CS231083B1 - Processing method of 4-(1-methyl-4-piperidyliden)-4,9-dihydrothieno (2,3-c)-2-benzothiepine and its hydrogen-(p-tartarate - Google Patents

Abstract

4-(1-Methyl-4-piperidylidene)- 4,9-dihydrothieno(2,3-c)-2- benzothiepin of formula I <IMAGE> and its hydrogen (+) tartrate (a novel salt) are prepared by the reaction of thieno(2,3-c)-2-benzothiepin-4(9H)- one with 1-methyl-4- piperidylmagnesium chloride in tetrahydrofuran and subsequent acid- catalysed dehydration of the resulting 4- (1-methyl-4-piperidyl)-4,9- dihydrothieno(2,3-c)-2-benzothiepin- 4-ol after removal of the simultaneously formed 7-(1-methyl-4- piperidyl)thieno(2,3-c)-2-benzothiepin -4(9H)-one. Compound I and especially its hydrogen (+) tartrate possess high antihistamine, antiserotonin, antireserpine and anticataleptic activity and are expected to find use in the therapy of migraine.

Description

The present invention relates to a process for the preparation of 4- (1-methyl-4-yl-piperazin-4-yl) -4- (9-dihydrothieno) (2,3- c) - (2) - (2-enzothiophenyl) - (I)

(I) and its hydrooene - (+) - tartrate.

The compound of formula I and its hydrooene - (+) - tartrate have a high degree of antihisjmin, antiserotonin, antireserpine and anticataleptic efficacy and, with their relatively low toxicity, are well suited to practical use in migraine theraa. formulas

Substance"! has been tested pharmacologically in the hydrogen (+) - tartrate form by oral or intraperioneal administration; the stated doses are based on the calculation. In the first place, its effects in a series of pharmacological tests are similar to those of the triclclic antidepressants of the imipramine group: the substance acts antagosistically to reserpine in masses (antagonizes reserpine hypothermia at 2 mg / kg ip) and in rats (starting at subcutaneous 20 m> / kg) suppresses the ulcerogenic effect of reserpine), has a pronounced effect in rats (in the perfenazine cathepsis test, its median protective dose is PD ^ q - 7.0 mg / kg sc) and antagonizes oxotremorine tremor in the flies (threshold yields significant signaling) The tremor is 1.0 m ^ / kg pp). Furthermore, the substance Y1 demonstrates a distinctive quality of the total anisotonin effect: this effect can be demonstrated by

231,083 is not a behavioral manifestation induced by administration of 5-hydroxytryptophan in rats, in affecting chipazine hyperthermia in rabbits, and to some extent in interaction with tryptamine in rats. The intensity of the central antiserotonin effect of Compound I in influencing behavioral syndrome following administration of 5-hydroxytryptophan in rats is expressed as mean protective doses (PD ^ g for subcutaneous administration) against tremor (2.9 mg / kg) and vertical paw movements (tapping) ( 2.6 mg / kg). In this test, Compound 1 is similar in activity to cyproheptadine and substantially more potent than amitriptyline.

Among the peripheral effects of Compound I, the most intense effects were antihistamine and antiserotonin. When administered orally in guinea pigs, the antihistamine efficacy in the histamine aerosol test is expressed as the mean protective dose, PD ^ q = 0.046 mg / kg.

Even in the histamine detoxification and histamine bronchoconstriction tests, substance I is one of the most effective antihistamines known. The antiserotonin effect in the rat paw edema test after 5-hydroxytryptamine is statistically significant at an oral dose of 0.3 mg / kg. Furthermore, Compound I has mild peripheral anticholinergic effects: it acts mydriatically in mice and blocks the lethal action of acetylcholine in guinea pigs.

Compared to the known anti-migraine preparation pizothifen (Dixon AG et al., Arzneim.-Forsch. 27, 1968, 1977), compound I shows a distinct advantage in lower central buffering activity. Following oral administration, Compound I inhibits the screening activity of mice in the Boissier and Simon observation test by three times less intense than pizothifen (for ^{D 1} = 50 mg / kg and pizothifene ^D 50 = 7 mg / kg). In the test the spontaneous locomotor activity in mice using ray method according Dews (photocell), the inhibitory activity of the substance or even seven times less than the effect pizothifenu (substances ID ^ q = 24.2 mg / kg for pizothifen ^d 50 ^{e 3 »4} mg / kg). In a less specific assay for potentiation of thiopental sleep in mice, the threshold dose of Compound I corresponds to 10% of its oral LD 50; for pizothifen it is 2.5% of its oral LD 40 (oral toxicity of both substances in mice is similar). In rats, Compound I has a distinct tendency to behavioral stimulation: when monitoring the effect on overall activity using Animex, oral doses of Compound I 10 and 30 mg / kg have a slight stimulatory effect.

231 083 (increase in activity to 125 to 131% of the control group), while oral doses of 3 to 30 mg / kg of pizothifene cause a statistically significant decrease in activity (to 57 to 64% compared to the control group).

The oral toxicity of substance I in rats is surprisingly low; following a 1 g / kg p.o. no animals of the 10-member group die within 7 days. Only slight suppression is observed at 30 min post-administration. In mice, the oral LD ≥ q = 129 mg / kg; intravenous LD50 = 26.6 mg / kg. Single administration of Compound I at doses of 50 and 100 mg / kg p.o. it does not induce any change in behavior, nor does it lead to toxic effects or death of dogs.

The compound of formula I has been described in the literature (Rajsner M., Metz J., Protiva M., Collect.Czech.Chem.Commun. 32, 2854, 1967; U.S. Patent 115,241). It was prepared by reacting thieno (2,3-c) -2-benzothiepin-4 (9H) -one with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran followed by acid-catalyzed dehydration of the resulting 4- (1-methyl-4-piperidyl) - 4,9-dihydrothieno (2,3-c) 2-benzothiepin-4-ol of formula II.

It has been overlooked that substance II, resulting from the Grignard reaction, reportedly in 74% yield, is inhomogeneous and highly contaminated by another substance which remains unchanged in subsequent acid-catalysed dehydration (heating with dilute sulfuric acid) and contaminates the final product, ie substance I The quoted yield at the dehydration stage, i.e. 95%, refers to a residue, i.e. raw material I, containing an unspecified amount of said contaminant. The presence of this contaminant also explains the low melting points for substance II, crystallized from a mixture of benzene and petroleum ether (125 ° C), respectively. from acetone (119-120 ° C). These low melting products are free

231 083 of any license identified as solvates, which is nothing other than mixtures of substance II with the said contaminant.

Reaction of thieno (2,3-c) -2-benzothiepin-4 (9H) -one with 1-methyl-

4-Piperidylmagnesium chloride in tetrahydrofuran has now been studied more closely and the crude product obtained is separated by a combination of crystallization and chromatography techniques. Thin layer chromatography of silica gel revealed that it was substantially inhomogeneous and that the amino alcohol quartz II contained a significant amount of less polar impurities. Pure amino alcohol II can be obtained from the crude product by extraction with ethanol, the desired compound II remaining undissolved and a less polar impurity is added to the solution. This can be obtained from the mother liquor by silica gel column chromatography and purified by further crystallization. It is surprising that Pure amino alcohol II and pure less polar impurities melt at exactly the same temperature of 212 to 213 ° C. However, their mixture melts with deep depression and these are the melting points 'solvates' mentioned in the cited work.

While the analysis of the less polar additive showed a composition very similar to that of the amino alcohol II, the mass spectrum for it showed a C ^ ^H ^NOSg composition, i.e. a compound of 2 hydrogen atoms lighter than the amino alcohol II. The ultraviolet spectrum of the novel substance indicates a high degree of conjugation corresponding to the diaryl ketone. It is a diaryl confirmed by infrared spectrum bands at 1611 cm ^'1. This spectrum and the ¹ H NMR spectrum were shown

- absence of a hydroxyl group. Significant is the difference in the H NMR spectra of Compound II and the less polar impurity in the region of aromatic proton signals. While the spectrum of substance II indicates the presence of 6 aromatic protons, of which five signals merge into an indistinguishable multiplet and only the proton at position 5 of the skeleton is clearly distinguished, the spectrum of the less polar substance shows only five aromatic protons whose signals are largely clearly differentiated localize to individual skeletal positions; the proton in position 7 is missing. Further evidence of the difference in substance II and less polar impurities is provided by the mass spectra in the fragment-related portion. While the major fragment of Compound II has m / z 98, which corresponds to an ammonium ion with 1-methylpiperidine residue retained, the major fragment of m / z 70 has a corresponding graft to the 4-carbon methylpiperidine residue. The first case is typical of methyl piperidyl bound

231 083 on aliphatic carbon, the second case corresponds to the behavior of methylpiperidyl bound to aromatic Al. From all of these spectral findings, the less polar compound yields the structure of 7- (1-methyl-4-piperidyl) thieno (2,3-c) -2-tenzothtepin-4C9H) -one.

The formation of III is necessary. explained by 1,6-addition of Grignard reagent to the system of three double bonds in the molecule of the starting ketone - (including the double bond of the keto group C0O), respectively, to the dipole formed by forced enolization of the starting ketone under reaction conditions (Gaertner R, Chem.Revs. 5 »493, 1949)» This addition of fading methanol hydrolysis is followed by elimination of two hydrogen atoms, ie oxidation - probably by action - of air oxygen »This is a relatively rarely observed reaction sequence, which was studied mainly on reactions stoically strongly inhibited by an ^ β-ketones, e.g. 2,3,5 6 6-tetramethyl-2,3,5 6- 6,6-α-β-2-α-2-α-α-α-2-α-α-α-α-methyl-2-methyl-2-methyl-2-methyl-2-methoxy-2 [iota], with Grignard reagents (Puson eC et al., J.Amer. Chem. Soc. 5, 60, 1943, 71, 2543, -1949, J. Org. Chem., 13, 496). , 1948) »

The purpose of the present invention is to protect a process for the preparation of a compound of formula I which comprises providing a compound III from the amino alcohol II, which is then used in a pure state to the dehydration stage, and further removing the last residues of the compound. III from the final product I »These measures take advantage of the good solubility of III - in - ethanol» For this reason, the crude product of the first stage, ie the Grignard reaction, is suspended in ethanol, the suspension is heated to boiling and The practically pure aminoalcohol II is filtered off in this way in a yield of only about 50% and from the caustic liquors, which contain a considerable amount of the substance III, it is no longer possible to economically obtain a larger quantity of the substance II. remove by crystallization from ethanol, whereupon

231 083 this contaminant remains in the mother liquor. Finally, an inseparable part of the present invention is a process for the preparation of a novel hydrogen (-) - tartrate compound I by neutralizing it. (+) - tartaric acid in aqueous ethanol. Hydrogen - (+) - tartrate excellently crystallizes, is slightly soluble in water, and is more advantageous from the point of view of formulation than the other salts previously described (cited) (succinate, fumarate, hydrogen maleate). The process for the preparation of the compound III in the pure state is not described in the present invention because it is not an object thereof.

Thus, the preparation of the compound I according to the invention is carried out in practice as follows:

To 24 g of magnesium and add 50 ml of tetrahydrofuran and then add about 25% / solution of 134 g of 4-chloro-1-methylpiperidine (Adlerová E, et al., Česk.Farm. 12. 122, 1963) in 300 ml of tetrachloride. hydrofuran (dried with Molecular Sieve 4 A) and the mixture was heated with an oil bath heated to 50-55 ° C. 0.5 g of iodine and 1 ml of 1,2-dibromoethane are added and the reaction is allowed to start, which takes 10 to 30 minutes. When the mixture began to boil vigorously at reflux, the oil bath was removed and the remaining 4-chloro-1-methylpiperidine solution was added dropwise so that the mixture boiled vigorously. When the reaction is fully running, the stirrer is started. At the end of the addition, which lasts 40-50 min, the mixture is gently warmed. It is then refluxed under stirring for a further 1.5 hours. After cooling to 10 ° C with ice water, a solution of 155 g of thieno (2,3-c) -2-benzothiepine 4 (9H) is added dropwise over 1 hour while stirring and cooling with ice water. Ion (Protiva M, Rajnar M. et al., Collect.Czech.Chem. Commun. 2, 2161, 22, 22, 2854, 1967-1386, 1974) in 325 ml tetrahydrofuran. The temperature is maintained between 10 and 15 ° C. After completion of the dropwise addition, the cooling was discontinued and the mixture was stirred for 30 min, reaching room temperature. A solution of 225 g of (+) - tartaric acid in 2 liters of water is then added dropwise to the dark solution with vigorous stirring so that the temperature of the mixture does not exceed 20 ° C (intensive external cooling is required at first). Toluene (500 ml) was then added and the mixture was stirred vigorously for 10 min. The toluene layer containing the neutral substances was separated, the aqueous layer was washed with a further 200 ml of toluene, then 1600 ml of chloroform were added and the mixture was made alkaline with vigorous stirring and cooling, with 300 ml of concentrated ammonium hydroxide.

231 083

The chloroform layer is separated, the aqueous is extracted with 200 ml of chloroform, the combined chloroform solutions are washed with 300 ml of water and, after 30 hours, 30 g of anhydrous potassium sulphate and 10 g of active urine are added. The solids were then aspirated and washed with 50 ml of chloroform. The chloroform is stripped off under a slightly reduced pressure (10 to 20 kPa). Ethanol (200 ml) was added to the residue, and the mixture was extracted with ethyl acetate. briefly heat to reflux and cool to 5 ° C. The crystalline 4- (1-mehyl «· 4-pipeeiděl) -4 9dihydrothieno _s ^ 3 - cis) -2 - benzothiepine" -4ol (II) is removed, promy- * 100 ml of ethanol and then 100 ml of petroleum ether. Dry at room temperature under reduced pressure. It is obtained. yield: 113 g (51%) and melts at 209-211 ° C. In this state it is almost clean and suitable for further processing. Crystallization of the sample from ethanol yields a pure substance, m.p. 212-213 ° C.

To a solution of 240 g of sulfuric acid in 1170 m. Of water at 40-50 ° C was added 166 g of the preceding amino alcohol II and refluxed for 15 min with stirring. After cooling, the mixture is diluted with 200 ml of water, 400 ml of water are added and the mixture is made alkaline by dropwise addition of 220 g of conc. ammonium hydroxide. Temperature sramě! is maintained between 20 and 30 ° C. The chloroform layer was separated and the aqueous extracted twice more with 100 ϋ chloroform. The combined chloroomium solutions are washed with 150 mL of water, dried with 20 g of potassium carbonate and, after standing overnight, the desiccant is filtered off with suction. The filtrate is evaporated under reduced pressure (10 to 20 kPaa). The crystalline residue is passed through 900 mL of ethanol and brought to the solution by heating to boiling with stirring. C. After standing for 12 h, the precipitated base of 4- (1-methyl-4-piperidene) -4,9-methylsthieno [2,3-d] -2-benzsthiepine (I) is filtered off with suction and washed with 50 ml of ethanol and then with 100 ml of petroleum ether. drying at room temperature yielded 124 g of product I. Evaporation of the mother liquor to a volume of 200 mL and standing at 5 ° C yielded an additional 14 g of the corresponding product, overall yield 138 g (88%, mp 160-160 ° C). 161 [deg.] C. The substance is sufficiently pure for the preparation of the salt.

Base I (94 [mu] g) was dissolved in 650 mL of ethanol while boiling. After dissolution, heating is discontinued and hot r * is slowly drunk.

231.083 of 47 g of (+) - viral acid in 85 ml of water. With stirring, the tartrate solution is then cooled to 10 ° C, during which crystallization occurs. After 12 hours of cooling, the precipitated crystalline product is filtered off with suction and washed twice with 50 '. ml of ethanol. The still wet product was dissolved in a mixture of 1250 m of ethanol and 1000 ml of water by heating to boiling with stirring. The hot solution is filtered and the filtrate is crystallized with stirring and cooling in an ice bath for 4 hours. It is then filtered off with suction, washed twice with 30 m of ethanol and dried. in air at room temperature. The caustic liquor is evaporated under reduced pressure (3 to 5 kPa) to about half its original volume and, by cooling to 5 ° C, a second crop of product is obtained. A total of 125 g (90%) of hydro- (+) - tartrate base I melting at 228-231 ° C decomposes.

Claims (1)

A process for the preparation of 4- (1-methyl-4-piperidinyl ⁾ -4,9-dilydro-thieno [2,3-c] -2-benzothiepine of formula I (1) and its - hf (irooeei - [*]) of the tar-tarate by reaction of thisno [2,3-c] -2H-benzothiepin-4 (9B) -one with 1-methyl-.beta.-para-methylmainiesimide chloride in tetralyrirourane followed by acid-catalyzed dehydration of the resulting 4- (methyl) -4-piperidinyl. (44, 9) Hydroxyhino-2,3-c-9-2-benzothiepin-4-ol of formula (II), characterized in that the crude alcohol of formula (II) is freed of the resulting 7- (1) -methyl-4-piperidinyl-thieno [2,3-c] -2-benzothiepin-4 (93) -one of formula III 231 083 by extraction with ethanolim, a pure alcohol of formula II, which is obtained as an insoluble fraction, and is then subjected to dehydration, and the crude base of formula I is treated. frees the last - residue of the compound of formula III by crystallization - from ethanol, after which the pure base of formula I is converted to the said salt by neutralization with acid (*) - in aqueous ethanol ·