CS260098B1 - (Z) - and (E) -4- (3-Dimethylaminopropylidene) -4,10-dihydrothieno [2,3-c] -1-benzothiepine-6-carbonitriles and their oxalates - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is (Z)- and (E)-4- - (3-dimethylaminopropylidene)-4,10-dihydrothieno/2,3-c/-1-benzothiepin-6-carbonitriles (I) and their oxalates, which exhibit the properties of thymolytics and potential antidepressants of a new activity profile. Only the (Z)-18-omer exhibits pronounced antireserpine effects, typical of classical antidepressants, while both are selective inhibitors of serotonin reuptake in the brain. Their preparation is based on the reaction of 5-bromothiosalicylic acid with 2-(chloromethyl)thiophene. The obtained 5-bromo-2-(2-thienylmethylthio)benzoic acid is cyclized to. 6-bromothieno/2,3-c/-1-benzothiepin-4(10H)-one. Reaction of this ketone with 3-dimethylaminopropylmagnesium chloride gives 6-bromo-4-(3-dimethylaminopropyl)-4,10- -dihydrothieno/2,3-c/-1-benzothiepin-4-ol, which is dehydrated by boiling with dilute hydrochloric acid. From the resulting mixture, the predominant (E)-N,N-dlmethyl-3-(6- -bromo-4,10-dihydrothieno/2,3-c/-1-benzothiepin-4-ylidene)propylamine ((E)—II) is isolated by crystallization of the maleate; the minor isomer (Z)-II is obtained by crystallization of the oxalate from the mother liquors. Both isomers are converted to isomers (E)-I and (Z)-I by reaction with soft cyanide in hexamethylphosphoric triamide at 150 °C.

Description

The invention relates to (Z) - and (E) -4- (3-dimethylaminopropylidene) -4,10-dihydrothieno [2,3-c] -1-benzothiepine-6-carbonitriles of formula I

CHCH ₂ CH ₂ N (CH ₃ ) 2 and oxalate thereof. The (Z) (cis) -isomer is a compound of formula I in which the double bond configuration allows approximation of the amino group of the branch chain and the cyano group on the nucleus. In contrast, the (E) (trans) -isomer is a compound of formula (I) whose double bond configuration allows the approach of the amino group of the branch chain and the thiophene nucleus.

Both geometric isomers of formula I were evaluated pharmacologically in the form of oxalates and showed properties of thymoleptics and potential antidepressants of very interesting activity profile. The effects of the two isomers are only partially similar, some of which differ considerably, indicating the dependence of the active profile on the double bond configuration. Only the (Z) -isomer shows significant antidepressant effects, typical of classical antidepressants. Both isomers agree that they are selective inhibitors of serotonin reuptake in the brain. The method that made this finding possible

3 is a study of displacement of [H] imipramine and [H] desipramine binding from binding sites in the rat brain hypothalamus, wherein imipramine displacement is a measure of serotonin reuptake and desipramine displacement is a measure of norepinephrine reuptake; their ratio is a measure of the selectivity of effect. Methods that directly allow the assessment of the effect on serotonin reuptake (H) in rat cortex and noradrenaline ( ³ H) reuptake in rat brain were also used.

In particular, the following pharmacological and biochemical-pharmacological data are given for both isomers of formula I. The compounds were evaluated as oxalates, which were administered orally in vivo tests (dosages reported are based on bases).

The (Z) -isomer of Formula I at a dose of 10 mg / kg significantly reduced the spontaneous locomotor activity of the mouse at 1 hour post administration using the beam method (Dexs). The substance thus has a centrally dampening effect. At 25 mg / kg, the compound significantly antagonizes reserpine ptosis in mice. At a dose of 50 mg / kg, it significantly inhibited gastric ulceration in reserpine-induced rats. The substance very strongly inhibits the binding of 4 nM / H / desipramine in the same brain structure is much weaker; is 493.4 nM. Thus, the selectivity to the [ ³ H] imipramine binding sites is very pronounced. To inhibit 10 nM / ³ H / serotonin re-uptake in rat cortex, an IC ₅₀ value of 32.85 nM was experimentally determined. Similarly, an IC ₅₀ value of 84.1 nM was determined to inhibit 10 nM / H / noradrenaline reuptake. Thus, the substance is a potent inhibitor of the uptake of both said biogenic amines; selectivity is expressed here by a coefficient of 2.6. Finally, the substance has a strong affinity for muscarinic receptors in rat brain, as determined by a binding study using 0.5 nM / H / quinuclidyl benzilate as a ligand; IC ₅₀ '= = 22.4 nM. Thus, the drug is a potent central anticholinergic, typical of many antidepressants.

(E) -isomer of formula I. Acute toxicity in mice (female), LDjq = 162 mg / kg. In the acute toxicity test, central attenuation occurs first, then convulsions. At a dose of 10 mg / kg, the agent significantly reduced the spontaneous motor activity of mice at intervals of 1 and 3 h after administration; the central damping effect is therefore pronounced. The antireserpine effects, on the other hand, are noticeable in both the ptosis test in mice (25 mg / kg dose) and the reserpine ulcer test in rats (dose 50 mg / kg). A binding study with 4 nM ( ³ H) imipramine in rat hypothalamus resulted in a mean inhibitory concentration IC ₅₀ value of 219.2 nM. The affinity of this substance for imipramine binding sites is thus two orders of magnitude weaker than that of the previous isomer. Also, the affinity for 4 nM / ³ H / desipramine binding sites in rat hypothalamus is weaker than for the (Z) -isomer; IC 50 = 6 316 nM. Certain selectivity is retained. This selectivity is more pronounced than in the previous isomer in direct studies of inhibition of 10 nM / H / serotonin reuptake in rat cortex (ICjq = 22.06 nM) and 10 nM / ³ H / noradrenaline in rat brain (ICjq = 141.2 ). The coefficient expressing selectivity in this case is 6.4. A substance with a strong serotonin reuptake inhibitor and a relatively strong noradrenaline reuptake inhibitor in brain structures. It is also a central anticholinergic with strong affinity for muscarinic receptors in the brain; in a binding study with 0.5 nM / H / quinuclidylbenzilate as ligand, a ΙΟ ^ θ = 102 nM was found.

Compounds of formula X are accessible by synthesis, details of which are described in the example. The synthesis is based on the reaction of 5-bromothiosalicylic acid (Katz L. et al., J. Org. Chem. 18, 1380,

1953) with 2- (chloromethyl) thiophene (Wiberg, B., McShane, H. F., Org. Synth., Coll. Vol., 1953, 1955). This is carried out in boiling aqueous ethanol in the presence of sodium hydroxide. The product is 5-bromo-2- (2-thienylmethylthio) benzoic acid, which is converted by reaction with thionyl chloride to the acid chloride, which is cyclized without isolation by treatment with zinc chloride in boiling benzene. Chromatography of the resulting mixture gave the desired 6-bromothieno [2,3-c] -1-benzothiepin-4 (10H) -one. Reaction of this ketone with 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran results in 6-bromo-4- (3-dimethylaminopropyl) -4,10-dihydrothieno [2,3-c] -1-benzothiepin-4-ol, whose acid catalyzed dehydration (boiling with dilute hydrochloric acid) to give a mixture of (E) - and (Z) -isomers of N, N-dimethyl-3- (6-bromo-4,10-dihydrothieno [2,3-c] -1-benzothiepin-4-ylidene) of propylamine of formula II

CHCH ₂ CH ₂ N (CH ₃ ) 2

The mixture of isomers of formula (II) is separated by converting the purified crude base by neutralization with maleic acid to a maleate which, after two crystallizations from a mixture of ethanol and ether, is homogeneous and decomposes to give a homogeneous and crystalline base identified as (E) - II. The base released from the mother liquor of the maleate is converted to a hydrogen oxalate which, after three crystallizations from ethanol or a mixture of ethanol and ether, is an almost homogeneous salt of the (Z) -II isomer (still containing about 10% of the (E) -isomer). The pure (E) -isomer is obtained by chromatography of the base liberated from this hydrogen oxalate by alkalization. (E) -base II provides crystalline hydrochloride. The preparation shows that the (E) -II and (Z) -II isomers are formed approximately in the ratio of 3: 1. The final operations are the transformation of the (E) -II and (Z) -II isomers by reaction with cuprous cyanide in hexamethylphosphoric triamide at 150 ° C to the desired isomeric cyano compounds (E) -I and (Z) -I. While base (E) -I is crystalline, base (Z) -I is oily. Both gave crystalline hydrogenoxalates. The NMR spectra of the isomers were used in detail to attribute the double bond configuration.

Example

5-Bromo-2- (2-thienylmethylthio) benzoic acid

To a solution of 8.0 g of sodium hydroxide in 40 ml of water and 160 ml of ethanol is added, with stirring, first 20.9 g of 5-bromothiosalicylic acid and then a solution of 12.2 g of 2- (chloromethyl) thiophene in 20 ml of ethanol and boiled. 2 hours under reflux. The ethanol was evaporated under reduced pressure, the residue was dissolved in water, washed with ether and acidified with hydrochloric acid. After shorter standing, the precipitated product is filtered off with suction, washed and dried under vacuum; 26.5 g (90%), m.p. Mp 166-172 ° C. The pure material was obtained by recrystallization from a mixture of benzene and ethanol. Mp 170-173 ° C.

6-bromothieno [2,3-c] -1-benzothiepin-4 (10H) -one

To a suspension of 55.5 g of the preceding acid in 850 ml of benzene was added 120 ml of thionyl chloride and the mixture was refluxed for 2 hours. The resulting solution was evaporated under reduced pressure at a bath temperature of 50 ° C and the residue of thionyl chloride was removed by adding 150 ml of benzene and evaporating it again. The residue (53.5 g) is the crude acid chloride which is dissolved in 740 ml of benzene, 21 g of freshly remelted zinc chloride is added, diluted with an additional 740 ml of benzene, and the mixture is refluxed for 12 h. After cooling, it is decanted by pouring into 1.5 l of water, shaken, the benzene phase is separated, washed with 300 ml of 10% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated under reduced pressure. The residue (33.5 g) is chromatographed on a column of 600 g of silica gel. The less polar component was eluted from the column with benzene / petroleum ether, and 20.7 g (40%) of the crude ketone was eluted with benzene alone, which crystallized from benzene / petroleum ether and melted at 95-96 ° C pure.

6-Bromo-4- (3-dimethylaminopropyl) -4,10-dihydrothieno [2,3-c] -1-benzethiepin-4-ol

By reaction of 4.15 g of magnesium and 20.7 g of 3-dimethylaminopropyl chloride in 55 ml of tetrahydrofuran a Grignard reagent solution is prepared. The reaction is started with a bead of iodine and 0.3 ml of 1,2-dibromoethane. After the exothermic reaction is completed, the mixture is refluxed for 2 hours to complete reagent formation. It is then cooled to 10 ° C and a solution of 26.4 g of the preceding ketone in 125 ml of tetrahydrofuran is slowly added dropwise at 10 to 15 ° C with stirring. The mixture was stirred at room temperature for 2 h and allowed to stand overnight. It is decomposed with stirring by adding a solution of 36 g of ammonium chloride in 150 ml of water, the organic phase is separated, the aqueous phase is extracted with ether and the organic solutions are combined, dried over anhydrous potassium carbonate and evaporated. The residue (35.8 g) was dissolved in 350 ml of ethanol, the insoluble material (2.5 g) was removed by filtration, and 26.1 g (77%) of the desired amino alcohol crystallized from the filtrate after partial concentration. 127 DEG-139 DEG C. (ethanol).

(E) - and (Z) -N, N-dimethyl-3- (6-bromo-4,10-dihydrothieno [2,3-c] -1-benzothiepin-4-ylidene) propylamine (II)

A mixture of 8.3 g of the preceding amino alcohol and 90 ml of 1: 1 dilute hydrochloric acid was refluxed for 1 h. After cooling, it was basified with 20% sodium hydroxide solution and the crude product was isolated by extraction with benzene. The residue obtained by evaporation of benzene was characterized by thin layer chromatography as a mixture of two substances in which one component had the same Rp as the starting material without being identical to it. This mixture is chromatographed on a column of 400 g of neutral alumina; elution with benzene gave 5.9 g (74%) of a purified mixture of the (E1- and (Z) -isomer of Formula II) by neutralization with maleic acid in ethanol and addition of ether to give 3.6 g of the maleate, which after two crystallizations from ethanol and ether is 3.0 g (29%) of homogeneous maleate (E) -II, mp 169-171 C.

The (E) -base II released from this maleate crystallizes from a small volume of ether and melts at 58-63 ° C. ^The @ ¹ H NMR spectrum confirms the stated configuration. Neutralization with hydrogen chloride in ether gives the hydrochloride which melts at 189-194 ° C (ethanol). The combined mother liquors after crystallization of the maleate are evaporated, the aqueous ammonia liberates the base, which is isolated by extraction with ether and after evaporation the neutralization with oxalic acid hydrate in acetone / ether is converted to hydrogen oxalate (2.75 g, mp 163-169 ° C). ). Three crystallizations from ethanol or a mixture of ethanol and ether yielded 1.5 g of almost homogeneous base (Z) -II hydrogen oxalate, mp 179-176 ° C. According to the ¹ H NMR spectrum, it still contained about 10% of the (E) -isomer. A completely homogeneous oily (Z) -base II is obtained by chromatography of the base released from the described hydrogen oxalate on a silica gel column. Elution with ethyl acetate elutes firstly a mixture of (Ε, Ζ) -ΙΙ approximately 1: 1, (Z) -II predominates in the next fractions and completely homogeneous (Z) -II elutes in the final fractions, as shown by the ² H NMR spectrum .

(E) -4- (3-dimethylaminopropylidene) -4,10-dihydrothieno [2,3-c] -1-benzothiepine-6-carbonitrile ((E) -1)

A mixture of 6.8 g of base (E) -II, 4.5 g of copper (I) cyanide and 10 ml of hexamethylphosphoric triamide was stirred at 150 ° C for 13 h under a nitrogen atmosphere. After cooling, it was partitioned by shaking between benzene and dilute aqueous ammonia, the mixture was filtered, the benzene phase of the filtrate was separated and evaporated under reduced pressure. Zbytex (6.4 g) was chromatographed on a column of 100 g of neutral alumina (activity II). 3.93 g (67%) of base (E) -1 was eluted with benzene, which crystallized from methanol and melted at 105.5-106.5 ° C. Neutralization with oxalic acid dihydrate in ethanol gives the hydrogen oxalate, which crystallizes from ethanol and melts at 205-206.5 ° C pure.

(Z) -4- (3-dimethylaminopropylidene) -4,10-dihydrothieno [2,3-c] -1-benzothiepine-6-carbonitrile ((Z) -I)

As in the previous case, 4.6 g of oily base (Z) -II are reacted with 3.0 g of cuprous cyanide in 15 ml of hexamethylphosphoric triamide at 150 ° C. Chromatography of the crude product on a 120 g neutral alumina column (activity II) gave 2.77 g (70%) of the oily base (Z) -I which was converted to the hydrogen oxalate by neutralization with oxalic acid dihydrate in ethanol, m.p. 200-203 ° C (aqueous ethanol-ether).

Claims (1)

OBJECT OF THE INVENTION (Z) - and (E) -4- (3-dimethylaminopropylidene) -4,10-dihydrothieno [2,3-c] -1-benzothiepine-6-carbonitriles of formula I. •WITH. clay ^CN CHCH ₂ CH ₂ N (CH ₃ ) ₂ (I) and their oxalates.