = ⁽ = 6 mg / kg) The substance is an antidepressant with mild central depression component of effect.

11- (dimethylaminomethyl) -1H-dibenz (b, f) -1,4-oxathiepine (tested as hydrogen oxalate, 14089 J: Incoordinating effect, ED 50 = 23.8 mg / kg. Antireserpine effect on ptose, ED 50 - = 10 mg / kg The substance is an antidepressant with a mild central depressant effect.

As already mentioned, the present invention also includes salts of the compounds of formula I with pharmaceutically acceptable inorganic or organic acids. In particular, hydrochlorides and acid salts with dicarboxylic aliphatic acids (oxalic, maleic, fumaric), which are sparingly soluble in water, are suitable for the preparation of dosage forms for oral use. They are also more suitable than the free bases to perform pharmacological tests.

The present invention further provides processes for preparing the compounds of Formula I and salts thereof. In the synthesis of the compounds according to the invention, the following methods are mainly used:

(a) A portion of the compounds of the invention of formula I wherein R is dimethylamino and n is 2 or 3 is obtained by alkylation of compounds of formula II

wherein X and R ¹ have the same meaning as in formula I, aminoalkyl of the general formula III ·

Z- (CH ₂ ) _n N (CH 3) ₂ , (ΙΠ) in which Z is a chlorine or bromine atom and _n is 1 or · 3. In these alkylations it is necessary to use butyllithium as the metallating agent to form the necessary carbonium anion and of ether. The starting materials of the formula II are new and are obtained according to the methods described in the examples. The starting annnoalkyl halides of the formula ΙΙΊ are known.

(bj Compounds of formula I in which R is methylamino) can be prepared from the corresponding N-methylderivatives accessible by the method (aj) by a two-step process consisting in the first stage of ethylnaphthalic chloroformate in boiling benzene and the second in alkaline hydrolysis of the carbamates obtained IV

. ·. ^CH i av) in which X, R ¹ and ⁿ are the same as in formula I. These carbamates need not be isolated in the pure state, but only as neutral to the hollows of the first phase of the reaction sequence. For alkaline hydrolysis, preferably potassium hydroxide in a 20-40%, preferably 30% solution in ethanol is used; the hydrolysis is carried out at the boiling point of this solution.

(c) Compounds of formula I wherein n = 1 are prepared by reduction of dimethylamides of formula V

wherein X and R ¹ have the same meaning as in formula I. The reduction using a complex hydride, preferably lithium aluminum hydride, or diborane · generated from sodium borohydride and boron trifluoride etherate. The starting amides of formula V are accessible from acids of formula VI

wherein X and R ¹ have the same meaning as in formula I, two step process in which in a first stage the acid is converted with thionyl chloride to the crude acid chloride by treatment with dimethylamine in an inert solvent, preferably benzene, to provide the necessary dimethylamides. The acids of the formula VI are known in part and their preparation is cited in the respective exemplary embodiment.

The process for the preparation of the salts, which is also a subject of the invention, consists in neutralizing the bases of the formula I with the appropriate inorganic or organic acids in suitable solutions, in particular in ethanol or in a mixture of ethanol and ether. The salts obtained are crystalline and are also suitable for characterizing the bases of formula I. The identity of all the critical substances described in the invention, ie end products and novel intermediates, was ensured not only by analyzes but also by all commonly used spectra (UF, IC, —NMR, MS). ).

Further details of the implementation of the invention will be apparent from the following examples, which, however, are merely illustrative of the possibilities of the invention and are not intended to fully describe these possibilities.

Examples

1. 11- (2-Dimethylaminoethyl) -11H-dibenzoyl, 1,4-dithiepine

To a solution of 3.40 g of 11H-dibenzo (b, e) -1,4-dithiepine (U.S. Ser. No. 202 239) in 50 mL of ether was added dropwise under stirring under nitrogen for 20 min. 10 ml of a 15% solution of n-butyllithium in hexane. The mixture was stirred for a further 30 min. 10 ml of 2-dimethylaminomethyl chloride are added dropwise under external cooling with ice and water and the mixture is stirred at room temperature for 2 hours. It is then washed with water and the basic product is extracted into a slight excess of dilute hydrochloric acid (1: 1). The acidic aqueous layer was separated, basified with aqueous ammonia and the base extracted with ether. The extract was dried over potassium carbonate and evaporated. The residual oily base was dissolved in 7 ml of acetone and a solution of 1.81 g was added

Oxalic acid in 5 ml of acetone. Crystalline hydrogen oxalate (5.31 g) precipitated, which was filtered off with suction and recrystallized from aqueous ethanol. It melts at 195 to 197 ° C in pure state.

2. 11- (3-dimethylaminopropyl) -11H-dibenzo (b, e j -1,4-dithiepine)

To a solution of 3.10 g of 11H-dibenzo (b, e) -1,4-dithiepline (Example 1, cited) in 50 ml of ether was added dropwise 10 ml of a 15% solution of n-butyllithium in hexane over 15 minutes under nitrogen. . The mixture was stirred for a further 30 min. at room temperature. 10 ml of 3-dimethylaminopropyl chloride are then added dropwise, stirred for a further 4 hours and washed with water. The basic product is then extracted into dilute hydrochloric acid, the acidic phase is made alkaline with aqueous ammonia and the base is extracted with ether. The extract is worked up

3.7 g of an oily base which is chromatographed on a column of 200 g of neutral alumina (activity II). Benzene eluted first with a small amount of low-polar contaminants, and then 2.89 g of a homogeneous oily base was obtained, which was neutralized with oxalic acid to hydrogen oxalate, m.p.181-182 ° C (ethanol).

3. 11- (2-Dimethylaminoethyl) -11H-dibenz (b, f) -1,4-oxathiepine

To a solution of 10.1 g of 11H-dibenz (b, f) -1,4-oxaihiepine (cf. No. 202 238) in 120 ml of ether was stirred under nitrogen for 30 min. 30 ml of a 15% solution of n-butyllithium in hexane are added dropwise. The mixture was stirred for 30 min. at room temperature, then 30 ml of 2-dimethylaminoethyl chloride are added and stirred for a further 5 hours. After standing for 24 hours, it is washed with water and the basic product is extracted with dilute hydrochloric acid. The acidic aqueous solution was separated, basified with aqueous ammonia and the base extracted with benzene. The extract was dried with potassium carbonate and succeeded. 11.5 g (86%) of a crude oil base are obtained, which is neutralized by

5.4 g of oxalic acid in acetone. It is obtained

15.2 g of crude hydrogen oxalate melting at 186-186.5 ° C, which is recrystallized from a mixture of aqueous ethanol and ether, m.p.

187.5-189.5 ° C.

4. 11- (3-Dimethylaminopropyl) -11H-dibenz (b, f -1,4-oxathiepine)

To a solution of 10.1 g of HH-dibenz (b, f, 1,4-oxaithiepine (Example 3, cited) in 120 ml of ether) is added dropwise, under stirring under nitrogen, at 5 ° C for 15 min. The mixture was stirred for a further 30 min, then 30 ml of 3-dimethylaminopropyl chloride was added and stirred at room temperature for 5 hours, washed overnight with water and the basic product was extracted with dilute hydrochloric acid. The extract was dried with potassium carbonate and evaporated to give 12.6 g (89%) of a crude oily base which was neutralized with 5.3 g of oxalic acid in acetone. hydrogen oxalate, mp 118 to 122 ^Q C Crystallization from acetone, 95% ethanol and ether gave pure hydrogen oxalate hemihydrate with mp 118-121 ° C.

5. 2-chloro-11- (3-dimethylaminopropyl) -H-dibenz (b, f) -1,4-oxathiepine

To a solution of 6.0 g of 2-chloro-11H-dibenz (b, n-1,4-oxathiepine in 100 ml of ether) was added dropwise 18 ml of a 15% solution of n-butyllithium in hexane over 15 minutes under nitrogen. The mixture was stirred at room temperature for 45 min, 20 ml of 3-dimethylaminopropyl chloride was added and stirred for 7 hours, after standing overnight, washed with water and the base was extracted with dilute hydrochloric acid. The extract was dried with potassium carbonate and evaporated to give 6.43 g of an inhomogeneous oil which was chromatographed on a column of 450 g of neutral alumina (activity II), eluting with benzene and then with chloroform to give 4.8 g. a homogeneous oily base which, by neutralization with oxalic acid in acetone, yields hydrogenbenoxalate which melts at 167-168 ° C after crystallization from a mixture of acetone and ethanol.

The starting 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine is a novel compound which is prepared by the following procedure:

To a solution of 120 g of 5-chloro-2-iodo-benzoic acid (K. Pelz et al., Collect. Czech. Chem. Commun. 33, 1852 (1968) in 145 ml of tetrahydroifuran is added at 10-20 ° while stirring for 45 minutes. C. Sodium borohydride (16.1 g) The mixture is stirred at that temperature for 30 minutes and then the solution is added dropwise.

80.3 g (71.4 ml) of boron trifluoride etherate in 40 ml of tetrahydrofuran. Stirring is continued for 3 hours and, under cooling with ice water, is decomposed at a maximum of 8 ° C by the dropwise addition of 50 ml of 5%. hydrochloric acid. Dilute with water and extract with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. 110 g (96%) of crude 5-chloro-2-iodobenzyl alcohol with mp 115-117 ^C C. Analytically pure compound was obtained by crystallization from ethanol, m. P .116 to 117 ° C.

While cooling a mixture is prepared folsforítého bromide 41.5 g, 25 ml of benzene and 8.2 ml of pyridine with stirring at a maximum ^of 10 ^g was added dropwise over 1.5 hours, 108.3 g

Of 5-chloro-2-iodobenzyl alcohol, diluted with 40 ml of benzene, stirred at room temperature for 4 hours and at 50 ° C for 1 hour. After cooling, dilute with 120 ml of chloroform, wash with 25 ml of 5% hydrochloric acid, 5% hyd7 8 6 π

sodium hydroxide and water, dried over magnesium sulphate and evaporated. 12.8 g (95%) of crude 5-chloro-2-iodo-benzyl bromide are obtained, which melts at 75-79 ° C. The pure product is obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 77-79 ° C.

To a mixture of 640 ml of dimethylformamide, 52.4 g of potassium carbonate and 47.8 g of 2-hydroxythiophenol [R. Leuckart, J. Prakt. Chem. (2) 41, 192, 1890] was added a solution of 125.6 g

Of 5-chloro-2-iodobenzyl bromide in 500 ml of dimethylformamide, stirred for 1 hour at room temperature, then 57 g of potassium carbonate and 4.5 g of copper are added and refluxed for 6 hours. Dimethylformamide was distilled off under reduced pressure, the residue was diluted with water and shaken with benzene. After aspiration, the benzene layer was separated, washed with water, dried over potassium carbonate and evaporated. The residue was distilled

42.5 g (45%) of 2-chloro-11H-dibenzo (b, f) -1,4-Oxathiepine having a m.p. of 148-168 ° C / 0.6 mm Hg and mp 6-6 ° C. The pure product is obtained by crystallization from methanol and melts at 78-79 ^° C.

6. 11- (2-Methylaminoethyl) -11H-dibenz (b, f) -1,4-oxathiepine

To a boiling solution of 3.9 g of ethyl chloroformate in 15 ml of benzene was added dropwise a solution of 7.65 g of 11- (2-dimethylaminoethyl) -1H-dlbenz (b, f) -1,4-oxathiepine (Example 3) in 30 ml. The mixture was refluxed for 1.5 hours, washed with water, 10% sulfuric acid and water again, dried (MgSO4) and evaporated. The residue (crude carbamate) was dissolved in 10 ml of ethanol and added. 9.0 g of potassium hydroxide and refluxed in a 130 [deg.] C. bath for 2 hours, diluted, extracted with benzene and extracted from the benzene solution by shaking with excess 10% hydrochloric acid. An oil layer of hydrochloride, basified with aqueous ammonia and the liberated base was extracted with benzene, dried over potassium carbonate and evaporated to give 4.0 g of an oily base which was neutralized with 1.9 g of oxalic acid in acetone. 5.15 g of hydrogen oxalate crystallized, which was recrystallized from aqueous ethanol and melted at 210 DEG-211 DEG C. in pure form.

7. 11- (3-methylaminopropyl) -11H-dibenz (b, f) -1,4-oxathiepine

A solution of 8.2 g of 11- (3-dimethylaminopropyl) -1H-dihenz (b, f) -1,4-oxathiepine (Example 4) in a solution of 8.2 g of eithyl chloroformate in 15 ml of benzene was added dropwise over 1 hour. 30 ml of benzene, refluxed for 1.5 hours, washed with water, 10% sulfuric acid and water again after cooling, dried over magnesium sulphate and evaporated to dissolve the residue (carbamate) in ethanol (10 ml), add 9 ml. The solution was diluted with water and extracted with benzene, and the base was removed by shaking with excess 10% hydrochloric acid and the acidic aqueous phase separated. together with an oily hydrochloride layer, basified with aqueous potassium ammonia, and evaporated to give 6.1 g (79%) of an oily base, dissolved in acetone and neutralized with 2.8 g of oxalic acid in acetone. 7 grams of hydrogen oxalate The residue was recrystallized from ethanol and melted at 151-162 ° C in pure state.

8. 11- (dimethylaminomethyl) -1H-dibenzyl b, f -1,4-oxathiepine

To a solution of 2.60 g of HH-dibenz (b, f) -1,4-oxathiepine-11-carboxylic acid dimethylamide in 40 ml of tetrahydrofuran was added

Sodium borohydride (1.9 g) was stirred for 45 min with stirring under nitrogen and external ice cooling. 6 ml of boron trifluoride etherate is added dropwise. The mixture was refluxed for 3 hours and evaporated. The residue was dissolved in 50 ml of ethanol, 25 ml of 20% sodium hydroxide solution was added, and the mixture was refluxed for 6 hours. Then the ethanol is evaporated, the residue is diluted with water and extracted with benzene. The oily base obtained is dissolved in ethanol and the solution is neutralized with 1.3 g of oxalic acid. On standing, 2.45 g of hydrogen oxalate crystallized from a mixture of acetone, ethanol and ether and melted in the pure state at 179.5 to 180 ° C.

180.5 ° C.

The starting dimethylamide of HH-dlbenz (b, f) -1,4-oxathiepine-11-carboxylic acid is a novel substance obtained by the following procedure:

A mixture of 2.50 g of 11-H-dibenzic acid (b, f-1,4-oxathienine-11-carboxylic acid (cf. No. 202 241)), 10 ml of benzene and 5 ml of thionyl chloride is boiled 2, The volatiles were evaporated, the remaining crude acid chloride was dissolved in 20 ml of benzene, and the solution was added dropwise over 5 minutes to a solution of 15 g of dimethylamine in 50 ml of non-ice-cooled benzene. The mixture was stirred at room temperature overnight, washed with water, dried (MgSO4) and evaporated to give 2.65 g (96%) of crystalline 11H-dibenz (b, f) -1,4-oxathiepine-11-carboxylic acid dimethylamide, which melts at 144.5 to 146 ° C.

Claims (5)

I will invent the object 1. The 11- (aminoalkyl) derivatives of 11H-dihenzo (b, e) -1,4-diithlepines and 11H-dlbenz (b, f) -1,4-oxathiepines of the general formula I are subjected to a two-stage derivative of the formula I (R = dimethylamino). procedure consists in a first stage in the action of ethyl chloroformate in refluxing benzene and in the second stage of hydrolysis of the crude carbamates of general · formula IV wherein X represents oxygen or sulfur, R is dimethylamino, N _(CH3) 2 or methylamino NHCH 3, R ¹ represents a hydrogen atom or a chlorine atom and n is 1, 2 or 3, and their salts with pharmaceutically acceptable inorganic or organic acids. 2. A process for the preparation of compounds of formula (I) wherein R is dimethylamino and n is 2 or 3 according to claim 1, characterized in that the compounds of formula (II) (CH3 NOOOC3 H6) are: CH, ^Λ (IV) wherein X, R ¹ and n are the same as in Formula I boiling a 20-40%, preferably 30% solution of potassium hydroxide in ethanol. 3. A process for preparing compounds of formula I wherein R is methylamino, according to claim 1, characterized in that the dimethylamiCONtCHL (V) wherein X and R ¹ have the same meaning as in formula I, are reduced with complex hydrides, preferably lithium aluminum hydride, or diborane, generated from sodium borohydride and boron trifluoride etherate. 4. A process for preparing compounds of formula I in which n = 1, according to claim 1, characterized in that the dimethylamides of the general formula V · (II) wherein X and R ¹ represents (same as in formula I, alkylated aminoalkyl formula III Z- (CH 2) _n N (CH ₃ ) 2, (IH) in which Z is a chlorine or bromine atom and _n is 2 or 3, after prior treatment with butyllithium as a metallating agent in ether. 5. A process for the preparation of salts of the compounds of the formula I according to claim 1, characterized in that the bases of the formula I are neutralized with pharmaceutically acceptable inorganic or organic acids in suitable solutions, preferably in ethanol or in a mixture of ethanol and ether.