DE3327138C2 - - Google Patents

Description

The invention relates to a new process for the production of pure 4- (1-methyl-4-piperidylidene) -4.9-dihydrothieno- [2.3-c] -2-benzothiepi-n of formula I.

and its salts, especially hydrogen (+) - tartrate, and the use of hydrogen (+) - tartrate for the production of pharmaceutical agents for the treatment of migraines.

The compound of formula I above is described in the literature (M. Rajner et al., Collect. Czech. Chem. Commun. 32 (1967) 2854; CS-PS 1 15 241).

It was in the form of its hydrogen maleate on its pharmacological Properties examined and demonstrated in guinea pigs a pronounced antihistamine effect, in rats anitserotonin and antireserpine effect and a central damping effect Mice with low acute toxicity.

The hydrogen - (+) - tartrate of the compound of formula I has also a pronounced antihistamine, antiserotonin,  Antireserpine and anticatalepsy effectiveness at the same time proportionate low toxicity and is suitable accordingly for the manufacture of pharmaceutical agents for treatment of migraines.

The compound of formula I has been pharmacologically described in Form of hydrogen (+) - tartrate after oral and intraperitoneal Administration checked; the cans listed refer to the base. First and foremost are their effects in a number of pharmacological tests the effects of tricyclic imipramine antidepressants similar because of the connection to reserpine in mice has an antagonistic effect (it significantly antagonizes the Reserpine hypothermia at a dose of 2 mg / kg i. p.) and in rats (starting with a subcutaneous dose of 20 mg / kg it statistically significantly inhibits the ulcerogenic Reserpine effect), a pronounced anticataleptic effect in rats (in the test of perphenazine catalepsy their mean protective dose PD₅₀ is 7.0 mg / kg s. c.) and antagonizes the oxotremorine tremor in mice (the Threshold dose at which tremors are significantly inhibited is 1.0 mg / kg i. p.). The compound of formula I. also has a pronounced central antiserotonin effect on who is affected by administration of 5-hydroxytryptophan in rats Behavioral, in influencing Quipazin hyperthermia in rabbits and to some extent in the interaction with tryptamine in rats. The intensity the central antiserotonin effect of the compound of Formula I in influencing behavioral syndrome after administration of 5-hydroxytryptophan in rats is used as the mean protective dose (PD₅₀ after subcutaneous  Administration) in terms of tremor (2.9 mg / kg) and in terms of on the vertical movements of the front paw ("tapping") (2.6 mg / kg). In this test is the effectiveness the compound of formula I similar to that of cyproheptadine and much higher than amitriptyline.

Among the peripheral effects of the compound of formula I the antihistamine and antiserotonin activity was shown as the strongest. After oral administration, the Antihistamine activity in guinea pigs in the histamine aerosol test, expressed as mean protective dose PD₅₀, 0.046 mg / kg. Even after the histamine detoxification and The compound is one of histamine bronchoconstriction tests of formula I to the most effective antihistamines known. The antiserotonin effect in the test in rat photo edema after administration of 5-hydroxytryptamine is after one oral administration of 0.3 mg / kg was statistically significant. The Compound of formula I also has moderate peripheral Anticholinergic effects: It has a mydriatic effect in mice and blocks the lethal acetylcholine effect Guinea pig.

In comparison with the well-known migraine drug pizothiphene (9.10-dihydro-4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1-, 2b] thiophene) (A.G. Dixon et al., Arzneimittel-Forsch. 27 [1977] 1968) the compound of formula I has the distinct advantage of one lower central inhibitory effect. After oral administration the compound of formula I inhibits movement activity in mice in the observation test according to Boissier and Simon three times less strong than Pizothiphen (D₅₀ for the Compound of formula I 23 mg / kg and for pizothiphene 7 mg / kg). In the test of tracking the spontaneous locomotor Activity in mice using the beam method according to Dews (photocell) is the inhibitory effect  the compound of formula I even seven times less than that von Pizothiphen (D₅₀ for the compound of formula I 24.2 mg / kg, for pizothiphene 3.4 mg / kg). In the less specific test corresponds to the potentiation of thiopental sleep in mice the threshold dose of the compound of formula I 10% of it oral LD₅₀; in Pizothiphen it is 2.5% of the LD₅₀, whereby the oral toxicity of both substances in mice is similar. In rats, the compound of the formula I was administered there was a clear tendency to stimulate behavior: When tracking the impact on overall activity (using the "Animex" device) resulted with oral administration of the compound of formula I of 10 and 30 mg / kg a moderate stimulating effect (increased activity to 125 to 131% of the control group), while oral doses of 3 to 30 mg / kg pizothiphene a statistical significant inhibition of activity (to 57 to 64% compared to the control group).

The oral toxicity of the compound of formula I at Rats are surprisingly small; after administration of a Administration of 1 g / kg p. o. no dead within 7 days Animal from a group of 10 animals. It was just moderate attenuation for 30 min after administration observed.

The oral LD₅₀ in mice is 129 mg / kg; the intravenous LD₅₀ is 26.6 mg / kg. A single administration the compound of formula I in doses of 50 and 100 mg / kg p. o. does not change behavior in dogs and does not lead to any signs of toxicity or to die.

The compound of formula I, known from the literature (see above M. Rajner et al., Collect. Czech. Chem.  Comm. 32 [1967] 2854 or CS-PS 1 15 241) has so far by reaction of thieno- [2.3-c] -2-benzothiepin-4- [9H] -one with 1-methyl-4-piperidylmagnesium 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-ols of formula II

produced.

It was not considered that the compound of formula II, which by the Grignard reaction is said to be in a yield of 74% d. Th. Arises, is not uniform, but with another compound that is contaminated in the subsequent acid-catalyzed dehydration (heating with dilute sulfuric acid) remains unchanged and even the final product, d. H. the compound of formula I, contaminated. The one mentioned in the above-mentioned publication Yield of 95% of theory Th. In dehydration also relates to the evaporation residue, i. H. on the raw Compound of formula I, the one unspecified Contains amount of said impurity. By the presence this contamination is also the specified Melting points for those from a benzene-petroleum ether mixture or compound of formula II crystallized from acetone (125 or 119-120 ° C). These low-melting ones Products are referred to as solvates without any evidence, however, it is nothing more than a  Mixture of the compound of formula II with the above impurity acts.

The invention has for its object a method for Preparation of the pure compound of formula I and its salts, in particular of the hydrogen (+) - tartrate with which the compound of formula I and their salts in higher purity with a good yield let, as well as specify their pharmaceutical use.

The task is solved according to the requirements.

The reaction of thieno- [2.3-c] -2-benzothiepin-4- [9H] -one with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran was examined in more detail within the scope of the invention, the resultant Crude product with a combination of crystallization methods and chromatographic methods. By thin layer chromatography on silica gel it was found that it is considerably inconsistent and in addition to the amino alcohol of the formula II, a large amount contains a less polar accompanying substance. The pure one Amino alcohol of formula II can pass through from the crude product Extraction can be obtained with ethanol, the desired Compound of formula II remains undissolved, and the less so polar accompanying substance goes into solution. You can from the Mother liquor obtained by column chromatography on silica gel and further purified by crystallization. It is surprising that the pure amino alcohol of the formula II and the pure less polar accompanying substance with exactly that melt the same temperature from 212 to 213 ° C. Mixtures however, both substances melt with a strong depression; the corresponding mixed melting points were in the above cited prior art associated with solvates.

While the analysis of the less polar accompanying substance revealed a composition which was very similar to the composition of the amino alcohol of the formula II, its mass spectrum corresponded to the composition C₁₇H₁₆NOS₂, that is to say a compound which has 2 hydrogen atoms less than the amino alcohol of the formula II. The UV spectrum the new compound indicates a strong conjugation corresponding to a diaryl ketone. That a diaryl ketone is also confirmed by the IR spectrum with a band at 1611 cm ^-1 . The IR spectrum and the 1 H-NMR spectrum also show the absence of a hydroxyl group. There are strong differences in the 1 H-NMR spectra of the compound of the formula II and the less polar accompanying substance in the region of the signals of the aromatic protons. While the spectrum of the compound of formula II reveals the presence of 6 aromatic protons, the signals of 5 protons being present in a multiplet that cannot be resolved and only the proton in the 5-position of the skeleton being significantly different from this, this results Spectrum of the less polar accompanying substance the presence of only five aromatic protons, the signals of which are all clearly differentiated and can be assigned to individual positions of the framework; the proton is missing in the 7 position. Further information about the difference between the compound of formula II and the less polar accompanying substance can be found in the mass spectra in the part corresponding to the fragments. While the main fragment of the compound of formula II has an m / e value of 98, which corresponds to an ammonium ion with the 1-methylpiperidine residue obtained, the main fragment of the accompanying substance has an m / e value of 70, which corresponds to a fragment of the methylpiperidine residue with 4 C. -Atoms corresponds. The first case is typical of a methylpiperidyl residue attached to the aliphatic carbon, the second case corresponds to the behavior of a methylpiperidyl residue attached to the aromatic carbon.

From these spectral results, less results polar compound the structure of 7- (1-methyl-4-piperidyl) - thieno- [2.3-c] -2-benzothiepin-4- [9H] -ons of the formula III

The formation of the compound of formula III can be by 1.6 attachment of the Grignard reagent to the von system three double bonds in the molecule of the starting ketone (including the double bond of the keto group C = 0) or by the enolization of the starting ketone Dipole formed under the reaction conditions explain (cf. R. Gaertner, Chem. Revs. 45 [1949] 493). After this addition and subsequent hydrolysis the elimination of two hydrogen atoms, i.e. H. an oxidation, probably follow through exposure to atmospheric oxygen. This is a proportionate one reaction sequence rarely observed, mainly reactions of strongly hindered aromatic Ketones, for example 2.3.5.6-tetramethyl- and 2.3.5.6-tetramethyl-2'-methoxybenzophenone, with Grignard reagents was investigated (R.C. Fuson et al., J. Am. Chem. Soc. 65 [1943] 60; 71/1949, 2543; J. Org. Chem. 13 [1948] 496).

The inventive method for cleaning the Compound of formula I is based on the fact that the compound of formula III separated from the amino alcohol of formula II  which is then practical in the dehydration stage pure form is used, and also the last Residues of the compound of formula III from the end product of Formula I to be eliminated. With these measures the good solubility of the compound of formula III in ethanol exploited. For this reason, the raw product is the first stage, d. H. the Grignard reaction, suspended in ethanol, the suspension heated to boiling, and after cooling the practically pure amino alcohol of the formula I is suctioned off. It is obtained in a yield of only about 50% d. Th. Received, but it does not succeed, from the mother liquor, which contains a substantial amount of the compound of formula III contains, economically, additional amounts of the compound Formula II win. From the end product of Formula I are the last residues of the compound of Formula II separated by crystallization from ethanol, this contamination remaining in the mother liquor. The invention also relates to the manufacture corresponding salts by neutralizing the base of the Formula I with acids and in particular the production of Hydrogen - (+) - tartrate of the compound not previously described of formula I by neutralizing with (+) - tartaric acid in aqueous ethanol. The hydrogen - (+) - tartrate Excellent crystallization, only slightly soluble in water and its use in drugs more advantageous than other salts already described (sucrose, fumarate, hydrogen maleate, see. above).

The compound of the formula I according to the invention is prepared as follows:
50 ml of tetrahydrofuran are added to 24 g of magnesium, and 1/4 of the volume of a solution of 134 g of 4-chloro-1-methylpiperidine (E. Adlerová et al., Esk. Farm. 12 [1963] 122) is then added dropwise in 300 ml with molecular sieve (Potasit 4 A) dried tetrahydrofuran and the mixture is heated in an oil bath preheated to 50 to 55 ° C. Then 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-1-methylpiperidine solution is added dropwise so rapidly that the mixture boils vigorously. When the reaction is in full swing, the stirrer is switched on. Towards the end of the dropping, which lasts 40 to 50 minutes, the mixture is warmed moderately. Then it is kept under reflux with stirring 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 with stirring and cooling with ice water (M. Protiva et al., Collect. Czech. Chem. Commun. 29 [1964] 2161; 32 [1967] 2854; 39 [1974] 1366). The temperature is kept between 10 and 15 ° C. After the dropping has ended, the mixture is no longer cooled and the mixture is stirred for 30 minutes, reaching room temperature. A solution of 225 g (+) - tartaric acid in 2 l of water is then added dropwise to the resulting dark solution with vigorous stirring in such a way that the temperature does not exceed 20 ° C., intensive external cooling initially being required. Then 500 ml of toluene are added and the mixture is stirred intensively for a further 10 min. The toluene layer, which contains the neutral substances, is then separated off; the aqueous layer is then washed with 200 ml of toluene and mixed with 1600 ml of chloroform, whereupon the mixture is concentrated with 300 ml of concentrated and cooled. Ammonium hydroxide is made alkaline. After the chloroform layer has been separated off, the aqueous phase 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. Then the solids are suctioned off and washed with 50 ml of chloroform. The chloroform is then distilled off under moderately reduced pressure (10 to 20 kPa). The residue is mixed with 200 ml of ethanol, the mixture is briefly heated to reflux and then cooled to 5 ° C. The precipitated crystalline 4- (1-methyl-4-piperidyl) -4.9-dihydrothieno [2.3-c] -2-benzothiepin-4-ol of the formula II is filtered off with suction and washed with 100 ml of ethanol and 100 ml of petroleum ether and at room temperature dried under reduced pressure. The compound is obtained in a yield of 113 g (51% of theory); F. 209 to 211 ° C. In this condition, the product is almost pure and suitable for further processing. The pure substance is obtained by crystallizing a sample from ethanol; F. 212 to 213 ° C.

To a solution of 240 g sulfuric acid in 1170 ml water are at 40 to 50 ° C 166 g of the above amino alcohol Formula II added, whereupon the mixture with stirring for 15 min is heated to reflux. After cooling, dilute the mixture with 200 ml of water gives 400 ml of chloroform add and while stirring by dropping 220 g conc. Ammonium hydroxide alkaline, the temperature the mixture is kept between 20 and 30 ° C. After this The aqueous phase is separated off from the chloroform layer extracted twice with 100 ml of chloroform. The combined chloroform solutions with 150 ml of water washed and dried with 20 g of potassium carbonate; to The drying agent is suctioned off and left to stand overnight. The filtrate is evaporated under reduced pressure (10 to 20 kPa). The crystalline residue is mixed with 900 ml of ethanol  added and dissolved with stirring by heating to boiling. The hot solution is filtered off with 10 g activated carbon decolorized, whereupon the filtrate crystallize at 5 ° C leaves. After standing for 12 hours, the base which has been eliminated is removed des 4- (1-methyl-4-piperidyl) -4.9-dihydrothieno [2.3-c] -2-benzothiepin of formula I aspirated and with 50 ml Ethanol and then washed with 100 ml of petroleum ether. On this way 124 g after drying at room temperature Received product. By evaporating the mother liquor a volume of 200 ml and by standing at 5 ° C another 14 g of product are obtained; the total yield is 138 g (83% of theory; mp 160 to 161 ° C). For the production of salt, this substance is sufficiently pure. By Crystallization of a sample from ethanol gives the pure Base of formula I; F. 162 to 164 ° C.

The base of formula I (94 g) is dissolved in boiling 650 ml of ethanol. After dissolving, the heating is interrupted and slowly pour a hot solution of 47 g (+) - tartaric acid in 85 ml of water. The tartrate solution is then stirred cooled to 10 ° C, the crystallization taking place. After cooling for 12 h, the excreted product is sucked out crystalline product and washes it twice with 50 ml each Ethanol. The still moist product is mixed of 1250 ml of ethanol and 1000 ml of water by heating dissolved at the boil with stirring. The hot is filtered Solution and leaves the filtrate with stirring and cooling in Crystallize ice bath for 4 h. Then you suck it Product, wash it twice with 30 ml of ethanol and it dries in the air at room temperature. The mother liquor is under reduced pressure (3 to 5 kPa) evaporated about half of the original volume; a second portion crystallizes by cooling to 5 ° C of the product. A total of 125 g (90% of theory) of hydrogen - (+) - tartrate the base of formula I obtained; F. 228 to 231 ° C (with decomposition).

Claims (3)

1. Process for the preparation of pure 4- (1-methyl-4-piperidylidene) -4.9-dihydrothieno [2.3-c] -2-benzothiepi-n of the formula I. and its salts, by reacting thieno- [2.3-c] -2-benzothiepin-4- [9H] -one with 1-methyl-4-piperidylmagnesium 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-ols of the formula II, characterized in that

• - The crude alcohol of the formula II by extraction with ethanol from the simultaneously formed 7- (1-methyl-4-piperidyl) thieno [2.3-c] -2-benzothiepin-4- [9H] -one of the formula III is liberated
• - The pure alcohol of formula II, which is obtained as an insoluble fraction, is then dehydrated, and
• the crude base of the formula I is freed from the last residues of the compound of the formula III by recrystallization from ethanol,
• - After which the pure base of the formula I is converted into the corresponding salt, if appropriate by neutralization with an appropriate acid in aqueous ethanol.

2. The method according to claim 1, characterized in that by Neutralize the hydrogen - (+) - tartrate with (+) - tartaric acid is obtained. 3. Use of the hydrogen - (+) - tartrate of 4- (1-methyl-4-piperidylidene) -4.9-dihydrothieno- [2.3-c] -2-benzothiepi-ns for the manufacture of pharmaceutical agents for treatment the migraine.