CS240698B1 - Substituted 11-(piperidinoalkyl)-6,11-dihydrodibenzo (b,c) thiepin-11-carbonitriles - Google Patents

Abstract

Synthetic drugs wherein the 11- (piperidinoalyl) -6,11-dihydrobibenzo [b, e] thiepine-11-carbonitriles of formula (I) are substituted, wherein R 1 is hydrogen, hydroxyl, or alkoxycarbonyl, R 2 is phenyl, phenyl substituted at any position with methyl or halogen, 2-oxo-1-benzimidazolinyl, or wherein the entire CR 1 R 2 moiety is spirocyclically bonded 1-phenyl-4 - oxo-5,5-imidazolidinylidene, n is 2 or 3, and their hydrochlorides. The compounds of formula I and their hydrochlorides are antidiarrheals. drugs with antifungal activity. They are obtained by substitution reactions 11- (2-bromoethyl) - and 11- (3-bromopropyl) -6,11 dihydrodibenzo / b, e / thiepine-11-carbonitrile with piperidino wherein R 1, R 2, and R 2, respectively. all the rest of CR ^ R2, is the same as in formula I.

Description

The present invention relates to substituted 11- (piperidinoalkyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitriles of formula (I),

Wherein R is hydrogen, hydroxyl, or ethoxycarbonyl, R is phenyl, phenyl substituted at any position by methyl or halogen, 2-oxo-1-benzimidazolinyl, or wherein the remainder 1 2

CR R denotes a spirocyclically bonded 1-phenyl-4-oxo-5,5-imidazolidinylidene, δ is 2 or 3, as well as their hydrochlorides. The compounds of formula I are antidiarrheal drugs, i.e. drugs with anti-diarrheal activity.

Alkaloid morphine exhibits a whole complex of pharmacodynamic effects, including an anti-diarrhea effect resulting from a direct effect on the intestinal wall musculature. However, due to its properties of an addictive opiate drug, morphine is therapeutically unusable in this respect. Systematic investigations have developed structurally distant morphine analogs which have an anti-diarrhea effect without having undesirable morphine effects; these include, in particular, the diphenoxin, diphenoxylate and loperamide preparations (Bradshaw M.J., Harvey R.P., Drugs 24, 440, 1982). All three preparations are substituted piperidinoalkyldiphenylacetonitriles or diphenylacetamides. It has now been found that some new substituted piperidinoalkyl derivatives

240 698

6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile exhibits antidiarrheal efficacy in animal experiments (mice) and has some advantages over the known diphenoxylate (Janssen PAJ et al., J.láed.Pharm.Chem) J., 299 (1959).

For example, 11- [2- (4-ethoxycarbonyl-4-phenylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, which has been tested orally in the form of hydrochloride, at a dose of 500 mg / kg in mice, is practically non-toxic and does not induce animal death. In contrast, diphenoxylate has a mean lethal dose of LD 50 -337 mg / kg. While diphenoxylate has about 3% of the analgesic activity of morphine in the mouse peritoneal test, the compound of the invention is practically ineffective in this test. Also diskoordinační action of the present substance in the rotarod test in mice (ED ^ ₀ is greater than 50 mg / kg) is less than the effect of diphenoxylate (EDtj _Q = 33 mg / kg). In an experimental test for diarrhea induced in mice by intravenous administration of serotonin at a dose of 10 mg / kg (Děmina et al., Farmakol. Toksikol., 91, 1981). the aforementioned compound of the invention has an anti-diarrhea effect of statistically significant at an oral dose of 10 mg / kg (diphenoxylate acts at an oral dose of 5-10 mg / kg). Thus, it can be concluded that the therapeutic agent against diarrhea of different origin at lower side effects than those associated with the use of diphenoxylate can be expected for the said substance according to the invention.

The compounds of the invention of formula I are accessible by substitution reactions of 11- (2-bromoethyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile and 11- (3-bromopropyl) -6,11-dihydrodibenzo [b], e / thiepin11-carbonitrile (K. Sindelar et al. Collect.Czech.Chem · Commun., 48. 1898, 1983) with a piperidine derivative of formula II ^{μ / IIZ} wherein R and R, respectively. the entire radical CR R 'is the same as in formula I. These piperidine derivatives are mostly known and are referred to in the literature in the individual examples. The substitution reactions are carried out by heating the components with potassium carbonate in a suitable solvent, preferably acetone. The products are obtained either in the form of the hydrochlorides which are purified by crystallization or in the form of bases which are purified by chromatography on silica gel.

240 698

- 3 'and only then optionally converted to the hydrochloride. The compounds of the invention are novel and have been used in addition to analyzes of all conventional spectral methods to identify them. Further details of the preparation thereof are evident from the examples below, which are merely illustrative of the possibilities of the invention, but are not intended to limit the scope of the invention in any way.

Example 1

1- [3- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] -4-phenylpiperidin-4-ol

A mixture of 3.6 g of 11- (3-bromopropyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, 1.8 g of 4-phenylpiperidin-4-ol (Protiva M. et al., Collect. Czech Chem., 47, 636 (1982). 1.4 g of anhydrous potassium carbonate and 30 ml of chloroform are stirred and refluxed for 11 hours. While still hot, undissolved inorganic salts (1.85 g) are filtered off and the filtrate is evaporated under reduced pressure. The residue was dissolved in ether, dried over potassium carbonate and neutralized with ethereal HCl to give crystalline hydrochloride. The crude product was purified by crystallization from ethanol; 2.5 g (51%), m.p. Mp 228-231 ° C. Example 2

1- [3- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] -4- (2-tolyl) piperidin-4-ol

A mixture of 6.1 g of 11- (3-bromopropyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, 2.0 g of 4- (2-tolyl) piperidin-4-ol, 1.6 g of potassium carbonate and 150 ml of acetone was stirred and refluxed for 7 hours. The insoluble material was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in ether and the solution was shaken with excess dilute hydrochloric acid. The precipitated oily hydrochloride together with the aqueous acidic phase are basified with aqueous ammonia, the liberated base is isolated by extraction with ether, the extract is dried over potassium carbonate and neutralized with ethereal hydrogen chloride to give crystalline hydrochloride which crystallizes from 95% ethanol / ether as monohydrate; 1.4 g (16%), m.p. Mp 133-138 ° C.

The starting 4- (2-tolyl) piperidin-4-ol is best obtained as follows:

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By reacting 5.84 g of magnesium with 41.4 g of 2-bromotoluene in 180 ml of ether (an iodine bead and 0.6 ml of ethyl iodide is used to start the reaction) a Grignard reagent solution is prepared. While stirring, a solution of 34.0 g of 1-ethoxycarbonyl-4-piperidone (Sindelář K. et al., Collect.Czech.Chem.Commun. 38, 3879, 1973) in 200 ml of ether was added dropwise over 40 minutes. The mixture was stirred at room temperature for 1 h, refluxed for 90 min, quenched with stirring by slowly adding 200 mL of 20% ammonium chloride solution, the ether phase was separated, dried over magnesium sulfate and evaporated. The residue was dissolved in 120 ml of warm hexane and crystallized to give 33.0 g of 1-ethoxycarbonyl-4- (2-tolyl) piperidin-4-ol (63% yield), which melted pure at 118-119 ° C. (ethanol-hexane).

A mixture of the preceding carbamate (38.3 g), potassium hydroxide (42 g) and ethanol (52 ml) was stirred and refluxed (bath temperature 120-130 ° C) for 5 h. After cooling, it was diluted with water (300 ml) and extracted with dichloromethane. The extract was dried (MgSO4) and evaporated. The residue crystallized from 40 ml of boiling acetone; 13.5 g (49%) of the desired 4- (2-tolyl) piperidin-4-ol, m.p. 141-142 ° C (benzene-hexane).

Example 3

1- [3- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] -4- (4-fluorophenyl) piperidin-4-ol

A mixture of 7.7 g of 11- (3-bromopropyl) -6,11-dihydrodibenzo [b, e] thiepine 11-carbonitrile, 2.8 g of 4- (4-fluorophenyl) piperidin-4-ol (Protiva M. et al. Collect.Czech.Chem.Commun. 47, 636 (1982). 1.8 g of potassium carbonate and 100 ml of acetone are stirred and refluxed for 10 h. Insoluble inorganic salts are suctioned off while hot and the filtrate is evaporated under reduced pressure. Excess aqueous ammonia was added to the residue and extracted with chloroform. The extract was evaporated and the residue was chromatographed on a column of 200 g of silica gel. Chloroform initially eluted with 0.38 g of neutral fractions which were discarded. Then, 3.25 g (32%) of the desired oily base is eluted with a mixture of chloroform and ethanol, which is dissolved in acetone and converted to the hydrochloride by treatment with a slight excess of ethereal hydrogen chloride solution. This precipitates first in oily form, but crystallizes after addition of a small amount of water as the hemihydrate; 2.65 g, m.p. Mp 133-138 ° C.

Example 4 240 698

1- [2- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) ethyl] 4-ethoxycarbonyl-4-phenylpiperidine

A mixture of 4.5 g of 11- (2-bromoethyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, 2.8 g of 4-ethoxycarbonyl-4-phenylpiperidine (Eisleb 0., Ber.Deut.Chem.Ges 74, 1433 (1941). 1.6 g of potassium carbonate and 100 ml of acetone are refluxed for 6 hours, filtered while hot and the filtrate is evaporated in vacuo. The residue was dissolved in chloroform and chromatographed on a column of 180 g of silica gel. First, 1.47 g of the starting bromonitrile was eluted with chloroform. Then, 4.26g of crude desired base is eluted with the same solvent, which is converted to the hydrochloride with ethereal hydrogen chloride solution. After crystallization from a mixture of acetone and ether, the salt is obtained in a yield of 3.37 g (72% on the conversion) and melts in the pure state at 192-196 ° C (the remainder up to 208 ° C).

Example 5

1- [2- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) ethyl] 4- (2-oxo-1, -benzimidazolinyl) piperidine

A mixture of 2.7 g of 11- (2-bromoethyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, 1.65 g of 4- (2-oxo-1-benzimidazolinyl) piperidine (Rossi A. et al. , Helv. Chim.Acta 43, 1 298, 1960). 1.2 g of potassium carbonate and 150 ml of acetone are stirred and refluxed for 10 h. The mixture is allowed to stand overnight at room temperature and then a mixture of product and inorganic salts is filtered off with suction. These are washed on the filter with water and the remaining product is dried under vacuum. 2.7 g of the desired base monohydrate (69%) are obtained, which crystallizes from a mixture of 98% ethanol and chloroform and melts at 202-205 ° C. Example 6

1- [3- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] 4- (2-oxo-1-benzimidazolinyl) piperidine

Mixture of 3.6 g of 11- (3-bromopropyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, 2.2 g of 4- (2-oxo-1-benziraidazolinyl) piperidine, 1.4 g of potassium carbonate and 50 ml of acetone was refluxed for 10 h. It is then diluted with an additional 50 ml of boiling acetone

The filtrate is evaporated under reduced pressure and the residue is crystallized from a mixture of acetone and benzene; 2.2 g (44%) of a base melting at 192-199 ° C. Recrystallization from a mixture of ethanol and chloroform gives a pure base with m.p. Mp 198-202 ° C.

Example 7

1-Phenyl-8- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] -1,3,8-triazaspiro (4,5) decan-4-one

A mixture of 3.6 g of 11- (3-bromopropyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitrile, 2.32 g of 1-phenyl-1,3,8-triazazpiro / 4,5 / decane4 -on (Belg. Pat. 633 914), 1.4 g of potassium carbonate and 150 ml of acetone are stirred and refluxed for 15 hours. The insoluble material is then filtered off and the inorganic salts are washed out with water. The residue on the filter is the first product. Evaporation of the acetone filtrate and crystallization of the residue from acetone gave a second product. The two products were combined and crystallized from a mixture of chloroform and ethanol. Yield: 3.57 g (61%) of the title compound as a 2: 1: 1 mixture of chloroform and ethanol, m.p. Mp 210-213 ° C.

Claims (1)

SUBJECT OF THE INVENTION Substituted 11- (piperidinoalkyl) -6,11-dihydrodibenzo [b, e] thiepine-11-carbonitriles of formula I, 240 698 (1) in which R is hydrogen, hydroxyl or ethoxycarbonyl, R is phenyl, phenyl substituted in any position by methyl or halogen, 2-oxo-1'-benzimidazolinyl, or wherein the entire radical CR R is a spiro-cyclically bonded 1- phenyl-4-oxo-5,5-imidazolidinylidene, π is 2 or 3, and their hydrochlorides.