CS211323B1

CS211323B1 - 2,3-Diarylpropylamines, derivatives and salts

Info

Publication number: CS211323B1
Application number: CS652680A
Authority: CS
Inventors: Vladimir Valenta; Miroslav Protiva; Jana Turinova
Original assignee: Vladimir Valenta; Miroslav Protiva; Jana Turinova
Priority date: 1980-09-29
Filing date: 1980-09-29
Publication date: 1982-02-26

Abstract

Vynález se týká nových 2,3-diarylpropylaminů a jejich derivátů, v jejichž molekulách aryl značí 3,5-dichlor-2-(fenylthio)fenyl nebo 3,5-dichlor-2-(4-chlorfenylthio)fenyl, aminoskupina je bud primární nebo terciární (dimethylaminoskupina). Z derivátů se uplatňují pouze N-aminoacylderiváty specifické struktury, v nichž aminoacyl je 4-methylpiperazinoacetyl. Vynález zahrnuje též soli s farmaceuticky nezávadnými anorganickými nebo organickými kyselinami. Látky podle vynálezu mají antiraikrobiální účinnost v testech in vitro, takže přicházejí v úvahu jako chemotherapeutika. Zvláště výrazná je antituberkulosní aktivita jednoho z aminoacylderivátů. Postupy přípravy, které jsou podrobně popsány v příkladech provedení, vycházejí z 2,3-diarylpropionitrilů, u nichž aryl značí totéž, co bylo uvedeno. Redukcí těchto nitrilů komplexními hyčridy se získávají primární aminy podle vynálezu. Methylací primárních aminů resultují příslušné dimethylaminosloučeniny podle vynálezu, a konečně acylací primárních aminů chloracetylchloridem a následující substituční reakcí s 1-methylpiperazinem se získají uvedené 4-Kethylpiperazinoacetylderiváty.The invention relates to new 2,3-diarylpropylamines and their derivatives, in whose molecules aryl denotes 3,5-dichloro-2-(phenylthio)phenyl or 3,5-dichloro-2-(4-chlorophenylthio)phenyl, the amino group being either primary or tertiary (dimethylamino group). Of the derivatives, only N-aminoacyl derivatives of a specific structure are used, in which the aminoacyl is 4-methylpiperazinoacetyl. The invention also includes salts with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention have antimicrobial activity in in vitro tests, so that they are considered as chemotherapeutic agents. The antituberculosis activity of one of the aminoacyl derivatives is particularly pronounced. The preparation procedures, which are described in detail in the examples, are based on 2,3-diarylpropionitriles, in which aryl denotes the same as stated. Reduction of these nitriles with complex hydrides yields the primary amines according to the invention. Methylation of the primary amines results in the corresponding dimethylamino compounds according to the invention, and finally acylation of the primary amines with chloroacetyl chloride and subsequent substitution reaction with 1-methylpiperazine yields the aforementioned 4-ethylpiperazinoacetyl derivatives.

Description

1 211323

The present invention relates to novel 2,3-diarylpropylamines and derivatives of formula I,

Wherein R is hydrogen or chlorine, R is hydrogen or methyl and R is hydrogen, methyl or 4-methylpiperazinoacetyl, and their salts with pharmaceutically acceptable inorganic or organic acids. The compounds of the invention exhibit antimicrobial activity in in vitro assays, making them useful as chemotherapeutics in various infectious diseases. Examples of active compounds are 2,3-bis (3,5-dichloro-2- (phenylthio) phenyl) propylamine (IA), N, N-di-methyl-2,3-bis (3,5- dichloro-2- (phenylthio) phenyl) propylamine (IB) and N- (2,3-bis / 3,5-dichloro-2- (4-chlorophenylthio) phenyl) propyl) -4-methylpiperazinoacetamide (IC). Compounds IA and IB were tested as hydrochlorides, IC as bis (hydrogen maleate). The following are the microorganisms used, the substance numbers and their minimum inhibitory concentration in g / ml: Streptococcus faecalis, IC 100; Staphylococcus pyogenes aureus, I-C100; Mycobacterium tuberculosis H37 Rv, IA 25, IC 6.25; Saccharomyces pasterianus, I-A100, IB 100, IC 100; Tetrophyton mentagrophytes, IA 100, IB 100, IC 100; Candida albieans, IA 100, IB 100, IC 100, Aspergillus niger, IC 100. The anti-tuberculosis activity of IC is very pronounced. The compounds of the invention may be prepared by procedures detailed in the Examples. The starting materials are nitriles of the general formula II,

wherein R is the same as in formula I. These nitriles are novel, not described in the literature, and their preparation is exemplified. Reduction of these nitriles with complex hydrides, preferably lithium aluminum hydride in ether or tetrahydrofuran yields the primary amines of the invention, i.e., formula I, R = R = H. By methylation of these primary amines using various methylation methods, the dimethylemine derivatives of the invention are obtained, ie. Formula I, R 1 = R 2 = CH 2 A particularly preferred method for this purpose is the methylation of formeldehyde with formic acid.

Reactions of said primary amines with chloroacetyl chloride produce N-chloroacetylderates which provide a third type of compound according to the invention, i.e. 4-methylpiperazinoacetyl derivatives of formula I, R 1 H, R 2 = COCH 2 N 4, CH 3 by the following substitution reaction with 1-methylpiperazine. 2) 1323 All types of compounds of the invention are basic in nature and provide crystalline salts as neutralized by pharmaceutically acceptable inorganic or organic acids. These salts are preferable to free bases to carry out biological assays and to prepare dosage forms. The identity of the compounds of the invention as well as the novel intermediates was assured analytically and by spectra (UF, IR, Ni4R). Examples:,. 2,3-Bis (3,5-dichloro-2- (phenylthio) phenyl) propylamine

A mixture of 2.0 g of lithium aluminum hydride, 125 ml of ether and 11.2 g of 2,3-bis (3,5-dichloro-2- (phenylthio) phenyl) propionitrile was refluxed for 2.5 hours. With external cooling, 20 ml of 20% sodium hydroxide and 6 ml of water are added dropwise by careful dropwise addition of 50 ml of potassium carbonate and 3 g of potassium carbonate and the mixture is stirred for 30 minutes. The solid is then filtered off, washed with ether and the filtrate is evaporated. The residual oily base is dissolved in 25 ml of ethanol and the solution is neutralized with a solution of hydrogen chloride in ether. The hydrochloride of the desired compound is precipitated in microcrystalline form by addition of 50 ml of ether. It was melted at 225 DEG-229 DEG C. in a yield of 10.6 g (88%) and recrystallized from ethanol / ether. The starting material 2,3-bis (3,5-dichloro-2- (phenylthio) phenyl) propionitrile is a novel material which can be prepared from known raw materials as follows:

A solution of 103 g of 3,5-dichloroanthranilic acid (M. Endicott et al., J. Amer. Chem. Soc. 68 1 303 1946). Sodium nitrite (35 g) and 5M NaOH (100 ml) in water (800 ml) was added dropwise with vigorous external cooling to a stirred solution of 165 ml of hydrochloric acid (650 ml) (0-5 ° C). cooling for 30 minutes is then added to a stirred solution of 125 g of potassium iodide and 37.5 ml of sulfuric acid in 200 ml of water over 30 minutes.

The mixture is slowly heated to 50 ° C, stirred for 30 minutes at this temperature, which is then raised to 100 ° C and the iodine is removed by steam distillation. After 2 h, the mixture was cooled, 7.0 g of sodium metabisulfite was added and left overnight. The precipitated product is then filtered, washed with water and dried in vacuo. 148 g (94%) of crude 3,5-dichloro-2-iodobenzoic acid are obtained, mp 75-80 ° C. Crystallization from aqueous ethanol yielded analytically pure material, mp 183.5-185 ° C. To a stirred solution of 63.4 g of the previous iodic acid and 26.6 g of thiophenol in 40 ml of dimethylformamide was slowly added 31.5 g of anhydrous potassium carbonate, followed by 5.0 g of chloridummium. The mixture was heated at 30-30 ° C for 4 h. After cooling to 80 ° C, the mixture was diluted with 500 mL of water and acidified with 50 mL of 5M-HCl. After cooling and standing overnight, the precipitated product is filtered off with suction and recrystallized from aqueous ethanol. 46.4 g (78%) of crude 3,5-dichloro-2- (phenylthio) benzoic acid are obtained, m.p. , 35-138 ° C. Crystallization from benzene gave an analytically pure product with mp 14, 43 cC.

A solution of 61.5 g of the above acid in 400 ml of ether is slowly added to a stirred suspension of 16 g of lithium aluminum hydride. in ether (100 ml) and refluxed for 2.5 h.

After cooling, it was quenched by slow dropwise addition of 16 ml of 20% sodium hydroxide solution and 50 [mu] l of water. Potassium carbonate (16 g) was added and after 1 h the mixture was filtered. The solid was washed with ether and the filtrate was evaporated. The rest is crystallized by standing. 49.6 g (87%) of crude 3,5-dichloro-2- (phenylthio) benzyl alcohol are obtained, mp 53-57 ° C. Crystallization from a mixture of cyclohexane and petroleum ether gave an analytically pure substance with mp 58-60. A solution of 37.4 g of thionyl chloride in 25 ml of benzene at 25-30 was added over 20 min to a stirred solution of 44.4 g of the previous alcohol in 80 ml of benzene. ° C. The mixture is stirred for 1 hour at 50 ° C 211323 to 60 ° C and boiled. under reflux for 1.5 h. The solvent and excess thionyl chloride were evaporated under reduced pressure and the product crystallized on standing. 45.1 g (96%) of crude 3,5-dichloro-2- (phenylthio) benzyl chloride are obtained, mp 66-70 ° C. Crystallization from cyclohexane / petroleum ether gave an analytically pure substance, mp 66-68 ° C.

A mixture of 10.0 g of the preceding chloride, 16 ml of acetone, 2.5 g of sodium cyanide and 0.5 g of potassium iodide was stirred and refluxed for 5 hours. The solid was filtered off, washed with acetone and benzene, and the combined filtrates were evaporated to dryness under reduced pressure. 7.8 g (85%) of crude 2,3-bis (3,5-dichloro-2- (phenylthio) phenyl) propionitrile are obtained, m.p. 142-151 ° C. Crystallization from ethanol / cyclohexane gives analytical purification at mp 152-154 ° C. 2. 2,3-Bis (3,5-dichloro-2- (4-chlorophenylthio) phenyl) propylamine 2,3-Bis (3,5-dichloro-2- (4-chlorophenylthio) phenyl) propionitrile (30.8 g) is reduced by 5.0 g of lithium aluminum hydride in 375 ml of ether similarly to the case of Example 1. 29.0 g (94%) of a crystalline base are obtained, melting at 45 DEG-52 DEG C. Crystallization from a mixture of cyclohexane and petroleum ether yields analytically pure material, mp 94-97 ° C. As in the previous example, crystalline hydrochloride is prepared, mp 252-253 ° C (ethanol-ether). The 2,3-bis (3,5-dichloro-2- (4-chlorophenylthio / phenyl) propionitrile starting material is a novel material which can be prepared from known raw materials by the procedure described below, which is analogous to that described in Example 1:

A mixture of 94.8 g of 3,5-dichloro-2-iodobenzoic acid (described in Example 1), 52.5 g of 4-chloro-thiophenol, 70 ml of dimethylformamide, 52 g of potassium carbonate and 8.25 g of copper chloride are treated similarly as in the first example. There were obtained 83.2 g (83%) of crude 3,5-dichloro-2- (4-chlorophenylthio) benzoic acid, mp 157-161 ° C. Crystallization from aqueous ethanol yields analytically pure substance melting at 158-161 ° C. The acid obtained (33.3 g) is reduced with 7.6 g of lithium aluminum hydride in 270 ml of the like, as described in the first embodiment. 29.5 g (92%) of crude 3,5-dichloro-2- (4-chlorophenylthio) benzyl alcohol are obtained, melting at 98-105 ° C. The cyclohexane crystallization is obtained analytically pure substance, e.g. mp 110-112 ° C.

Reaction of 28.7 g of the previous alcohol with 25 g of thionyl chloride in 65 ml of benzene, as in Example 1, yields 24.0 g (80%) of crude 3,5-dichloro-2- (4-chlorophenylthio) benzyl chloride melting at 50-55 ° C. Crystallization from petroleum ether gave an analytically pure material, mp 57-60 ° C.

A mixture of 20.4 g of the preceding chloride, 6.0 g of sodium cyanide, 40 ml of dimethylformide and 16 ml of water is stirred for 1 hour at 60 ° C and 4 hours at 35 to 40 ° C. It is then diluted with 100 ml of water, the solid is filtered off with suction and 500 ml of ethanol are extracted. After cooling to 30 ° C, the undissolved solid is filtered, washed with a little cold ethanol and dried under vacuum. 7.3 g (39%) of practically pure 2,3-bi- (3,5-dichloro-2- (4-chlorophenylthio) phenyl) propionitrile are obtained at 152-153 ° C. Recrystallization from a mixture of cyclohexane and ethanol leads. to the same substance 3. N, N-Dimethyl-2,3-bis (3,5-dichloro-2- (phenylthio) phenyl) propylamine

A mixture of 11.2 g of 2,3-bis (3,5-dichloro-2- (phenylthio) phenyl) propylamine (preparation thereof described in Example 1), 12.5 g of 3696 formaldehyde, 10.2 g of 10095 formic acid and 12 g 5 ml of water is stirred for 12.5 h at 100 ° C. After cooling, 45 ml of 20% sodium hydroxide solution was added and extracted with chloroform. Treatment of the extract yielded 11.7 g of crude base which was converted to the crystalline hydrochloride by neutralization with an ethereal solution of hydrogen chloride in a mixture of ethanol and ether.

Claims

2.1323 4 is obtained in a yield of 9.5 g (75%) and melts at 214-218 ° C. Crystallization from acetone / ethanol / ether gave an analytically pure substance, mp 228-230 ° C. 4. N- (2,3-Bis / 3,5-dichloro-2- (4-chlorophenylthio) phenyl) propyl) -4-methylpiperazinoacetamide To a stirred mixture of 25.3 g of 2,3-bisC3,5-dichloro-2 (4-chlorophenylthio) phenyl) propylamine (Example 2), 90 ml of benzene and 3.0 g of sodium carbonate were added dropwise over 45 min to a solution of 6.0 g of chloroacetyl chloride in 25 ml of benzene. The mixture was stirred for 1 h at room temperature and 30 min at 45 ° C. 100 ml of water are then added and extracted with benzene. The extract is filtered, dried over sodium sulfate and evaporated. 18.6 g (66%) of crude N- (2,3-bis / 3,5-dichloro-2- (4-chlorophenylthio) phenyl) propyl) chloroacetamide were obtained, which was used for further purification and without characterization. A mixture of 16.8 g of this material, 7.5 g of 1-methylpiperazine and 35 ml of toluene was refluxed for 3 hours and then evaporated. The residue was dissolved in 100 ml of chloroform, washed with water and extracted with IM-HgSO4. The obtained aqueous sulfate solution was basified with 20% sodium hydroxide, and the liberated base was extracted with chloroform. Treatment of the extract yielded 17.6 g (98.56) of crude oil base, which gave crystalline bis (hydrogen maleate) by neutralization with maleic acid in ethanol and addition of ether; 15.9 g, m.p. 24-127 ° C (ethanol). OBJECT OF THE E U S U 2,3-Diarylpropylamines and derivatives of the general formula,

Wherein R is hydrogen or chlorine, R is hydrogen or methyl and R is hydrogen, methyl or 4-methylpiperazinoacetyl, as well as their pharmaceutically acceptable inorganic or organic acids. Severografia, n. P., Plant 7, Most