CH655117A5 - METHOD FOR PRODUCING 4- (1-Methyl-4-PIPERIDYLIDENE) -4,9-dihydro-thieno (2,3-C) -2-Benzothiepin AND ITS HYDROGEN - (+) - tartrate. - Google Patents

Description

655 117

2nd

PATENT CLAIM Process for the preparation of 4- (l-methyl-4-piperidylidene) -4,9-dihydrothieno- [2,3-c] -2-benzothiepin of the formula I.

0

ch3 [i]

and its hydrogen (+) tartrate by reacting thieno [2,3-c] -2-benzothiepin-4- [9H] -one with l-methyl-4-pipe-ridylmagnesium chloride in tetrahydrofuran and subsequently acid-catalyzed Dehydration of the resulting 4- (1-methyl-4-piperidyl) -4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-ol of the formula II

OH

Ih3 im characterized in that this crude alcohol of formula II from the simultaneously formed 7- (l-methyl-4-piperidyl) thieno- [2,3-c] -2-benzothiepin-4- [9H] -one of formula III

[III]

freed by extraction with ethanol, the pure alcohol of formula II, which is obtained as an insoluble fraction, then subjected to dehydration and the crude base of formula I freed from the last residues of the substance of formula III by recrystallization from ethanol, after which the pure base of the formula I into the salt mentioned by neutralization with (+) -tartaric acid in aqueous ethanol.

The invention relates to a process for the preparation of 4- (l-methyl-4-piperidylidene) -4,9-di-hydrothieno [2,3-c] -2-benzothiepin of the formula I.

and its hydrogen (+) tartrate.

The compound of the formula I and its hydrogen (+ hartrate have a high degree of antihistamine, antiserotonin, antireserpine and anticatalepsy activity and, with relatively low toxicity, they meet the requirements for practical use in the treatment of migraine.

The compound of the formula I was tested pharmacologically in the form of the hydrogen (+) tartrate after oral and interperitoneal administration; the gifts given relate to the base. In a number of pharmacological tests, their effects are primarily similar to the effects of tricyclic antidepressants from the imipramine group: the compound has an antagonistic effect on reserpine in mice (it significantly antagonizes reserpine hypothermia in a dose of 2 mg / kg ip) and in rats (starting with subcutaneous administration of 20 mg / kg, it statistically significantly inhibits the ulcerogenic reserpine effect), it has a pronounced anticataleptic effect in rats (in the test of perfenazine catalepsy, its mean protective dose is PDso = 7.0 mg / kg sc) and antagonizes the oxotremorine tremor in mice (the threshold dose which significantly inhibits the tremor is 1.0 mg / kg ip). The compound of the formula I also demonstrates a pronounced quality of the central antiserotonin action: this action can be demonstrated in influencing the manifestations of behavior caused by administration of 5-hydroxytryptophan in rats, in influencing quipazine hyperthermia in rabbits and to a certain extent in the interaction with Tryptamine in rats. The intensity of the central antiserotonin activity of the compound of the formula I in influencing the behavioral syndrome after administration of 5-hydroxytryptophan in rats is expressed as mean protective doses (PDso after subcutaneous administration) against tremors (2.9 mg / kg) and against vertical movements the front paw («tapping») (2.6 mg / kg). In this test, the activity of the compound of the formula I is similar to that of cyproheptadine and considerably higher than that of amitriptyline.

Among the peripheral effects of the compound of formula I, the most intense was the antihistamine and antiserotonin activity. After oral administration to the guinea pigs, the antihistamine activity in the Hista-minaerosol test, expressed as a mean protective dose, is PD 50 = 0.046 mg / kg. The compound of formula I is also one of the most effective known antihistamines in the histamine detoxidation and histamine bronchoconstriction tests. The antiserotonin effect in the test of rat paw edema after 5-hydroxytryptamine is statistically significant after oral administration of 0.3 mg / kg. The compound of formula I also has moderate peripheral anticholinergic effects: it has a mydriatic effect in mice and blocks the lethal acetylcholine effect in guinea pigs.

In comparison with the known migraine drug Pizothi-phen (A.G. Dixon and co-workers, Pharm.-Forsch. 27, 1968, 1977), the compound of formula I has a clear advantage in a lower central inhibitory effect. After oral administration, the compound inhibits the

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3rd

655 117

Formula I the research activity of the mice in the observation test according to Boissier and Simon three times less intensive than Pizothiphen (for the compound of Formula I Dso = 23 mg / kg and for Pizothiphen Dso = 7 mg / kg). In the test of tracking the spontaneous locomotor activity in mice using the Dews beam method (photocell), the inhibitory activity of the compound of the formula I is even seven times less than that of the pizothiphene (for the compound of the formula I Dso = 24.2 mg / kg, for Pizothiphen D5o = 3.4 mg / kg). In the less specific test of promoting thiopental sleep in mice, the threshold dose of the compound of the formula I corresponds to 10% of its oral LDso; in Pizothiphen it is 2.5% of its LDso (the oral toxicity of both substances in mice is similar). In rats, the compound of the formula I has a clear tendency to stimulate behavior: when monitoring the influence on the overall activity using the "Animex" device, the oral administration of the compound of the formula I of 10 and 30 mg / kg shows a moderate stimulating effect ( Increase in activity to 125 to 131% of the control group), while oral doses of 3 to 30 mg / kg pizothiphene cause a statistically significant inhibition of activity (to 57 to 64% in comparison with the control group).

The oral toxicity of the compound of the formula I in rats is surprisingly low; after administration of 1 g / kg po.o. no animal from a ten-member group died within 7 days. Only moderate attenuation is observed in an interval of 30 minutes after administration. In mice, the oral LD 50 = 129 mg / kg; the intravenous LD 50 = 26.6 mg / kg. A single administration of the compound of formula I in doses of 50 and 100 mg / kg p.o. does not cause changes in behavior and does not lead to any signs of toxicity or death in dogs.

The compound of formula I has been described in the literature (M. Rajsner and co-workers, Collect. Czech. Chem. Commun. 32, 2854, 1967; CS PS 115 241). It was obtained by reaction of thieno [2,3-c] -2-benzothiepin-4 [9H] -one with l-methyl-4-piperidyimagnesium chloride in tetrahydrofuran and subsequent acid-catalyzed dehydration of the resulting 4- (l-methyl-4 -piperidyl) -4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-ol of the formula II prepared.

(II) l

CH3

It has escaped here that the compound g of the formula II, which allegedly results from the Grignard reaction in a yield of 74% of theory, is not homogeneous and that it is contaminated with a further compound which is used in the subsequent acid-catalyzed dehydration (Heating with dilute sulfuric acid) remains unchanged and even the final product, ie the compound of formula I contaminated. The yield given in the work mentioned in the dehydration stage, i.e. 95% of theory relates to the evaporation residue, i.e. to the crude compound of the formula I which contains an unspecified amount of the impurity mentioned.

The presence of the impurity mentioned also explains the melting points given for the compound of the formula II crystallized from a benzene / petroleum ether mixture (125 ° C.) or from acetone (119 to 120 ° C.). 5 These low-melting products are called solvates without any proof, which is nothing more than a mixture of the compound of formula II with the impurity mentioned.

The reaction of thieno [2,3-c) -2-benzothiepin-4 [9H] -one io with l-methyl-4-piperidylmagnesium chloride in tetrahydrofuran was now subjected to closer study and the crude product obtained was mixed with a combination of crystallization methods chromatographic method isolated. Using silica gel thin layer chromatography 15 it was found that it is considerably non-homogeneous and that it contains a large amount of a less polar accompanying substance in addition to the amino alcohol of the formula II. The pure amino alcohol of the formula II can be obtained from the crude product by extraction with ethanol, the desired compound of the formula II remaining undissolved and the less polar accompanying substance being passed into the solution. This can be obtained from the mother liquor by chromatography on a silica gel column and purified by a further crystallization. It is surprising that the pure aminoal alcohol of formula II and the pure, less polar accompanying substance melt at exactly the same temperature 212 to 213 ° C. However, the mixture of both substances melts in a deep depression and these are the melting points of the «Solvate» mentioned in the work mentioned.

30 While the analysis of the less polar accompanying substance had shown a composition that was considerably similar to the composition of the amino alcohol of the formula II, the mass spectrum for them showed the composition CnHioNOSi i.e. it is a compound which has 35 2 hydrogen atoms less than the amino alcohol of the formula II. The UV spectrum of the new compound indicates a high degree of conjugation corresponding to a diaryl ketone. The presence of a diaryl ketone also confirms the IR spectrum with a band at 1611 cm-1. This spectrum and the 'H KMR spectrum demonstrate the absence of a hydroxyl group. The difference in the 'H KMR spectrum of the compound of the formula II and the less polar accompanying substance in the region of the signals of the aromatic protons is significant. While the spectrum of the compound of formula II indicates the presence of 6 aromatic protons, the signals of 5 protons flowing together in a multiplet that cannot be distinguished, and only the proton in the 5-position of the skeleton clearly the spectrum of the less polar so compound shows the presence of only five aromatic protons, the signals of which are clearly differentiated overall and can be localized in individual positions of the skeleton, the proton being missing in the 7 position The difference between the compound of For-55 mei II and the less polar accompanying substance is given by the mass spectra in the part corresponding to the fragments, while the main fragment of the compound of formula I has an m / z of 98, which corresponds to an ammonium ion with a 1-methylpiperine residue obtained , the main fragment of the 60 accompanying substance has an m / z of 70, which is a fragment of the methylpiperidine residue with 4 cabbages corresponds to atomic atoms. The first case is typical of a methylpiperidyl radical attached to the aliphatic carbon, the second case corresponds to the behavior of a methylpiperidyl residue bound to the aromatic carbon. From all of these spectral results, the structure of the 7- (l-methyl-4-piperidyl) thieno [2,3-c] -2-ben-zothiepin-4 [9H] -one of the formula III results for the less polar compound

655 117

4th

0

The formation of the compound of formula III can be explained by the 1,6-attachment of the Grignard reagent to the system of three double bonds in the molecule of the starting ketone (including the double bond of the keto group C = 0) or to the one by force Enolysis of the starting ketone under the reaction conditions dipole (R. Gaertner, Chem. Revs. 45, 493, 1949). . After this attachment and subsequent hydrolysis, the elimination of two hydrogen atoms had to follow, i.e. oxidation - probably due to the action of atmospheric oxygen. It is a relatively rarely observed reaction sequence, which is mainly based on reactions of sterically hindered aromatic ketones, for example 2,3,5,6-tetramethyl- and 2,3,5,6-tetra-methyl-2'-methoxybenzophenone, with Grignard reagents (RC Fuson et al., J. Amer. Chem. Soc. 65, 60, 1943; 71, 2543, 1949; J. Org. Chem. 13, 496, 1948).

The purpose of this invention is to protect such a process for the preparation of the compound of Formula I which includes a measure to eliminate the compound of Formula II from the amino alcohol of Formula II which is subsequently used in the dehydration step in its pure form, and further such measures , with which even the last residues of the compound of formula II are removed from the end point of formula I. These measures take advantage of the good solubility of the compound of the formula III in ethanol. For this reason, the raw product of the first stage, i.e. the Grignard reaction, suspended in ethanol, the suspension is heated to boiling and, after cooling, the virtually pure amino alcohol of the formula I is suctioned off. It is obtained in a yield of only 50% of theory and it is not possible to obtain further amounts of the compound of the formula II in an economical manner from the mother liquor which contains a considerable amount of the compound of the formula III. The last residues of the compound of formula II are removed from the end product of formula I by crystallization from ethanol, this impurity remaining in the mother liquor. Finally, an inseparable part of this invention is a process for the preparation of new hydrogen (+ hartrate of the compound of formula I by neutralizing it with the (+) - tartaric acid in aqueous ethanol. The hydrogen (+) tartrate crystallizes excellently, it is moderately water-soluble and from the standpoint of processing into the pharmaceutical form, it is more advantageous than other salts which have already been described (already cited) (succinate, fumarate, hydrogen maleate). The process for the preparation of the compound of the formula III in pure form is described in not described in this invention because it is not an object of the same.

In practice, the compound of the formula I according to this invention is thus prepared as follows:

50 ml of tetrahydrofuran are added to 24 g of magnesium, and then about 'A of the volume of a solution of 134 g of 4-chloro-methylpiperidine (E. Adlerovâ and co-workers, Cesk. Farm. 12, 122, 1963) in 300 ml of tetrahydrofuran ( dried with the molecular sieve Potasit 4 A) and warmed the mixture with an oil bath preheated to 50 to 55 ° C. Add 0.5 g of iodine and 1 ml of 1,2-dibromoethane and wait until the reaction begins, which takes 10 to 30 minutes.

When the mixture begins to boil vigorously under reflux, the oil bath is removed and the remaining 4-chloro-l-methylpiperidine solution is added dropwise so rapidly that the mixture boils vigorously. When the reaction is in full swing, the agitator is switched on. Towards the end of the dropping, which takes 40 to 50 minutes, the mixture is warmed up moderately. Then it is boiled with stirring under reflux for a further 1.5 h. After cooling with ice water to 10 ° C., a solution of 155 g of thieno [2,3-c] -2-benzothiepin-4 [9H] -one in 350 ml of tetrahydrofuran is added dropwise while stirring and cooling with ice water (M. Prativa et al., Collect. Czech. Chem. Commun. 29.2161, 1964; 32.2854, 1967; 39, 1366, 1974). The temperature is kept between 10 and 15 ° C. When the dropping is complete, the cooling is stopped and the mixture is stirred for 30 minutes, reaching room temperature. A solution of 225 g (+) tartaric acid in 2 liters of water is then added dropwise to the dark solution with vigorous stirring so that the temperature does not exceed 20 ° C (intensive external cooling is initially necessary). Then 500 ml of toluene are added and the mixture is stirred intensively for 10 min. The toluene layer, which contains the neutral substances, is separated off, the aqueous layer is washed with 200 ml of toluene, then 1600 ml of chloroform are added and the mixture is made alkaline with intensive stirring and cooling with 300 ml of conc. Ammonium hydroxide. The chloroform layer is separated off, the aqueous layer is extracted with 200 ml of chloroform, the combined chloroform solutions are washed with 300 ml of water and left for 12 hours with 30 g of anhydrous potassium carbonate and 10 g of activated carbon. The solid substances are then suctioned off and washed with 50 ml of chloroform. Chloroform is distilled off under moderately reduced pressure (10 to 20 kPa). The rest is mixed with 200 ml of ethanol, the mixture briefly heated to boiling under reflux and cooled to 5 ° C. The precipitated crystalline 4- (l-methyl-4-piperidyl) -4,9-di-hydrothieno [2,3-c] -2-benzothiepin-4-ol (formula II) is filtered off with 100 ml of ethanol and 100 ml of ethanol washed. It is dried at room temperature under reduced pressure. It is obtained in a yield of 113 g (51% of theory) and melts at 209 to 211 ° C. In this state it is almost pure and suitable for further processing. Crystallization of a sample from ethanol gives a completely pure substance melting at 212 to 213 ° C.

166 g of the above amino alcohol of the formula II are added to a solution of 240 g of sulfuric acid in 1170 ml of water at 40 to 50 ° C. and the mixture is refluxed for 15 minutes with stirring. After cooling, the mixture is diluted with 200 ml of water, 400 ml of chloroform are added and the mixture is made with stirring by dropwise addition of 220 g of conc. Alkaline ammonium hydroxide. The temperature of the mixture is kept between 20 and 30 ° C. The chloroform layer is separated off and the aqueous layer is extracted twice with 100 ml of chloroform. The combined chloroform solutions are washed with 150 ml of water, dried with 20 g of potassium carbonate and, after standing, the drying agent is suctioned off overnight. The filtrate is evaporated off under reduced pressure (10 to 20 kPa). The crystalline residue is poured over with 900 nil of ethanol and dissolved with stirring by boiling. The hot solution is decolorized by filtering with 10 g of activated carbon and the filtrate is allowed to crystallize at 5 ° C. After standing for 12 h, the secreted base of 4- (l-methyl-4-piperidylidene) -4,9-dihydrothieno [2,3-c] -2-benzothiepin (formula I) is suctioned off and washed with 50 ml of ethanol and then with 100 ml of petroleum ether. This gives 124 g of the 1st product after drying at room temperature. Evaporation of the mother liquor to a volume of 200 ml and standing at 5 ° C gives 14 g

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

655 117

a corresponding product; the total yield is 138 g (83% of theory), mp. 160 to 161 ° C. This substance is sufficiently pure to produce the salt. Crystallization of a sample from ethanol gives a completely pure base of the formula I, which melts at 162 to 164 ° C.

The base of formula I (94 g) is dissolved with boiling in 650 ml of ethanol. After dissolving, the heating is interrupted and a hot solution of 47 g (+) -tartaric acid in 85 ml of water is slowly poured in. The tartrate solution is then stirred with stirring to 10 ° C., during which the crystallization takes place. After cooling for 12 h, the crystalline product which has separated out is filtered off with suction and washed twice with 50 ml of ethanol each time. The still moist product is dissolved in a mixture of 1250 ml of ethanol and 1000 ml of water by heating to boiling with stirring. The hot solution is filtered and the filtrate is allowed to crystallize for 5 hours with stirring and cooling in an ice bath. The product is then suctioned off, washed twice with 30 ml of ethanol and dried in air at room temperature. The mother liquor is evaporated under reduced pressure (3 to 5 kPa) to about half the original volume and the second portion of the product crystallizes by cooling to 5 ° C. A total of 125 g (90% of theory) of hydrogen (+) tartrate of the base of the formula I is obtained, which melts at 228 to 231 ° C. with decomposition.

G