JPH0367072B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the following formula: 4-(1-methyl-4-piperidylidene) with
-4,9-dihydrothieno(2,3-C)-2-
This invention relates to a method for producing benzothiepine and its (+)tartrate. The compound of the formula (pipethiadene) and its (+)tartaric acid group have a high degree of antihistamine, antiserotonin, antireserpine and anticataleptic activity, and their relatively low toxicity makes them useful for the treatment of migraine. is expected to be used for. The compound was tested pharmacologically in the form of the (+)tartrate salt, and the salt was administered orally and parenterally. Doses were calculated relative to base. Its effects in many pharmacological tests are similar to those of the three-membered anti-inhibitors of the imipramine group: the compound acts antagonistically to reserpine in mice (the compound was administered at 2 mg/Kg (ip) reserpine significantly antagonizes hyperthermia at doses of 20 mg/Kg) and antagonizes reserpine in rats (starting with subcutaneous administration of 20 mg/Kg, the compound satisfactorily and significantly inhibits the ulcerogenic effects of reserpine). Furthermore, it has a markedly pronounced anticatalepsy effect in rats (perphenazine catalepsy studies showed that its moderate protective dose PD ₅₀
7.0 mg/Kg (sc)), and also antagonizes oxotremorine tremor in mice (the threshold dose that significantly suppresses tremor is 1.0 mg/Kg (ip). , Compound I has pronounced central antiserotonergic effects; this property is shown to be similar to quipazine in domestic rabbits by affecting the behavior elicited by administering 5-hydroxytryptophan to rats. This has been shown to affect hyperthermia and, to a certain extent, by interacting with tryptamine in rats. After administration of 5-hydroxytryptophan to rats, a central antiserotonergic effect of the compound on behavioral symptoms was demonstrated. Intensity is expressed as a moderate protective dose (PD ₅₀ for subcutaneous administration) of (2.9 mg/Kg) against tremor and also vertical movement of the forelimb (“tapping”) (2.6
mg/Kg). The effect of the compound in this test is similar to that of cyproheptadine and is also substantially stronger than that of amitriptyline. The antihistamine and antiserotonin effects of the compound are the most potent of its peripheral effects. Moderate protective dose when administered orally to guinea pigs
The antihistamine effect in the histamine aerosol test expressed as PD ₅₀ is 0.046 mg/Kg. In histamine detoxification and histamine bronchial stenosis tests, the compound is among the most potent known antihistamines. After administration of 5-hydroxytryptamine, the antiserotonin effect in the rat paw edema test is statistically significant after oral administration of 0.3 mg/Kg. The compound also has a mild peripheral anticholinergic effect: it exhibits a pupil-dilating effect in mice and abrogates the local effects of acetylcholine in guinea pigs. Known anti-migraine drug pizotifen (Dixon et al., Arzneim.-Forsch. 27 , 1968,
(1977), the compound has a clear advantage in its lower anti-inhibitory effect. When administered orally, the compound inhibited exploration activity in mice by one-third of that of pizothiifene in an observational study by Bossier and Simon (the _D50 of the compound was 23 mg/Kg;
_D50 is 7mg/Kg). In the locomotor activity test in mice using the light-cell method according to Dews, the inhibitory activity of the compound was 7 times lower than that of pizotifen (the _D50 of the compound was 24.2 mg/day).
Kg and Pizotifen D ₅₀ is 3.4 mg/Kg).
In a weakly specific study of sleep synergy of thiopental in mice, the threshold dose of the compound corresponds to 10% of its oral LD ₅₀ , whereas the threshold dose of pizotifen is only 2.5% of its oral LD ₅₀ (in mice). The oral toxicity of the two compounds is similar). The compound has a clear tendency towards behavioral stimulation in rats: when observing its effect on the total activity of the animals using the AniMex instrument, oral doses of 10 mg/Kg and 30 mg/Kg of the compound It has a mild stimulatory effect (the activity of the animals increases to a value of 125-131% of the control group), while oral doses of 3-30 mg/Kg of pizotifen reveal a statistical significance of the total activity of the animals. (up to a value of 57-64% compared to the control group). The oral toxicity of the compound in rats is surprisingly low: after administration at a dose of 1 g/Kg (po), not a single animal from the ten test groups died within 7 days. Only mild suppression was observed within 30 minutes after administration. Orally in mice
_LD50 is 129mg/Kg. 50-100 compounds
A single administration to dogs at a dose of mg/Kg does not cause any behavioral changes, toxicity or death of the animals. The compounds of the formula were described in the literature (Rajs〓ner M., Metys〓 J. and Protiua M.,
Collect.Czech.Chem.Commun. 32 , 2854, 1967;
(Ciekoslovakia Patent No. 115241). The compound was prepared as 1-methyl-4-chloride in tetrahydrofuran.
Piperidyl Agnesium and Thieno (2,3-C)
-2-benzothiepin-4(9H)-one and the subsequent formula obtained: 4-(1-methyl-4-piperidyl)-4,9-
Obtained by acid-catalyzed dehydration reaction of dihydrothieno(2,3-C)-2-benzothiepin-4-ol. The following was observed at that time:
The compound said to have been obtained from the Grignard reaction in 74% yield was not homogeneous and was considerably contaminated with other compounds remaining unchanged during subsequent acid-catalyzed dehydration (heating with dilute sulfuric acid). The final product, the compound, was highly contaminated. The dehydration yield reported in the paper mentioned above was 95
The percentages refer to the evaporation residue, ie the crude compound, which contained the undetermined impurities mentioned above. The impurities of the resulting products can also be explained by the low melting points reported for the compounds (125°C from benzene-petroleum ether and 119-120°C from acetone). These low melting products were thought to be solvated; however, they were actually a mixture of these compounds and the impurities mentioned above. Thieno(2,3-C) in tetrahydrofuran
-2-benzothiepin-4(9H)-one and chloride 1
The reaction with -methyl-4-piperidylmagnesium has recently been investigated in more detail and the crude product obtained was further isolated by a combination of crystallization and chromatography methods. Using thin layer chromatography on silica gel, the material obtained appears to be rather heterogeneous and, in addition to the aminoalcohol, appears to contain substantial amounts of less polar components. I was disappointed. Pure amino alcohols can be obtained from the crude product by extraction with ethanol; the desired compound remains undissolved, while the less polar substances go into solution. The latter material can be isolated from the mother liquor by column chromatography on silica gel and purified by crystallization. It is most surprising that both the amino alcohol and the less polar components melt exactly at the same temperature of 212-213°C. However, these mixtures melt with a considerable drop, then these are the melting points of the solvation as reported in the above literature. Although elemental analysis of the less polar components shows a composition very similar to that of the amino alcohol, the mass spectrum does not reveal its exact composition.
We demonstrate C ₁₇ H ₁₆ NOS ₂ , which corresponds to a component with a composition that has two fewer hydrogen atoms than the amino alcohol. The UV spectrum of the new compound shows a high degree of conjugation, which corresponds to a diarylketone structure. The infrared spectrum confirms the diaryl ketone with a characteristic absorption band at 1611 cm ^-1 . Both infrared and ¹ H NMR spectra demonstrate the absence of hydroxyl groups. Differences in the ¹ H NMR spectra of compounds and less polar substances are particularly significant in the aromatic proton signal band. Although the spectrum of the compound shows the presence of six aromatic protons, five of the signals merge into an unresolved multiplet, and only the signal of the proton at position 5 of the backbone is clearly separated, indicating the presence of less polar ¹ H NMR of the compound accounts for the presence of only 5 aromatic protons, the signals of which are all clearly distinct and can be localized to individual positions of the backbone, with the proton at position 7 being absent. Another proof of the structural differences between the compounds and the less polar components is provided by the mass spectra in the region corresponding to the fragments. The main fragment of the compound has m/z 98, which corresponds to the ammonium ion with a protected 1-methylpiperidine structure, and the main fragment of the less polar impurity has m/z 70; Corresponds to the methylpiperidine fragment at the carbon atom.
The first case is typical for methylpiperidyl groups attached to aliphatic carbons, and the second case corresponds to the behavior of methylpiperidyl groups attached to aromatic carbon atoms. All these spectra are for less polar compounds, with the formula 7-(1-methyl-4-piperidyl)thieno(2,3-C)-2-benzothiepine-4(9H)-
Gives structure on. The formation of the compound can be explained by the 1,6-addition of the Grignard reagent to the three double bond system in the molecule of the starting ketone (including the double bond of the keto group C=0) or This can be explained by the addition of the Grignard reagent to a dipole formed by forced enolization of the starting ketone under the reaction conditions (Gaerther R., Chem. Revs. 45 , 493, 1949 ). Such addition and subsequent hydrolysis had to be carried out by elimination of two hydrogen atoms, ie by oxidation, possibly under the action of oxygen in the air. This is a less commonly observed example of a reaction in which highly sterically hindered aromatic ketones, such as 2,3,5,6-tetramethyl and 2,3,5,6-tetramethyl-2'- Previously studied in the reaction of methoxybenzophenone with Grignard reagent (Fuson RC et al.; J. Amer.
Chem.Soc. 65 , 60, 1943 ; 71 , 2543, 1949 ; J.
Org. Chem. 13 , 496, 1948). The subject of the present invention is to provide a process for the preparation of a compound, which process allows the compound to be removed from an amino alcohol and then to be used in an almost pure state in a dehydration reaction, whereby almost all of the residues of the compound are removed. including a method for removing. These important additional operations take advantage of the compound's good solubility in ethanol. The product of the first reaction step, ie the Grignard reaction, is suspended in ethanol, the suspension is heated to the boiling point and, after cooling, the almost pure amino alcohol is filtered off with suction. This material is obtained in approximately 50% yield; the mother liquor containing significant amounts of compound does not allow for further economical recovery of the desired aminoalcohol intermediate.
The final residue of the compound is removed from the final product by crystallization from ethanol; this impurity remains in the mother liquor. Finally, part of the present invention resides in a process for preparing novel tartrate salts of compounds by neutralization with (+)tartaric acid in aqueous ethanol. The (+)tartrate salt, which crystallizes easily, is moderately soluble in water and is much more suitable for the preparation of the final dosage form than other acid addition salts; other acid addition salts are succinic acid salts. salts, fumarates and maleates, which have already been disclosed (see Rajsöner M. et al. IC). Methods for producing the compounds in pure form are not described here.
Because it is not included in the present invention. According to the invention, the compounds can be conveniently prepared by the procedure of the following examples, but this example is not intended to limit the scope of the invention in any way. 50 ml of dry tetrahydrofuran with magnesium 24
g and then 4-chloro-1-methylpiperidine (Adlerova' et al., Cesk.farm. 12 , 122,
Approximately 25% of 1963) dissolved in 300 ml of dry tetrahydrofuran (dried with Molecular Sieve Potasit 4A)
solution is introduced and the mixture is then warmed in an oil bath preheated to a temperature of 50-55°C. Iodine (0.5g)
and 1 ml of 1,2-dibromoethane are added and the mixture is allowed to stand for about 10-30 minutes until the reaction begins. When the mixture begins to reflux vigorously, the oil bath is removed and the remainder of the 4-chloro-1-methylpiperidine solution is added dropwise at such a rate that the reaction mixture continues to reflux vigorously. Once the reaction starts to start at a sufficient rate, start stirring. After about 40-50 minutes, when most of the solution has been added dropwise, the reaction mixture is allowed to warm moderately. Continue refluxing for an additional 1.5 hours with stirring. The mixture was then cooled to 10°C with ice-water, and under constant stirring and cooling with ice-water, thieno(2,3-C)-2-benzothiepin-4-(9H)-one (Protiva M., dissolved in 325 ml of dry tetrahydrofuran) was added.
Rajsöner M. et al., Collect.Czech.Chem.Commun.
29, 2161, 1964 ; 39 , 1366, 1974 ) with 155 g of solution within 1 hour. reaction mixture from 10 to
Maintain at a temperature of 15 °C. Once the solution has been completely added, the cooling is discontinued and the mixture is stirred for about 30 minutes until the solution naturally reaches room temperature. The resulting dark solution was stirred vigorously until the temperature of the mixture was 20°C.
Treat with a solution of 225 g of (+) tartaric acid dissolved in 2 parts of water at a rate such that the temperature does not exceed 0.degree. C. (intensive external cooling is initially necessary). Thereafter, 500 ml of toluene are added and the mixture is stirred vigorously for 10 minutes. The toluene layer containing neutral substances is then separated, the aqueous portion is washed with 200 ml of toluene, 9600 ml of chloroform are added and then made alkaline with concentrated aqueous ammonia with vigorous stirring and cooling. The chloroform layer is separated, the aqueous layer is extracted with 200 ml of chloroform, the combined chloroform solutions are washed with 300 ml of water and then left for 12 hours with 30 g of anhydrous potassium carbonate and 10 g of activated carbon.
The solid is then separated off and washed with 500 ml of chloroform. Chloroform under reduced pressure (10-20kPa)
The residue is diluted with 200 ml of ethanol, the mixture is then briefly refluxed and then cooled to 50°C. The precipitated crystals 4-(1-methyl-4-piperidyl)-4,9-dihydrothieno(2,3-
C)-2-Benzothiepin-4-ol () is filtered off with suction, washed successively with 100 ml of ethanol and then with 100 ml of petroleum ether and dried under reduced pressure at room temperature. The yield was 113g (51%) and the product was
Melts at 209-211°C. The material obtained is almost pure and quite stable for further processing. Crystallization of the sample from ethanol yields a completely pure material with a melting point of 212-213 °C. A solution of 240 g of sulfuric acid in 1170 ml of water is treated with 166 g of the above amino alcohol at 40-50 DEG C. and the mixture is refluxed for 15 minutes with stirring. After cooling, the mixture is diluted with 200 ml of water and the stirred mixture is made alkaline by adding 400 ml of chloroform and then 220 g of concentrated alkaline ammonia. Keep the mixture at a temperature of 20-30°C. The chloroform layer is separated and the aqueous portion is then extracted with 2×100 ml of chloroform. The combined chloroform solutions were washed with 150 ml of water, dried with 20 g of potassium carbonate, and then left to stand overnight, after which the desiccant was removed. Liquid under mild vacuum (10-20kPa)
The crystalline residue is dissolved by treatment with 900 ml of ethanol and heating with stirring to the boiling point. While heating the solution, add 10g of charcoal
The solution is decolorized by filtration using a filtrate and the solution is then crystallized at 5°C. After leaving for 12 hours, 4-
The crystallized base of (1-methyl-4-piperidylidene)-4,9-dihydrothieno-(2,3-C)-2-benzothiepine () was collected by suction and successively treated with 50 ml of ethanol and 100 ml of petroleum ether. Wash. Drying at room temperature gives 124 g of product.
Evaporation of the mother liquor to a volume of 200 ml and standing at 5° C. gives 14 g of product (second crop) with satisfactory purity. Overall yield is 138g (88%)
It has a melting point of 160-161°C. The entire amount of material is suitable for subsequent conversion into salts. Further crystallization of the sample yields a completely pure base with a melting point of 162-164°C. Dissolve the base (94 g) in 650 ml of boiling ethanol. After dissolution, heating is discontinued and a hot solution of 47 g (+) tartaric acid dissolved in 85 ml water is slowly added. The resulting solution is then cooled to 10° C. with stirring to induce crystallization. After cooling for 12 hours, the crystals are collected by suction and washed with 2 x 50 ml of ethanol. Add the wet product to 1250 ml of ethanol and water.
Dissolve by heating to boiling point temperature in 1000ml of mixture,
Then, the solution is filtered while maintaining the thermal state, and the filter is further stirred and cooled in an ice bath for 4 hours to crystallize. The product is then washed with 2 x 30 ml of ethanol and dried in air at room temperature. Mother liquor under reduced pressure (3~
5 kPa) to about half of the original volume and then cooled to 5° C. to obtain a second crop of product.
The overall yield is 125 g of base (+) tartaric acid.
(90%), and the salt melts (with decomposition) at 228-231°C.

Claims (1)

[Claims] 1. Thieno(2,3-C)-2-benzothiepin-4(9H)-one is reacted with 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran, followed by the following formula: 4-(1-methyl-4-piperidyl)-
4,9-dihydrothieno(2,3-C)-2-benzothiepin-4-ol was prepared by an acid-catalyzed dehydration reaction using the following formula: 4-(1-methyl-4-piperidylidene) with
-4,9-dihydrothieno(2,3-C)-2-
A method for producing benzothiepine and its (+)tartrate, which simultaneously yields the following formula: 7-(1-methyl-4-piperidyl)thieno(2,3-C)-2-benzothiepine-4(9H)-
by extracting the ion with ethanol to free it from its presence, separating the pure alcohol of the formula as an insoluble product and then subjecting it to said dehydration reaction, and then crystallizing the resulting crude base of the formula from ethanol. Said process, characterized in that said ketone of formula is free of residues and then optionally converted into said salt by neutralizing the pure base of formula with (+)tartaric acid in aqueous ethanol. .