FI57413C - PROCEDURE FOR THERAPEUTIC USE OF THERAPEUTIC ANVAENDBARA 3- (2- (4- (2-SUBSTITUTES-10,11-DIHYDRO-DIBENSO (B, F) THIEPIN-10-YL) -1-PIPERAZINYL) -THYL) -2-OXAZOLIDONE - Google Patents

Description

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National Board of Patents and Registration («) Nihavilctp» ^ |. kuLj «n« i.un pvm.-, n n] ftn

Patent- och regittentyreleen AmMcu utl ^ d oeh uti.tkrift * n public ·· *! 30. o 4. öo (32) (33) (31) Requested «tuolkeut— B * jlrd prlorltM 21.07.72

Switzerland-Switzerland (CH) 11001/72 (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) (72) Max Gerecke, Reinach, Jean-Pierre Kaplan, Bubendorf, Emilio Kyburz,

Reinach, Switzerland-Schweiz (CH) (7 * 0 Oy Kolster Ab (5 ^) Method for the use of therapeutically useful 3- {2- [U- (2-substituted-10,11-dihydro-dibenzo [b] f] thiepin-10-yl) ) for the preparation of -1-piperazinyl-7-ethyl} -2-oxazolidinones and their salts - For the preparation of tera-peutiskt användbara 3- (2-substituent-10,11-dihydro-dibenzo [fc, f] thiopin-10-yl) -1 ~ piperazinyl-7-ethyl-2-oxazolidinone

The present invention relates to a process for the preparation of therapeutically useful 3- [2 - [+ - (2-substituted-10,11-dihydro-dibenzo [b, f] thiepin-10-yl) -1-piperazinyl] -ethyl] -2-oxazolidinones. for the preparation of which the formula is

N-CIL-CIL-1 / I)

. , -A ^ Y

‘XXX) · wherein R 1j is chlorine or lower alkyl, and for the preparation of salts of these compounds.

Compounds of general formula I and their salts are prepared by a) reducing a compound of formula / vf N-CH - CH - N 0 r wherein R 1 represents a moiety as above, or b) administering a compound of formula formula

, s-J

1N ^ V V

| I! SABA> wherein is as defined above, react with a compound of formula / \

Y-CH0-CH -N 0 VI

V "o wherein Y represents a leaving group such as halogen or an alkyl- or aryl-substituted sulfonyloxy group, after which the product obtained is optionally converted into a salt.

The leaving group Y of the starting compounds of formula II is, for example, halogen or an alkyl- or aryl-substituted sulfonyloxy group; it is preferably chlorine, bromine, methyl, phenyl or tolyl.

The reduction of the enamine of formula IV is preferably carried out by treatment with an alkali metal borohydride in the presence of a strong acid. As the alkali metal borohydride, sodium or potassium borohydride, especially sodium borohydride, is preferably used. However, lithium borohydride can also be used. The strong acid can be both an organic and an inorganic acid. Suitable organic acids are straight-chain or branched, lower mono- or dicarboxylic acids having up to 4 carbon atoms and which may be halogen-substituted, e.g. formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid and oxoacetic acid, isionic acid, propionic acid. Acetic acid is preferred, oxalic acid is particularly preferred. Suitable inorganic acids are, in particular, sulfuric acid and hydrohalic acids, in particular hydrochloric acid. The most preferred inorganic acid is concentrated sulfuric acid. Since the enamine of formula IV decomposes in the presence of water, the reduction is conveniently carried out in the absence of water; only anhydrous acids or acids from which water is not removed, such as concentrated sulfuric acid, are suitably used. The reaction with the alkali metal borohydride and the strong acid is preferably carried out in an ether such as diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether or dimethoxyethane, and at a temperature between room temperature and the reflux temperature of the solvent. Preferably, work is carried out at reflux temperature. The reduction of the enamines of formula IV can also be carried out according to other methods, e.g. by treatment with formic acid or zinc and glacial acetic acid. These reactions are also preferably carried out at temperatures between room temperature and the reflux temperature of the solvent, preferably at reflux temperature.

The starting compounds of formula V can be prepared, e.g., by administering formula II

Y

R 'yN / -W

Ov U

react with a mono-N-protected piperazine, e.g. N-carbethoxy-piperazine. Finally, the condensation product is saponified with alkali, e.g. in aqueous solution. The leaving group Y has the same meaning as in formula V.

The starting compounds of the formula VI can be prepared, for example, by modifying the lactam of the formula m

V

o the corresponding alkali metal salt, e.g. the sodium salt. This can be done, for example, by treating a lactam of formula X with an alkali metal hydride or an alkali metal amide in an aromatic hydrocarbon such as benzene, toluene or dimethylformamide. Finally, the obtained alkali metal salt is reacted with a compound of formula

R50-CH2-CH2-Hal XI

Wherein Hal is halogen and is a suitable protecting group, e.g. benzyl or 2-tetrahydropyranyl.

The protecting group is finally cleaved by hydrogenation or hydrolytic. The resulting hydroxy compound is reacted with a halogenating agent, e.g. thionyl chloride, or an alkyl- or aryl-substituted sulfonic acid halide, e.g. chloride, to give the starting compound of formula VI.

The reaction of the starting compounds of formula V and VI is conveniently carried out in an inert organic solvent, e.g. an aromatic hydrocarbon, e.g. benzene or toluene, a chlorinated hydrocarbon, e.g. chloroform, ether, e.g. dioxane or dimethoxyethane, a lower alcohol such as methanol or ethanol, ketone in acetone or methyl ethyl ketone, or also in dimethylformamide or dimethyl sulfoxide. It is preferred to carry out the reaction in the presence of an acid scavenger, e.g. in the presence of an alkali metal carbonate, e.g. sodium or potassium carbonate, or in the presence of an inert organic base, e.g. triethylamine. An excess of a base of formula V is also contemplated as an acid scavenger. The reaction temperature is preferably in the range of room temperature to the boiling point of the reaction mixture.

The bases of formula I form salts with both inorganic and organic acids. Suitable acids include hydrohalic acids such as hydrochloric acid, hydrobromic acid, and hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid, as well as tartaric acid, citric acid, camphorsulfonic acid, ethanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, Preferred salts are hydrohalides, especially hydrochlorides, and maleates. Acid addition salts are preferably prepared in a suitable solvent such as ethanol, acetone or acetonitrile by treatment of the free base with the corresponding anhydrous acid.

The bases of formula I are in part crystalline solids which are highly soluble in dimethyl sulfoxide, dimethylformamide and chlorinated hydrocarbons such as chloroform and methylene chloride, and also in alcohols such as methanol and ethanol but insoluble in water.

The acid addition salts of the bases of formula I are crystalline solids. They are highly soluble in dimethyl sulfoxide and dimethylformamide and alcohols such as methanol. They are relatively sparingly soluble in benzene, ether and petroleum ether.

It has been found that the compounds of formula I and their salts have potent centrally damping and stress-releasing properties. They can thus be used, for example, for the treatment of acute or chronic appendicitis and also as a sedative. It is particularly advantageous that the new compounds have no or only minor cataleptic side effects, so that almost no or only insignificant motor disorders are observed.

5 5741 3

The cataleptic effect ("wax stiffness", i.e., the abnormally long abnormal persistence of compulsive posture) occurs in centrally attenuating or neuroleptic compounds as an interfering side effect and causes motor disorders. The compounds according to the invention have the advantage that they do not have this interfering side effect or only to a very small extent. To establish this, the compounds of the invention were administered to rats intraperitoneally. The following substances were studied:

Product A: 3- [2- [1- + (2-Chloro-10,11-dihydro-dibenzo [b, f] thiepin-10-yl) -1-piperazinyl] -7-ethyl] -2-oxazolidinone maleate.

Product B: 3- [2 - [+ (10,11-dihydro-2-methyl-dibenzo [b, f] thiepin-10-yl) -1-piperazinyl] -ethyl] -2-oxazolidinone maleate,

Chlorpromazine, a known centrally attenuating and neuroleptic agent, was used as a reference.

Animals were considered cataleptic if equilateral limbs remained crosswise for at least 10 seconds. Kataleptisten number of animals were recorded every half hour to six hours. ED ^ q is the dose that produces a state of stress stiffness in 50 # of animals. The result is shown in the following table:

Test compound ED, (s / ^ g) A 100 B 70 chlorpromazine 6

The table shows that the new compounds have no or only a small cataleptic effect, whereas chlorpromazine has a significant cataleptic effect.

In order to determine the centrally damping or neuroleptic properties of the final products, the following test was performed on typical representatives: I. Round rod test

The round rod test investigates the ability of mice to complete a coordinated, motorized execution. Mice are placed after oral administration of test substance to a horizontal slowly rotating rod and the time to fall is measured. ED, _q is the dose that reduces the residence time by 50 # compared to before the test substance.

Product A shows a strong effect in this experiment. (ED = 7.9 mg / kg; chlorpromazine ED = 5 mg / kg.

II. Determination of homovanillic acid

Rats are injected with the test substance. After two hours, the rats are sacrificed, and homovanillic acid is extracted from the brain homogenate with butyl acetate and water and oxidized with potassium ferricyanide to a fluorescent dimer. From the elevated concentration of homovanillic acid, it can be concluded that the test substance acts in the same way as chlorpromazine, i.e. it increases dopamine turnover in the nuclei of the brain.

6 57413

Test substance Dose Increase in homovanillic acid (mg / kg orally) A 50 3 ^ 0 B 50 255

Chlorpromazine untreated rats 20,321 In this experiment, A and B show almost the same effect as chlorpromazine.

III. Climbing test This test provides information on the behavioral reactions of rats. Rats are trained to climb up the vertical bar in the experimental space and to avoid electrical irritation (absolute irritation) caused through the floor grid a few seconds after the audible signal (conditional stimulus).

The inhibition of the conditional reaction is determined by the parameter ED ^ Q (mg / kg orally), the inhibition of the absolute reaction is determined by the parameter ED ^ Q (mg / kg orally).

The parameter ED, _q (conditional inhibition) gives the neuroleptic potency of the test substance. The quotient ED ^ (absolute reaction inhibition) / ED ,. Q (inhibition of conditional reaction) indicates the effect of the test substance: an increase in the quotient indicates a higher selectivity of the neuroleptic effect (less neurotoxic side effect).

Comparison between Compound A and chlorpromazine

Test compound ED ^ (^^ oHisen reaction quotient ED ^ (absolute inhibition) man reaction) / ED, ...

(inhibition of conditional reaction) A 10 U, 2 chlorpromazine 11.6 3.5 In this experiment, A shows both neuroleptic potency and also neuroleptic selectivity; the new compound is slightly more preferred than chlorpromazine.

In the following examples, all temperatures are expressed in degrees Celsius.

Example 1 2.7 g of 1- (10,11-dihydro-2-methyldibenzo [b] E, thiepin-10-yl) -piperazine are added to a mixture of U, 3 g of ground potassium carbonate, 200 mg of potassium iodide, 90 ml toluene and 3.2 g of N- (N-chloroethyl) -2-oxazolidinone, and heated at reflux for 2 hours. The mixture is then poured into ice water, diluted with benzene, and the organic phase is washed with saturated soda solution and then with water, dried over sodium sulfate and concentrated under reduced pressure. There is obtained 3- [2- [1 + - (10,11-dihydro-2-methyl-dibenzo [b] [b] thiepin-10-yl) -1-piperazinyl, 7-ethyl-2-oxazolidinone which is recrystallized from acetone. / petroleum ether. The maleate melts at 159-116 ° C.

The starting 1- (10,11-dihydro-2-methyl-dibenzo [b, f] thiepin-10-yl) -piperazine is prepared as follows: 7 57413 20 g of 5-methylanthranilic acid are suspended in 200 ml of 3N hydrochloric acid at 0 ° C: in. A solution of 10 g of sodium nitrite and 20 ml of water is added dropwise with stirring and stirred for 25 min. 0 ° C. At 5 ° C, a solution of 26.5 g of potassium iodide, 30 ml of 3N hydrochloric acid and 30 ml of water is then added dropwise. Stir further for 30 min. at room temperature and reflux for 2 hours. Cool, add sodium thiosulfate until the reaction mixture is yellow (5 g) and separate the crystalline 2-iodo-5'-methylbenzoic acid by suction filtration and wash with water until neutral. The crude acid obtained is dissolved in ether, washed thoroughly with sodium thiosulphate solution and water, dried over sodium sulphate and evaporated to dryness. A light brown crystalline substance is obtained, m.p. is 100-112 ° C.

To a solution of 855 g of potassium hydroxide in 7 liters of water is added U20 g of thiophenol at 50 [deg.] C. under an argon atmosphere and stirred for 15 min. 22.1 g of copper powder and 1 kg of 2-iodo-5-methyl-benzoic acid are then added and the mixture is refluxed for 7 hours. After cooling, the pH is adjusted to 3 with 600 ml of concentrated hydrochloric acid, and extracted with methylene chloride, washed with water, dried over sodium sulfate and evaporated until a thick crystalline powder is obtained. It is then filtered off with suction, washed with cold ethanol and low-boiling Petro ether and dried. 3 'Methyl-6- (phenylthio) -benzoic acid is obtained, m.p. is 156-157 ° C.

To 65 g of 3-methyl-6- (phenylthio) benzoic acid in 7 to 5 liters of anhydrous methanol is slowly added 300 ml of concentrated sulfuric acid and heated under reflux for 2 hours. Concentrate and pour the residue into ice-cold sodium bicarbonate solution. The whole mixture is extracted with ether, washed with water, dried over sodium sulfate and concentrated. 3-Methyl-6- (phenylthio) -benzoic acid methyl ester is obtained as a red-brown oil which crystallizes on standing.

To 322.5 g of 3-methyl-6- (phenylthio) -benzoic acid methyl ester in 3 liters of anhydrous tetrahydrofuran are added dropwise under argon and refluxing k20 ml of a 70% solution of sodium dihydro-bis (2-methoxyethoxy) aluminate in benzene (30 min). boil for a further 3 hours at reflux. It is then cooled to about U [deg.] C., diluted with 1 liter of benzene and hydrolysed with 700 ml of 2N hydrochloric acid, then poured into ice water and a further 1 * 00 ml of concentrated hydrochloric acid are added to obtain a clear solution. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. 3-Methyl-6- (phenylthio) -benzyl alcohol is obtained as a red-brown oil.

570.7 g of 3-methyl-6- (phenylthio) -benzyl alcohol are dissolved in 1.5 liters of benzene and heated to reflux. It is dropped into it * + 5 min. within 352 ml of thionyl chloride and further boil for 90 min. I drive. It is then concentrated under reduced pressure to give 3-methyl-6- (phenylthio) benzyl chloride as a red-brown oil.

19 g of potassium cyanide in 250 ml of water are heated under an argon atmosphere with 616.9 g of 3-methyl-6- (phenylthio) benzyl chloride in 900 ml of ethanol under reflux for 17 hours. The ethanol is then distilled off under reduced pressure, then diluted with water and extracted with ether. The extracts are washed with water, dried over sodium sulfate and evaporated. 3-Methyl-6- (phenylthio) -phenylacetonitrile is obtained as an oil.

500 g of 3-methyl-6- (phenylthio) phenylacetonitrile, 1.2 l of ethanol, 70 g of potassium hydroxide and 500 ml of water are heated under reflux for 12 hours. The ethanol is then evaporated off under reduced pressure. Water is added to the residue until it is completely dissolved, and the neutral substance is extracted with benzene. A little Dicalite and activated carbon are added to the aqueous solution, filtered, cooled and adjusted to pH 3 with concentrated hydrochloric acid. It is then extracted with 3 x 1 liter of chloroform, washed with water, dried over calcium chloride, filtered and concentrated under reduced pressure. The resulting crude 3-methyl-6- (phenylthio) -phenylacetic acid is recrystallized from benzene-hexane to give the pure product, m.p. 132-135 ° · 192 g of polyphosphoric acid are heated to 100 ° C under a nitrogen atmosphere, 20 g of 3-methyl-6- (phenylthio) -phenylacetic acid are added rapidly and the mixture is stirred for 1 hour at 100-103 ° C. The whole mixture is then poured into ice water and extracted with ether. The extracts are washed first with 2N sodium hydroxide solution and then with water and dried over sodium sulfate. Upon concentration, the resulting 10,11-dihydro-2-methyldi-benzo [b, f] thiepin-10-one begins to crystallize. Addition of petroleum ether and cooling gives complete crystallization. Sp. * From 82 to 81 ° C.

10 g of 10,11-dihydro-2-methyldibenzo [b, f] thiepin-10-one are dissolved in 100 ml of dioxane and 3.2 g of sodium borohydride in 5 ml of water are added. Finally, stir for 20 hours at room temperature. It is then concentrated under reduced pressure and the residue partitioned between ether and water. The ether solution is washed with brine, dried over sodium sulfate and concentrated.

10,11-Dihydro-2-methyldibenzo [b, f] thiepin-10-ol is obtained as a colorless oil.

10 g of 10,11-dihydro-2-methyldibenzo [b, f] thiepin-10-ol, 100 ml of anhydrous benzene and 10 g of finely ground calcium chloride are saturated at room temperature with dry hydrogen chloride (about 2 hours) and then stirred for a further 20 hours. Finally, the calcium chloride is filtered off with suction, washed with chloroform and the filtrate is concentrated under reduced pressure. 10-Chloro-10,11-dihydro-2-methyldibenzo-Tb.fTt is obtained as a yellow oil which crystallizes on standing.

19.7 g of 19-chloro-10,11-dihydro-2-methyldibenzo [f] thiepine are dissolved in 100 ml of chloroform and heated together with 36.5 g of 1-carbethoxy-piperazine for 2 hours at reflux. It is then concentrated under reduced pressure and the residue is crystallized from acetone-hexane. 1-Carbethoxy-U- (10,11-dihydro-2-methyldibenzo [b, f] thiepin-10-yl) -piperazine is obtained. Sp. 96-98 °.

5.1 * g of 1-carbethoxy-U- (10,11-dihydro-2-methyldibenzo [b, f] thiepin-10-yl) -piperazine, 80 ml of ethylene glycol, L, 61 * g of potassium hydroxide and 0.33 ml of water are heated For 3A hours at 160 °. It is then poured into water, extracted with 9 5741 3 of ether, the extracts are washed with saturated brine, dried over sodium sulfate and evaporated. 1- (10,11-Dihydro-2-methyldibenzo [b, f] thiepin-10-yl) -piperazine is obtained as an oil.

Example 2 To 7.8 g of 1- (2-chloro-10,11-dihydro-dibenzo [b, f] thiepin-10-yl) -piperazine are added 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide in 100 ml. toluene and 8.22 g of N- (β-chloroethyl) -2-oxazolidinone and heated at reflux for 22 hours. The whole mixture is then poured into water, the organic phase is separated off and washed with saturated soda solution and then with water, dried over sodium sulphate and concentrated under reduced pressure. Crude liquid 3- [2- [N- (2-chloro-10,11-dihydro-dibenzo [b] f] thiepin-10-yl) -1-piperazinyl-7-ethyl-2-oxazolidinone is obtained. The maleate is prepared by reacting in ethanol-ether with maleic acid; mp. 173-175 ° · The starting 1- (2-chloro-10,11-dihydro-dibenzo [b, f] thiepin-10-yl) -piperazine can be prepared as follows: 100 g of 2,10-dichloro-10,11-dihydro -dibenzoZb, f7thiepine in 300 ml of chloroform is heated together with 182 g of 1-carbethoxy-piperazine for 2 hours at reflux. It is then diluted with water and chloroform. The organic phase is washed several times with water and dried over magnesium sulfate. It is then concentrated under reduced pressure and the residue is crystallized from acetone-hexane. 1-Carbethoxy-N- (2-chloro-10,11-dihydro-dibenzo [b, f] thiepin-10-yl) -piperazine is obtained; mp. 92-93 °.

110 g of 1-carbethoxy-4- (2-chloro-10,11-dihydro-dibenzo [b, f] thiepin-10-yl) -piperazine, 1.5 l of ethylene glycol, 10 l of potassium hydroxide and 5.1 l of water are heated for one hour for 16 ° C. It is then poured into water and extracted with chloroform. The organic phase is washed with water, dried over magnesium sulphate and evaporated to give 1- (2-chloro-10,11-dihydrodibenzo [D, f] thiepin-10-yl) -piperazine as an oil.

Example 3

Under an argon atmosphere, a mixture of 750 mg of 3- [2- [1- (2-chloro-dibenzo [b] N-pyridin-10-yl) -1-piperazinyl] -ethyl] -2-oxazolidinone, 0.6 g of sodium borohydride and 30 ml of diglyme at 20-30 ° C over 15 min dropwise 2.7 g of oxalic acid dihydrate in 15 ml of diglyme. The reaction mixture is heated to 100 ° C for 1 hour and finally evaporated under reduced pressure. Chloroform and 2N sodium hydroxide solution are added to the residue. After equilibration, the aqueous phase is separated and washed twice with chloroform. The combined chloroform extracts are washed with water, dried over potassium carbonate and activated carbon, filtered and evaporated under reduced pressure. 3- [2- (N2-chloro-10,11-dihydro-dibenzo [b, e (thiopin-10-yl) -1-piperazinyl] -ethyl) -2-oxazolidinone is obtained in the form of a brown oil. The maleate is prepared by reacting it with maleic acid in ethanol-ether; mp. 173-175 ° C.

Claims (3)

A process for the preparation of therapeutically useful 3- [2- [N- (2-substituted-10,11-dihydro-dibenzo [b] f] thiepin-10-yl) -1-piperazinyl-7-ethyl] -2-oxazolidinones of the formula N-CH0-CH_- / ^ D. / YY OC 6 wherein R 1 is chlorine or lower alkyl, and for the preparation of salts of these compounds, characterized in that a) a compound of formula Y "YcHO-CH - / \ IV" 'tXD Ύ wherein R 1 is as defined above is reduced, or b) reacting a compound of formula Bi YY 'XXD wherein R 1 is as defined above with a compound of formula 11 5741 3 / \ Y-CH0-CH -NO VI V "0 wherein Y is a leaving group such as halogen or an alkyl- or aryl-substituted sulfonyloxy group, after which the product obtained is optionally converted into a salt. A process according to claim 1 for the preparation of 3- [2-N- (2-chloro-10,11-dihydrodibenzo [b],] thiepin-10-yl) -1-piperazinyl-4-stylyl-N-oxazolidinone and its salts, characterized in that that chlorine-containing starting compounds of formulas IV to VI are used 12 5741 3 A process for the preparation of a therapeutically active compound 3- [2- [N- (2-substituent-10,11-dihydro-dibenzo [E, f] thiepin-10-yl) -1-piperazinyl] ethyl] -2-oxazolidinone with a formulation [n- ch2-ch2-n 0 V from R. | it is chlorine or alkyl, and in the case of alkylation, känneteck-n at därav, att a) a reducing agent in the formulation with the formula f ^ N-CH -CH -N 0 irfiV Y .. for R1 is a reduction in some form, or b ) is the same as in the case of NH form R1 for R1 in the case of a form having a form,