CS236145B1 - Tertiary alcohols 3b, 9a-trans-3b, 4, 5 »6, 7» 9 »9a. 10-octahydro- (1) benzothiepino (2,3,4-ed) pyrido (2, 1-a; isoquinoline series and their hydrochlorides) - Google Patents

Abstract

The invention falls into the field of synthetic drugs. Its subject is tertiary alcohols 3b, 9a-trans-3b,4,5,6,7,9,9a,10- octahydro-(l)benzopthiepino(2,3,4-ed)pyrido(2,1-a)isoquinoline series of general formula I, in which R denotes tert. butyl or isopropyl, and their hydrochlorides. These substances are neuroleptics with a strong affinity for dopamine receptors in the brain and as such are useful in the therapy of schizophrenia as antipsychotic drugs. Their preparation consists in the reactions of 3b,9a-'crans-3b,4,5,6,7,9,9a,10-octahydro-(1)benzothiepino(2,3,4-ed)pyrido(2,1-a)isoquinolin-5-one (the preparation of which is described in the example) with organometallic reagents of the type tert. butylmagnesium chloride and isopropyllithium. The obtained bases provide crystalline hydrochlorides upon neutralization with hydrogen chloride.

Description

The invention relates to tertiary alcohols 3b, 9a-trans-3b, 4,5,6,7,9,9a, 10-octahydro- (1) benzothiepino (2,3,4-ed) pyrido (2,1-a) isoquinoline series of formula I,

wherein R is tert-butyl or isopropyl, and their hydrochloride *

Compounds of formula I and their hydrochlorides are neuroleptics with strong affinity for dopamine receptors in rat brain *

As such, they are useful in the therapy of schizophrenia as antipsychotic drugs *

A typical substance according to the invention is tert-butyl derivative I,

R »0 (0Η ^) ^ * This substance, when administered orally, is non-toxic to mice at 200 mg / kg * At 5 mg / kg orally, it causes a very strong increase in the level of homovanilic acid in the rat striatum striatum dopamine, typical of very potent neuroleptics * Homovanilic acid concentration increases to 527% of control value within 3 h after administration * Ten times lower dose, ie *

0.5 mg / kg increases the level of the named acid to 254% of the control value and still increases 0.1 mg / kg to 131% of the control *

236 145 has analgesic efficacy in the peritoneal test in mice, expressed as an ED ^ q of «13.2 mg / kg ·

For similar substances, see literature (Bruderlein F.T. et al., J. Med.Chera, 18, 185, 1975, Philipp A. H. et al., J. Med.Chem.

22. 768, 1979) butaclamol and isobutaclamol preparations, the pentacyclic backbone of which does not contain a sulfur atom and contains two carbon atoms in the skeleton more than the substances according to the invention.

The compounds of the formula I according to the invention can be prepared by reacting the pentacyclic ketone of the formula II

with the appropriate organometallic reagents, in particular tert-butylmagnesium chloride, tert-butyllithium, isopropylmagnesium chloride and isopropyllithium. The reactions are preferably carried out in appropriate inert solvents, for example · ether / benzene or pentane / benzene · ether to be used for Grignard reagents organometallic reagents are known from the literature: t ₀ butylchloride (Norrie JF, Olmsted AW Org.Syn ·, · Coll.Vol J., 144, 1932). tert-butylmagnesium chloride (Puntambeker SV, Zoellner EA, Org. Syn., Coll. Vol. J. 524 (1932)). isopropyl chloride (Morris JF,

Taylor H.B., J.Amer.Chem. Soc. 46, 756 (1924). isopropyllithiua (Gilman H. et al., J. America.Chem.Soc. 63, 2479, 1941) · Reactions provide mixtures of products that need to be separated by chromatography on alumina or silica gel · Acquired bases 3

236 145 whether oily or crystalline - provide neutralization with hydrochloric or hydrochloric acid hydrochlorides, which are largely crystalline. ba 9a, as well as mixtures of racemates in which this configuration relationship is not known »The starting ketone of formula II is a novel substance and its preparation is described in the example»

The identity of all the novel substances mentioned in the present invention was ensured both analytically and by spectral methods, in particular by mass spectra. The following examples are intended to illustrate some of the possibilities of the invention but are not intended to fully describe them.

Example 1

3b, 9a-trans-5 (OH), 9a (H) -trans-5-tert-butyl-3b, 4,5,6,7,9, 9a, 10-octahydro- (1) benzothiepino (2,3) 4-edpyrido [2,1-a] isoquinolin-5-ol

To a mixture of 4.9 g of magnesium and 20 ml of ether was added 0.5 g of tert-butyl chloride, and then a solution of 18.5 g of tert-butyl chloride in 100 ml. ml of ether »The mixture is stirred for a further 15 min and a solution of 3.95 g of 3b, 9a-trans-3b, 4, 5,6,7,9,9a, 10-octahydro- (1) is added dropwise over 2 min. benzothiepino (2,3,4-ed) pyrido (2,1-a) isoquinolin-5-one (II) in 60 ml benzene. The mixture was stirred for a further 30 min, allowed to stand at room temperature overnight and then refluxed for 4 h. After cooling, it is diluted with 100 ml of benzene and quenched by the slow addition of 150 ml of a 20% ammonium chloride solution. The organic layer was separated, dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 200 g of silica gel. The chloroform eluted with 3.31 g of homogeneous desired base, which crystallized from ethanol as an ethanol solvate melting at 98-108.5 ° C. Neutralization of hydrogen chloride in ethanol and ether provided the hydrochloride salt, crystallizing as the hemihydrate, mp 255-260 C dec ^G. An analogy to the butaclamol-isobutaclamol pair (cited) has been used to attribute the configuration on the carbon C ^^ and, given the high stereoselectivity of the effect of compounds of this type, confirms the attributed configuration4 or the biological activity found, 236 145

Starting 3b, 9a-trans-3b, 4,5,6,7,9,9a, 10-octahydro (1) benzothiepino (2,3,4 * ed) pyrido (2,1-a) isoquinolinone-5- on 3® • a new substance that can be prepared as follows:

To a stirred suspension of 3.8 g of lithium aluminum hydride in 100 ml of ether was added dropwise over 5 min under nitrogen atmosphere 10 g of aluminum chloride in 100 ml of ether and the mixture was stirred for 10 min. , 85 g of 10,11- »dihydrodibenzo (b, f) thiepine-10-carbonitrile (Šindelář K. et al., Collect.Czech.Chem,

Commun. 48, 1187 (1983) in a mixture of 100 ml of ether and 50 ml of tetrahydrofuran. The mixture is boiled for 3 hours under reflux, after cooling quenched with water and 150 ml 3M H ₂ SO ^. The aqueous acid layer was separated, basified with 20% sodium hydroxide solution, and the product was extracted with a mixture of benzene and chloroform. The extract was filtered, dried and evaporated to give 11.8 g (98%) of homogeneous oily 10,11-dihydrodibenzo (b, f) thiepine-10-methylamine. Neutralization of the sample with hydrogen chloride in ether gives the hydrochloride, which crystallizes from a mixture of ethanol and ether and melts at 220.5 to 223 ° C.

A mixture of 39.4 g of acetic anhydride and 17.8 g of 100% formic acid is stirred for 2 h at 60 ° C and then left to stand for 48 h. 36.4 g of the previous amine are added to the resulting mixed formic anhydride and acetic acid. The mixture is stirred at room temperature for 7 h and then left to stand overnight. It is quenched into a mixture of 350 g of ice and water, neutralized with 10% sodium hydroxide solution and the product is extracted with a mixture of ether and benzene. The extract is dried over potassium carbonate and evaporated. The residue crystallizes after mixing with 70 ml of ether; 29.4 g (72%) of K- (10,11-dihydrodibenzo [b, f] thiepin-10-ylmethyl) formamide, m.p. Mp 89-93 ° C. Recrystallization from a mixture of benzene and petroleum ether gave a sample of pure material melting at 93-96 ° C.

A mixture of 400 g of polyphosphoric acid and 33.2 g of the above formamide was stirred and heated at 160-170 ° C for 4 h. After cooling, it is poured on ice, made alkaline with a solution of 430 g of sodium hydroxide in 500 ml of water and extracted with chloroform. The extract is dried over potassium carbonate, evaporated and the inhomogeneous residue

236 145 chromatographs on a 1 kg neutral alumina column (activity II) * Eluting with benzene removes 0.5 g of less polar impurities and elutes with a mixture of benzene and chloroform

10.5 g of homogeneous oily base 12,12a-dihydro-1H- (1) benzothiepino (2,3,4-ed) isoquinoline. Elution with ethanol gave 13.3 g of a mixture containing two additional components in addition to the desired material. This fraction was rechromatographed on 400 g of silica gel and eluted with chloroform to give 3.66 g of the desired base.

The two base fractions were combined and combined by treatment with hydrogen chloride in ether to give crystalline hydrochloride which was obtained in a yield of 12.6 g. It crystallized from ethanol and melted at 223-225 ° C (small part up to 280 ° C).

A mixture of 13.1 g of the above hydrochloride and 100 ml of methyl vinyl ketone was heated under reflux in a bath maintained at 100 ° C for 2 h. After cooling, the mixture was diluted with ether and the solid was filtered. Quench with 10% sodium hydroxide solution and extract the base with chloroform. The extract was evaporated and the residue chromatographed on a silica gel column (400 g). The benzene / chloroform mixture was first eluted with 6.75 g of the less polar racemate of the desired product, which is of 3b, 9a-cis configuration and was not useful for further synthesis. After an intermediate fraction consisting of a mixture of the two racemates, the same solvent mixture elutes 4.2 g of the more polar racemate of the 3b, 9a-trans-configuration and the desired 3b, 4,5,6,7,9,9a, 10-octahydro- (1b). B-enzo thiepino (2,3,4-ed) pyrido (2,1-a) isoquinolin-5-one. The crystals formed from a mixture of benzene and petroleum ether and melted in a pure state at 161.5-163 ° C.

Example 2

3b, 9a-trans-5-isopropyl-3b, 4,5,6,7,9,9a, 10-octahydro (1) benzothiepino (2,3,4-ed) pyrido (2,1-a) isoquinolin-5- oly

To a boiling mixture of lithium (2.0 g) and pentane (100 ml), a solution of isopropyl chloride (11.3 g) in pentane (100 ml) was added dropwise under nitrogen atmosphere over a period of 1 h. The mixture was refluxed for 2 hours, the undissolved lithium was separated by decantation, and a solution of 2.3 g of 3b, 9a-trans-3b, 4,5,6,7,9,9a, 10-drug (1) was added to the isopropyl lithium solution. benzothiepino (2,3,4-ed) pyrido (2,1-a) isoquinolin-5-one (prepared as described in Example 1) in 50 ml benzene.

236 145

The mixture was refluxed for 1 h, allowed to stand at room temperature for 3 days, diluted with benzene and quenched with water. The organic layer was separated and evaporated and the residue chromatographed on 60 g of silica gel. The chloroform eluted first with 0.42 g of the minor stereoisomer of the desired substance, which was oily and converted into hydrochloride by treatment with hydrogen chloride in ether, which crystallized from a mixture of acetone and 96% ethanol as a hemihydrate, mp 216-218.5 ° C.

Continuation of the chromatography by eluting with ethyl acetate yields 1.04 g of the oily predominant stereoisomer of the desired product. As before, it was converted to the hydrochloride, which crystallized as a mixture of acetone and ethanol and melted with decomposition at 240-245 ° C.

Claims (1)

Tertiary alcohols 3b, 9a-trans-3b, 4,5,6,7,9,9a, 10-octahydro- (1) benzothiepino (2,3,4-ed) pyrido (2,1-a) isoquinoline A series of formula I, (I) wherein R is tert-butyl or isopropyl, and their hydrochlorides.