FI73686B - FOERFARANDE FOER FRAMSTAELLNING AV 4- / 1-METHYL-4-PIPERIDYLIDEN / -4,9-DIHYDROTIENO / 2,3-C / -2-BENZOTIEPIN OCH DESS VAETE - / + / - TARTRAT. - Google Patents

Description

73686

Process for the preparation of 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno-β-2,3-cis-2-benzothiepine and its hydrogen (+) - tartrate

The invention relates to a process for the preparation of 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno [2,3-c] -2-benzothiepine of formula I CH 3 O 6 CH 3 and its hydrogen - (+) - tartrate.

The compound of formula I and its hydrogen (+) - tartrate have a high antihistamine, antiserotonin, antireserpine and anti-cataleptic activity and, due to their relatively low toxicity, have the potential for use in the treatment of migraine.

The compound of formula I was tested pharmacologically in the form of hydrogen (+) - tartrate orally and intraperitoneally; said dosages are based on base. First, its effects in a series of pharmacological trials resemble those of tricyclic antidepressants belonging to the imipramine group: the compound antagonizes the effect of reserpine in mice (it significantly antagonizes reserpine-induced hypothermia at a dose of 2 mg / kg ip) and in rats (starting at a subcutaneous dose of 20 mg ulcerogenic reserpine effect), has a marked anticataleptic effect in rats (mean protective dose pD ^ g = 7.0 mg / kg sc in the perphenazine catalepsy test) and antagonizes oxotremorine tremor in mice 2,73686 (threshold dose to significantly inhibit tremor is 1.0 mg / kg ip). In addition, the compound of formula I has a marked central anterotinic effect: this is manifested by an effect on the behavior induced by administration of 5-hydroxytryptophan in rats, an effect on cipazine-induced overtemperature in rabbits and, to some extent, an interaction with tryptamine in rats. The intensity of the central anterotonin effect of a compound of formula I is expressed as the mean protective doses (PD, -q administered subcutaneously) for tremor (2.9 mg / kg) and for vertical movements of the forepaws ("drumming") (2.6 mg / kg). in rats when behavioral symptom was induced by administration of 5-hydroxytryptophan. In this experiment, the effect of the compound of formula I is similar to that of cyproheptanidine and considerably greater than that of amitriptyline.

Of the peripheral effects of the compound of formula I, the antihistamine and antiserotonin effects were the strongest. Oral administration to guinea pigs has an antihistamine effect in the histamine aerosol assay at a mean protective dose (PD ^ q) of 0.046 mg / kg. Also in the histamine toxic effect reversal test and the histamine-induced bronchoconstriction test, the compound of formula I is one of the most effective known antihistamines. The antiserotonin effect is statistically significant in the 5-hydroxytryptamine-induced edema test in the rat paw after oral administration of the test compound at 0.3 mg / kg. In addition, the compound of the formula I has considerable peripheral anticholinergic effects: in mice it has a blackening-expanding effect and blocks the lethal acetylcholine effect in guinea pigs.

Compared to the previously known migraine drug, pitsotifen (A.G. Dixon et al., Arzneim.-Forsch. 27, 1968, 1977), the compound of formula I has a considerable advantage due to its lower central nervous system inhibitory effect. When administered orally, the compound of formula I inhibited the research activity of mice li 3 73686 in the Boissier and Simon detection experiment three times less intensely than pitsotifen (D5Q 23 mg / kg for compound I and 7 mg / kg for pitotifen). In a spontaneous exercise monitoring experiment in mice using the Dewis beam method (photocell), the inhibitory activity of the compound of formula I is up to seven times lower than that of pizotifen (the D iq of the compound of formula I is 24.2 mg / kg and the D5Q of pitsotifen is 3.4 mg / kg). ). In a less specific thiopental sleep enhancement test, mice have a threshold dose of 10% of the oral LD50 value of the compound of formula I and 2.5% of its LD50 value for pizotifen (oral toxicity of both substances in mice is similar). The compound of formula I has a clear tendency to stimulate the behavior of rats: when monitoring the effect on total activity using the "Animex" device, oral doses of the compound of formula I at 10 and 30 mg / kg have a moderate stimulatory effect (125-131% increase in activity compared to the control group). , while pizotifen at a dose of 3 to 30 mg / kg orally has a statistically significant inhibitory effect (57-64% compared to the control group).

The oral toxicity of the compound of formula I in rats is surprisingly low; when administered orally at 1 g / kg, none of the ten animals died within 7 days. Only moderate attenuation is observed 30 minutes after administration. Mice have an LD50 dose of 129 mg / kg when administered orally and 26.6 mg / kg when administered intravenously. When dogs are administered a single dose of a compound of formula I at 50 and 100 mg / kg orally, there are no behavioral changes and no signs of intoxication or death.

The compound of formula I has been described in the literature (M. Rajsner et al., Collect. Czech. Chem. Commun. 32, 2854, 7 3 6 8 6 4 1967; CS Patent 115,241). It was prepared by the reaction of thieno [2,3-c] -2-benzothiepin-4 (9H) -one with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran, followed by 4- (1-methyl-4- piperidyl) -4,9-dihydrothieno [2,3-c] -2-benzothiepin-2-ol (Formula II) acid catalyzed cleavage.

0Q- * J ^ OH (II)

CH

3

It has then been overlooked that the compound of formula II, which is assumed to be formed in the Grignard reaction in 74% yield, is not homogeneous but contains as an impurity another compound which remains unchanged in the subsequent acid-catalyzed (heating with dilute sulfuric acid) water cleavage and even the final product the compound according to is impure. The yield reported in said work, i.e. 95% of theory, based on the evaporation residue, i.e. the impure compound of the formula I, which contains an undetermined amount of said impurity. The presence of said impurity also explains its melting points reported for the compound of formula II, crystallized from a benzene-petroleum ether mixture at 125 ° C and crystallized from acetone at 119-120 ° C. These low melting products are described as solvates without any evidence, except in the case of a mixture other than a compound of formula II and said impurity.

The product obtained by the reaction between thieno [2,3-c] -2-benzothiepin-2 (9H) -one and 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran has now been further investigated and the crude product obtained was isolated using a combination of crystallization and chromatography. Silikageeliohut-

II

5 73686 layer chromatography showed that the product was markedly inhomogeneous and contained a large amount of less polar by-product in addition to the amino alcohol of formula II. The amino alcohol of formula II can be recovered from the crude product with ethanol, as the desired product of formula II is insoluble and the less polar by-product is soluble. This can be obtained from the mother liquor by silica gel chromatography and purified by crystallization. It is surprising that the pure amino alcohol of formula II and the pure, less polar by-product melt at exactly the same temperature, 212-213 ° C. However, the mixture of these two substances melts at a much lower temperature and it is precisely these melting points of the "solvates" to which reference is made in said work.

Analysis of the less polar by-product showed that its structure is very close to that of the amino alcohol of formula II, and the mass spectrum showed the gross formula C17H162S2 'so' to be a compound with 2 less hydrogen atoms than the amino alcohol of formula II. The UV spectrum of the new compound suggests a very strong conjugation corresponding to diaryl ketone. The IR spectrum also confirms in the band 1611 cm x that it is a diaryl ketone.

This spectrum and the NMR spectrum show that no hydroxyl group is present. The compound of formula II and the less polar by-product show a significant difference in the NMR spectra of the aromatic proton signal. When the spectrum of the compound of formula II shows the presence of 6 aromatic protons, where the signals of 5 protons merge into a multiplet that cannot be separated and only the proton at position 5 of the backbone is clearly distinguished, the spectrum of the less polar compound shows the presence of only 5 aromatic protons. are clear overall and allow individual positions of the hull to be located; and then a proton at position 7 is missing. Further evidence of a difference between a compound of formula II and a less polar compound is provided by the 73686 mass spectral positions corresponding to these moieties. The major part m / z of the compound of formula II is 98, which corresponds to the ammonium ion with the obtained 1-methylpiperidine group, while the main part m / z of the by-product is 70, which corresponds to the part of the methylpiperidine group having 4 carbon atoms. The first case is typical of an aliphatic carbon-bonded methylpiperidyl group and the second case corresponds to an aromatic carbon-bonded methylpiperidyl group. Based on all these spectral results, the structure of the less polar compound corresponds to 7- (1-methyl-4-piperidyl) thieno [2,3-c] -2-benzothiepin-4 (9H) -one (formula III): ) o

The formation of a compound of formula III is explained by the 1,6-coupling of the Grignard reagent to a system of three double bonds of the starting ketone molecule (including the C = O double bond of the keto group) or to the dipole formed by forced enolization of the starting material under reaction conditions (R. Gaertner, Chem. Revs. 4j>, 493, 1949). This coupling and subsequent hydrolysis should be followed by the removal of two hydrogen atoms, i.e. oxidation - probably by the action of oxygen in the air. This is a relatively rare series of reactions that have been studied mainly with sterically strongly hindered aromatic ketones, e.g. 2,3,5,6-tetramethyl and 2,3,5,6-tetramethyl-2'-methoxybenzophenone, and Grignard between reagents (RC Fuson et al., J. Amer. Chem. Soc.

65, 60, 1943; 71, 2543, 1949; J. Org. Chem. 13, 496, 1948).

It is an object of the present invention to provide a process for the preparation of a compound of formula I which comprises removing a compound of formula III from an alcohol of formula II which is then used in pure form in aqueous

II

7 3 6 8 6 in the cleavage step, and further steps are taken to free the final product of formula I from the last residues of the compound of formula II. These procedures take advantage of the good solubility of the compound of formula III in ethanol. For this reason, it is suspended in the first step, i.e. In the Grignard reaction, the crude product obtained is taken up in ethanol, the suspension is heated to boiling point and, after cooling, practically pure amino alcohol of the formula II is separated off. It is obtained in only 50 to 5% yield from the theoretical solution and no additional compound of formula II can be economically recovered from a mother liquor containing a considerable amount of a compound of formula III. The final residue of the compound of formula II is removed from the final product of formula I by crystallization from ethanol, leaving this impurity in the mother liquor. An integral part of this invention is further provided by a process for the formation of a novel compound of formula I hydrogen - (+) - tartrate by neutralization with (+) - tartaric acid in aqueous ethanol. Hydrogen - (+) - tartrate crystallizes excellently, is moderately water soluble, and is more advantageous for administration in pharmaceutical form than other salts known in the art (referred to above) succinate, fungarate, and hydrogen maleate. The preparation of a compound of formula III in pure form is not described in this invention as it does not form any part of this invention.

Thus, the preparation of a compound of formula I according to the present invention is carried out in practice as follows: 50 g of tetrahydrofuran are added to 24 g of magnesium and then about 1/4 of a solution volume of 134 g of 4-chloro-1-methylpiperidine is added dropwise (E. AdlerovS et al. ., incl. Farm 1-2, 122, 1963) in 300 ml of tetrahydrofuran (dried on a molecular sieve Potasit 4 A), and the mixture is heated to 50-55 ° C with a partially heated oil bath. 0.5 g of iodine and 1 ml of 1,2-dibromoethane are added and 8 73686 reactions are expected to start, which takes 10 to 30 minutes. When the mixture begins to boil vigorously at reflux, the oil bath is removed and the remainder of the 4-chloro-1-methylpiperidine solution is added dropwise so rapidly that the mixture boils vigorously. When the reaction is complete, turn on the stirrer. Near the end of the drip, which lasts 40-50 minutes, the mixture is heated moderately. It is then boiled under stirring at reflux for a further 1.5 hours. The mixture is cooled to 10 [deg.] C. with ice water and, with stirring under ice-water cooling, a solution of 155 g of thieno [2,3-c] -2-benzothiepin-4 (9H) -one in 350 ml of tetrahydrofuran (M. Protiva) is added over 1 hour. et al., Collect. Czech. Chem. Commun. 29, 2161, 1964; 2854, 1967; 39, 1366, 1974). The temperature is then kept between 10-15 ° C. After completion of the dropwise addition, cooling is stopped and the mixture is stirred for 30 minutes, at which time it reaches room temperature. A solution of 225 g of (+) - tartaric acid in 2 liters of water is then added to the dark solution with vigorous stirring so rapidly that the temperature does not rise above 20 ° C (strong external cooling is initially required). 500 ml of toluene are then added and the mixture is stirred vigorously for 10 minutes. The toluene layer containing the neutrals is separated off, the aqueous phase is washed with a further 200 ml of toluene, then 1600 ml of chloroform are added and the mixture is basified by vigorous stirring and cooling with 300 ml of concentrated ammonium hydroxide. The chloroform layer is separated, the aqueous layer is extracted with a further 200 ml of chloroform, the combined chloroform solutions are washed with 300 ml of water and allowed to stand for 12 hours after first adding 30 g of anhydrous potassium carbonate and 1 g of activated carbon. The solid is then filtered off with suction and washed with 50 ml of chloroform. Chloroform is distilled off under moderately reduced pressure (10-20 kPa). To the residue is added 200 ml of ethanol, the mixture is briefly heated to reflux and then cooled to 5 ° C. The separated crystalline 4- (1-methyl-4-piperidyl) -4,9-dihydrothieno [7,3-c] -2-benzothiepin-4-ol (formula II) is filtered off with suction and washed with 100 ml of ethanol in two portions. times. The precipitate is dried at room temperature under reduced pressure. The yield is 113 g (51% of theory) and the melting point of the product is 209-211 ° C. In this state it is almost clean and suitable for further processing. Crystallization of a sample from ethanol gives a completely pure product with a melting point of 212-213 ° C.

To a solution of 240 g of sulfuric acid in 1170 ml of water is added at 40-50 ° C 166 g of the amino alcohol of the formula II obtained above and the resulting mixture is boiled under stirring for 15 minutes at reflux. After cooling, the mixture is diluted with a mixture of 200 ml of water and 400 ml of chloroform, and then the mixture is made alkaline by dropwise addition of 220 g of concentrated ammonium hydroxide with stirring. The temperature of the mixture is kept between 20-30 ° C. The chloroform layer is separated and the aqueous phase is extracted twice more with 100 ml of chloroform (2 x 100 ml). The combined chloroform solutions are washed with 150 ml of water, dried over 20 g of potassium carbonate, allowed to stand overnight and the desiccant is sucked off. The filtrate is evaporated under reduced pressure (10-20 kPa). 900 ml of ethanol are poured onto the crystalline residue and it is dissolved by stirring and heating to boiling point. The hot solution is decolorized by filtration with 10 g of activated carbon and the filtrate is allowed to crystallize at 5 ° C. The mixture is allowed to stand for 12 hours, during which time the separated 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno [2,3-c] -2-benzothiepine base of the formula I is separated off and washed with 50 ml of ethanol and then with 100 ml of petroleum ether. Thus, after drying at room temperature, 124 g of product of formula I are obtained. Evaporation of the mother liquor to a volume of 200 ml m and allowing to stand at 5 ° C gives 14 g of the corresponding product; the total yield is 138 g (83% of theory), m.p. 160-161 ° C. The substance is pure enough to make a salt. When the sample is crystallized from ethanol, a completely pure base of formula I is obtained, m.p. is 162-164 ° C.

The base of formula I (94 g) is dissolved in 650 ml of ethanol under boiling. After dissolution, heating is stopped and a hot solution of 47 g of (+) - tartaric acid in 85 ml of water is slowly poured into the resulting solution. The tartrate solution is cooled to 10 ° C with stirring, whereupon crystallization occurs. After cooling for 12 hours, the crystalline product which has separated is filtered off with suction and washed twice with 50 ml of ethanol (2 x 50 ml). The still moist product is dissolved in a mixture of ethanol (1250 ml) and water (1000 ml) by heating to boiling while stirring. The hot solution is filtered and the hot filtrate is allowed to crystallize under stirring for 4 hours in an ice bath. The product is then filtered off with suction, washed twice with ethanol (2 x 30 ml) and air-dried at room temperature. The mother liquor is evaporated off under reduced pressure (3-5 kPa) to about half its original volume and a second batch of product crystallizes on cooling to 5 ° C. A total of 125 g (90% of theory) of the hydrogen (+) - tartrate of the base of formula I with a melting point of 228-231 ° C (decomposes) is obtained.

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Claims (1)

A process for the preparation of 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno [2,3-c] -2-benzothiepine of the formula I and its hydrogen tartrate ζτρ CH 3 by reacting thieno [2,3-c] -2-benzothiepin-4 (9H) -one with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran and then cleaving water from the resulting 4- (1-methyl) compound of formula II by acid catalysis. -tyl-4-piperidyl) -4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-ol ocp OH (II) CH3, characterized in that this crude alcohol of the formula II is liberated from the concomitantly formed compound of the formula III 7- (1-methyl-4-piperidyl) -thieno [2,3-c] -2-benzothiepin-4 (9H) -one by extraction with CH3-O o ethanol followed by pure alcohol of formula II which forms an insoluble part , 12 73686 „cleaves water and the crude base of formula I is freed from the last residues of the compound of formula III by recrystallization from ethanol. after which the pure base of formula I is converted into said salt by neutralization with (+) - tartaric acid from aqueous ethanol. For the preparation of 4- (1-methyl-4-piperidylidene) -4,9-dihydrothieno [2,3-c] -2-benzothiepine and the (+) -tartrate of formula I and II of the CH 3 genome The thieno [2,3-c] -2-benzothiepin-4 (9H) -one with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran and the like after the reaction of water with the syrup catalyst was reacted with 4- {1-methyl -4-piperidyl) -4,9-dihydrothieno: / 2,3-c7-2-bensotiepin-4-II of the formula i as claimed in FY ~ j '-OH (II) in CH 3 characterized in that the Oreña to the alcohol according to the formula II is obtained from velvety 7- (1-methyl-4-piperidyl) -thieno [1,3-b] -2-benzothiepin-4 (9H) -one to give Form III II