CS239436B1 - Spiro / piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine / and its derivatives - Google Patents

Abstract

It relates to the field of synthetic drugs. The subject of the invention are spiro/piperidine- -4,6-dibenz(b,e)-1,4-oxathiepine/ and its derivatives of the general formula I, in which R denotes a hydrogen atom, methyl, 1-phenyl-2-propyl, formyl or ethoxycarbonyl, as well as their salts with pharmaceutically acceptable inorganic or organic acids. The substances have antireserpine and antimicrobial effects and are useful as drugs, primarily against mental depressive states. In this respect, the 1-methyl derivative (I, R = = CHj) and the basic secondary amine (I, R = H) are particularly noteworthy. The synthetic approach to the substances of this group is based on the reaction of 2-(2-fluorophenyl- ,hio)phenylmagnesium bromide with 1-ethoxy- :carbonyl-4-piperidone and subsequent cyclization with sodium hydride leads to :arbamate I, R = COOC2H5. The ethoxycarbonyl group can be converted to methyl by reduction with hydride reagents or removed by alkaline hydrolysis. The secondary amine I, R = H, obtained can then be converted to other substances by alkylation or acylation reactions. If the substances are basic in nature, they can be converted to the corresponding salts by neutralization with pharmaceutically acceptable inorganic or organic acids.

Description

The present invention relates to spiro (piperidine-4,6 ⁾ -dibenz (b, e) -1,4-oxathiepine) and derivatives thereof of formula (I): (I) wherein R is hydrogen, methyl, 1-phenyl-2- propyl, formyl or ethoxycarbonyl, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

Substances containing a spirocyclic backbone contained in the molecules of formula I have not been known hitherto. We have now found a method for their preparation and have been found to be pharmacodynamically active and useful as antidepressants in the treatment of mental depressive states. In addition, they also exhibit antimicrobial effects in vitro. They are therefore technically important substances. A typical compound of the invention is 1-methylspiro / piperidine-4,6-dibenz (b, e) -1,4-oxathiepine / (I, R = CH-j), which has been bioassayed in the maleate ferrum. Its toxicity in mice by oral administration, LD ^ q = 183 mg / kg. At an oral dose of 25 mg / kg, it significantly inhibits ptosis in mice induced by a standard dose of reserpine. At an oral dose of 50 mg / kg, it significantly inhibits reserpine-induced gastric ulceration in rats.

Both of these types of antireserpine activity suggest the likelihood of antidepressant efficacy in psychiatric patients. The base spiro / piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine / (I, R = H) exhibits antimicrobial activity at minimum concentrations of 25-100 <g / ml against the following microorganisms: Streptococcus / $ -haemolyticus, Streptococcus faecalis, Staphylococcus pyogenes. aureus, Escherichia coli and Proteus vulgaris.

The preparation of the compounds of the formula I according to the invention starts from the reaction of 2- (2-fluorophenylthio) phenylmagnesium bromide with 1-ethoxycarbonyl-4-piperidone, which results in a tertiary alcohol of the formula XI. The tenio alcohol is cyclized by treatment with sodium hydride in dimethylformamide at 90 ° C to give a compound of the invention of formula I wherein R = COOCgH 3. 2-bromo-2'-fluorodiphenylsulfide, which is the starting point for the preparation of said Grignard reagent, is a novel substance, the preparation of which is described in the example; 1-Ethoxycarbonyl-4-piperidone is a known substance.

(II)

Said spirocyclic carbamate of formula I (R = COOCgH4) is converted by reduction of sodium dihydridobis (2-methoxyethoxy) aluminate to a methyl derivative of formula J wherein R = CH-j. Alkaline hydrolysis of the carbamate under conditions (high concentration of potassium hydroxide in ethanol at the boiling point of the reaction mixture) yields the base compound of the invention, i.e., a compound of the invention.

I, where R = H.

This secondary amine can then be processed to further compounds of the invention by alkylation or acylation reactions. Thus, by alkylation of 1-phenyl-2-chloropropane in dimethylsulfoxide at

120 ° C using sodium hydride as the base gave the N- (1-phenyl-2-propyl) derivative of the formula

I where 8 = CH (CH ₃ ) CH ₂ C ₈ H ₅ .

Acylation of the secondary amine by heating with 98% formic acid at 170 ° C affords the N-formyl derivative of formula I wherein H = CHO. When the compounds of the invention are basic in nature, they provide neutralization with pharmaceutically acceptable inorganic or organic acids! The compounds of the present invention also form part of the present invention. Of the salts, hydrochlorides and maleate are preferred as well crystalline materials.

The identity of all the novel compounds described in this invention was assured by analyzes and conventional spectra. The examples below are merely illustrative of the possibilities of the invention, but are not intended to exhaustively describe all of the possibilities of the invention.

He did

1- (ethoxycarbonyl) spiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] (I, R = COOC3H3)

The Orignard reagent is prepared by reacting 9.0 g of magnesium with 48.1 g of 2-bromo-2'-fluorodiphenylsulfide in 150 ml of tetrahydrofuran (the reaction is started with a few drops of 1,2-dibromethene) and the mixture is refluxed for 1 h. A solution of 29.1 g of 1-ethoxycarbonyl-4-plperidone (shingle K. et. Al .: Collact. Czech. Chem. Commun. JS, 3,879,19731 in 40 ml of tetrahydrofuran) is then added dropwise with stirring over a period of 5 min. The reaction mixture was then diluted with ether and quenched with 20% ammonium chloride solution and water, the organic layer was dried over potassium carbonate and evaporated. to the solution was added 8.0 g of an 80% oil suspension of sodium hydride and the mixture was stirred and heated to 100 ° C for 5 h.

It is then poured into 2.5 l of water, acidified with hydrochloric acid and extracted with ether. The extract was dried over magnesium sulfate and evaporated. The oily residue is chromatographed on a column of 200 g of silica gel. Elution with benzene removes 23 g of less polar portions, and then a mixture of benzene and chloroform aluces 14 g (23%) of the desired oily base, the identity of which is confirmed analytically (C ₂ H ₁₁ NO ₃ S confirmed) and 16 1 H NMR spectra.

The starting 2-bromo-2'-fluorodiphenylsulfide is not yet described in the literature and can be prepared as follows:

To a solution of 19.8 g of sodium hydroxide in 350 ml of acetone is added 57.5 g of 2-fluorothiophenol (red I. et. Al .: Collect. Czech. Ghett: Commun. 41 * 2139, 19791) and, after dissolution, 70.8 g of 2-chloronitrobenzene, diluted with 150 ml of ethanol, refluxed for 6 hours, then evaporated under reduced pressure and the residue was triturated between 200 ml of water and 500 ml of chloroform and the organic layer was washed with water, 250 ml. ml of 111-NaOH, water, 250 ml of 5% hydrochloric acid and again with water, dried and evaporated.

The residue was crystallized from 300 ml of ethanol. A total of 91.5 g (82%) of crude 2-fluoro-2'-8-nitro-diphenylsulfide melting at 74-76 ° C was obtained by suction and treatment of the mother liquor. Recrystallization of the sample from ethanol gave a pure material, melting at 75-75.5 ° C.

To a solution of 84.6 g of 2-fluoro-2'-nitrodiphenylsulfide in 800 ml of ethanol was added 16 g of activated carbon, 61 ml of 100% hydrazine hydrate, and a solution of 4.0 g of ferric chloride hexahydrate in 80 ml of ethanol was added dropwise over 15 minutes. The mixture is refluxed for 10 h, filtered, the filtrate is evaporated under reduced pressure, the residue is diluted with 420 ml of water, acidified with acetic acid and the product isolated after cooling and standing overnight by filtration. 70.9 g (95%) of practically pure 2-amino-2'-fluorodiphenylsulfide melting at 42-44 ° C is obtained. Crystallization from ethanol increases mp to only 43-44 ° C.

To 175 ml of sulfuric acid, 28.0 g of sodium nitrite is added slowly with stirring

ΒΪ 10 ° C, slowly warm the mixture to 70 ° C and then cool to 15 to 20 ° C. A solution of 70.8 g of 2-amino-2'-fluorodiphenylsulfide in 315 ml of acetic acid is added with stirring at this temperature over 45 minutes. The mixture was stirred at room temperature for 3 hours and then added dropwise to a stirred mixture of 125 mL of 48% boric acid and 56 g of copper bromide heated to 70 ° C.

Stirring was continued at 70 ° C for 2 h and the mixture was allowed to stand overnight.

It is then poured into 1.3 l of water and extracted with 900 ml of benzene. The extract was washed with 50 ml of sulfuric acid, water and 250 ml of 8% sodium hydroxide solution, dried over calcium chloride and worked up by distillation. Yield 66.9 g (73%) of the desired 2-bromo-2'-fluorodiphenylsulfide boiling at 144 ° C / 40 Pa. The distillate solidifies to a crystalline substance which crystallizes from petroleum ether and melts at 41-43 ° C.

Example 2

1-methylspiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] (I, RCH3)

To a stirred solution of 24 g of 1- (ethoxycarbonyl) spiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] (see Example 1) in 400 mL of benzene was added dropwise 120 mL of 50% over 10 min. of a solution of sodium dihydridob 1 B (2-methoxyethoxy) aluminate in benzene and the mixture was heated at 60 ° C for 5 h. After cooling, it is quenched with water and 20% sodium hydroxide solution, the organic phase is dried over potassium carbonate and evaporated. The oily residue (18.8 g crude; desired base) was dissolved in ether and the solution was neutralized with a solution of maleic acid in ether. 21.4 g (77%) of the hydrogen maleate melting at 192 DEG-195 DEG C. (ethanol) crystallized.

Ex ^J íklad3

Spiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] (I, R = H)

A mixture of 13.8 g of 1- (ethoxycarbonyl) spiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine], ml of ethanol and 15 g of potassium hydroxide is refluxed in a heated bath for 3 h. at 130 ° C. After cooling, it is diluted with water and extracted with benzene. The extract is shaken with an excess of 10% hydrochloric acid, the oily hydrochloride formed is combined with the acidic aqueous phase, made alkaline with aqueous ammonia and extracted with benzene. The extract was dried over potassium carbonate and evaporated under reduced pressure. 10.2 g (93%) of a homogeneous oily base are obtained. Neutralization with maleic acid in acetone yields crystalline hydrogen maleate crystallizing from a mixture of aqueous ethanol and ether and melting in the pure state at 177-178.5 ° C.

Example 4 *

1- (1-Phenyl-2-propyl) spiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] (I, R = CH / CH3 / CH3CgHg)

To a solution of 29.5 g of spiro (piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine) (see Example 3) in 500 ml of dimethyl sulfoxide was added 3.0 g of 80% sodium hydride, the mixture was stirred for 15 min at 60 ° C, 92 g of 1-phenyl-2-chloropropane (Baddeley G., Williatnspn H., J. Chem.

Soc. 1956. 4,647) and stirred at 120 ° C for 3.5 h. After cooling, it was partitioned between benzene and 5% sodium hydroxide solution and the benzene solution was washed with 5% hydrochloric acid and water. Thereby, only the unreacted starting base is transferred to the aqueous phase, while the hydrochloride of the product remains dissolved in benzene, from which it is obtained by evaporation. It crystallized in the form of the monohydrate from a mixture of 95% ethanol and ether and melted at 246-252 ° C.

Example 5

1-Forraylspiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] (I, R = CHO) r

A mixture of 30 g of spiro / piperidine-4,6'-dibenz (b, e) -1,4-oxathiepino / (see Example 3) and 20 ml of 98% formic acid is heated for 15 h at 170 C. After cooling, ^e Dissolve in benzene and the benzene solution is washed with dilute hydrochloric acid and water. It is dried over magnesium sulphate and evaporated. The residue crystallized from a mixture of benzene and cyclohexane. 17.0 g (52%) of the desired product is obtained with mp 148-149.5 ° C.

Claims (1)

SUBJECT OF THE INVENTION Spiro [piperidine-4,6'-dibenz (b, e) -1,4-oxathiepine] and its derivatives of the general formula I in which R represents a hydrogen atom, methyl, 1-genyl-2-propyl, forms1 or ethoxycarbonyl, as well as and salts thereof with pharmaceutically acceptable inorganic or organic acids