CS262293B1 - 4- (aminoalkoxy) derivatives of dioxanthone and xanthone. as well as their hydrochlorides - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is 4-(aminoalkoxy) derivatives of thioxanthone and xanthone and their hydrochlorides. The substances according to the solution have demonstrated antimicrobial activity in in vitro tests, therefore they are considered as chemotherapeutics for infectious diseases. They are synthetically accessible mainly by the following procedures: (a) the reaction of 4-hydroxythioxanthone, resp. 4-hydroxyxanthone with dialkylaminoalkyl chlorides in a solution of sodium ethoxide in ethanol, (b, by reactions of 4-(bromoalkoxy)thioxanthones or -xanthones with primary or secondary amines, (c) partial demethylation of 4-(dimethylaminoalkoxy)thioxanthones or -xanthones by reaction with ethyl chloroformate and subsequent alkaline hydrolysis of the products, and (d) by reaction of 4-(2,3-epoxypropoxy)thioxanthones or -xanthones with primary or secondary amines. The substances according to the solution are of an alkaline nature, which, upon neutralization with hydrogen chloride, yield hydrochlorides.

Description

The present invention relates to 4- (aminoalkoxy) thioxanthone and xanthone derivatives of formula (I)

in which X represents a sulfur atom or an oxygen atom, n is a hydroxyl group, R1 is a hydrogen atom or a methyl cyclohexyl group, as well as their hydrochlorides.

O is 1, or 2, R is hydrogen or 2, and R is C 1 -C 4 alkyl;

The compounds of formula I and their hydrochlorides have antimicrobial activity in in vitro assays, which is a prerequisite for their practical application in the chemotherapy of infectious diseases. Their inhibitory effect against the growth of some pathogenic cocci, which are a particularly common source of common infections, is particularly typical. At the same time, their acute toxicity is quite mild.

The following are biological data for these compounds of the invention:

(A) 4- (4-methylaminobutoxy) thioxanthone (B) 4- (4-methylaminobutoxy) xanthone (C) 4- (2-dimethylaminoethoxy) thioxanthone (D) 4- (3-dimethylaminopropoxy) thioxanthone (E) 4- ( 4-Cyclohexylaminebutoxy) thioxanthone (F) 4- (2-hydroxy-3- (2-propylamino, propoxy) thioxanthone (G) 4- (3-methylaminopropoxy) thioxanthone

In the in vitro antimicrobial tests, the following minimum inhibitory concentrations (MIC in <µg / ml) were determined for individual substances against the following microorganisms:

Streptococcus beta-haemolyticus: A, 25; B, 50; D, 25; E, 25.

Streptococcus faecalis: A, 25; B, 6.25; C, 2; D, 25; E, 25; F, 50.

Staphylococcus pyogenes aureus: A, 25; B, 50; C, 4; D, 25; E, 25; F, 6.25.

Pseudomonas aeruginosa, C, 128.

Escherichia coli: C 8.

Proteus vulgaris: A, 100; B, 50; C, 16; D, 100; F, 50.

Trichophyton mentagrophytes: 50; C, 50; F, 50.

Acute Toxicity of Several Compounds of the Invention in Mice by Intravenous Administration (LD ₅₀ in mg / kg): ,50; D, 75; G, 76.2.

The compounds of formula (I) according to the invention are accessible by synthetic procedures starting from 4-hydroxythioxanthone (II) or 4-hydroxyxanthone (III) -. The preparation of both of these starting materials by the novel process is described in the examples, with substance II not yet described in the literature. Substance III has already been reported in the literature (Ullmann F., Zlokosoff H .: Ber. Dtsch. Chem. Ges. 38, 2111, 1905; Finnegan RA et al .: Tetrahedron Lett. 1966, 6 087; Finnegan RA, Patel JK Soc., Perkin Trans. (1972, 1896), but was obtained in a manner other than that described below.

The basic process for the preparation of the compounds of the invention is the reaction of the sodium salts of compounds II and III with dialkylaminoalkyl chlorides in ethanol. Alternatively, 4- (bromoalkoxy) thioxanthone and xanthone derivatives are reacted with primary or secondary amines; The starting 4- (bromalkoxy) derivatives of thioxanthone and xanthone are novel compounds whose preparation is described in the examples. Another variant of the synthesis of monoalkylamino derivatives, which is particularly suitable for monomethylamino alkoxy derivatives, is the partial demethylation of the dimethylaminoalkoxy derivatives by reaction with ethyl haloformate and subsequent alkaline hydrolysis of the resulting N-ethoxycarbones 7-ii-methyl-amino3 alkoxy compounds. Finally, for substances in which R is a hydroxyl group and n = 1, the method of choice is to react the corresponding 2,3-epoxypropoxy compounds with primary or secondary amines. The starting epoxy compounds are new and the preparation of one of them is described in the example. All of the compounds of formula (I) of the invention are basic in nature and neutralization with hydrochloric acid or hydrochloric acid provides the hydrochlorides which are also subject of the invention. These hydrochlorides are generally water-soluble and are more suitable than bases for conducting bioassays and preparing dosage forms.

Further details of the preparation of the compounds of the formula I according to the invention are given in the examples, which, however, are merely illustrative of the possibilities of preparative approaches to the compounds of the invention. All of the compounds of the invention are novel and their identity has been assured by conventional analytical and spectral methods.

Example 1

4- (2-dimethylaminoethoxy) thioxanthone

2-Dimethylaminoethyl chloride hydrochloride (7.0 g) was added to a solution of sodium ethoxide, which was previously prepared by dissolving 2.0 g of sodium in 100 ml of ethanol. The mixture was stirred for 10 min and then 7.3 g of 4-hydroxythioxanthone was added. The mixture is then stirred and refluxed for 10 hours, after cooling, the precipitated solid is filtered off, washed with a little ethanol and benzene, and the filtrate is acidified with hydrochloric acid. The crude product hydrochloride precipitates, which is filtered off and the filtrate is evaporated under reduced pressure. Aspirated hydrochloride was added to the residue, the mixture was dissolved in water, the solution was washed with benzene, the aqueous ammonia liberated the base, which was extracted with benzene. The extract was washed with water, dried over anhydrous potassium carbonate and evaporated under reduced pressure. 6.0 g (63%) of the desired base are obtained, which crystallizes from ethanol and melts at 93-95 ° C. Neutralization with hydrogen chloride in a mixture of methanol and ether gives the hydrochloride, which crystallizes from methanol and melts in the pure state at 258-262 ° C.

The starting 4-hydroxythioxanthone used is a novel substance which is best prepared by the following procedure from the known 4-methoxythioxanthone (NSR publication 2,504,642):

A mixture of 4-methoxythioxanthone (21.6 g) and pyridinium chloride (67.5 g) was melted by heating and then heated with stirring in a 230 ° C bath for 45 min (internal temperature of the mixtures was.

207 ° C). After cooling to 100 ° C, the mixture is quenched by the addition of 400 ml of water, the resulting suspension is allowed to stand at room temperature for 2 hours, the yellow product is then filtered off with suction, washed with water and crystallized from 1.4 l of methanol. 18.0 g of the desired 4-hydroxythioxanthone are obtained, melting at 280-285 ° C. By treatment of the mother liquor, 2.0 g of a suitable product are obtained, so that the overall yield is 20.0 g (98%).

Example 2

4- (3-dimethylaminopropoxy) thioxanthone

Similar to Example 1, 10.9 g (77%) was prepared by reacting 9.7 g of 3-dimethylaminopropyl-chloride hydrochloride with sodium ethoxide solution (from 2.6 g of sodium and 300 ml of ethanol) and 10.3 g of 4-hydroxythioxanthone. of the desired base, which crystallizes from cyclohexane and melts at 97-99 ° C. Neutralization with hydrogen chloride in ethanol-ether gives the hydrochloride which crystallizes from ethanol and melts at 207-209 ° C.

Example 3

4- (3-methylaminopropoxy) thioxanthone

To a solution of 10.2 g of 4- (3-dimethylaminopropoxy) thioxanthone (see Example 2) in 65 ml of benzene is added a solution of 7.2 g of ethyl chloroformate in 20 ml of benzene, the mixture is stirred for 30 min at room temperature and then boiled. , 5 hours under reflux. After cooling, the precipitated starting base hydrochloride (2.9 g) was removed by filtration. The filtrate was washed with dilute hydrochloric acid and water, dried over sodium sulfate and evaporated under reduced pressure. The non-monogenic residue (7.3 g) is chromatographed over a 215 g neutral alumina column (activity II). The less polar portions are eluted with benzene and the benzene / chloroform mixture, and then 4.8 g (40%) of homogeneous 4- (3- (N-ethoxycarbonyl-N-methylamino) propoxy) thioxanthone is eluted with chloroform, which solidifies to crystalline upon evaporation of chloroform. m.p. 82-85 ° C.

A mixture of 4.8 g of this material, 3.8 g of potassium hydroxide and 7.5 ml of ethanol is stirred and refluxed for 11 h (bath temperature 120 ° C). The ethanol was evaporated, the residue was partitioned between water and benzene and the benzene solution was shaken with excess 3M-HCl. The resulting aqueous hydrochloride solution was separated, basified with aqueous ammonia, and the base was obtained by benzene isolation: 3.8 g (100%), m.p. 98 DEG-101 DEG C. (cyclohexane). Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride of the desired compound, melting at 205-208 ° C.

Example 4

4- (4-methylaminobutoxy) thioxanthone

To a solution of 11.0 g of 4- (4-bromobutoxy) thioxanthone in a mixture of 400 ml of ethanol and 40 ml of benzene is added 50 ml of a 40% aqueous methylamine solution and the mixture is stirred at room temperature for 5 hours.

After standing for 48 h, an additional 50 mL of a 40% methylamine solution was added and the mixture was stirred for an additional 5 h at room temperature. It is then evaporated under reduced pressure, 100 ml of 10% sodium hydroxide solution are added to the residue, and the product is extracted with a mixture of benzene and ether. Workup of the extract gave a crude product which crystallized from cyclohexane: 7.0 g (74%), m.p. Mp 94-97 ° C (benzenhexane). Neutralization with hydrogen chloride in a mixture of methanol and ether gives the hydrochloride identified as a hemihydrate, m.p. Mp 214-218 ° C.

The required starting 4- (4-bromobutoxy) thioxanthone, which has not been described in the literature, is prepared as follows: To a stirred solution of 2.8 g of potassium hydroxide in 100 ml of methanol is added 9.1 g of 4-hydroxythioxanthone and then over 10 min. A solution of 17.3 g of 1,4-dibromobutane in 20 ml of methanol is added dropwise. The mixture was refluxed for 9 h, evaporated under reduced pressure and the residue extracted with benzene. The extract was washed with 2M-MaOH and water, dried over sodium sulfate and evaporated in vacuo. The residue gives crystallization from 90 ml of ethanol to 8.4 g (58%) of the desired intermediate which melts at 101-103 ° C pure.

Example 5

4- (4-methylaminobutoxy) xanthone

In a similar reaction to the previous example, 20.0 g (80%) of the oily desired base was prepared from 29 g of 4- (4-bromobutoxy) xanthone and a 40% solution of methylamine (230 and then 200 ml) in 1.5 L of methanol. is converted to the hydrochloride. This salt crystallizes from a mixture of ethanol and petroleum ether as a 2: 1 solvate with ethanol, m.p. Mp 195-198 ° C.

The starting, hitherto unknown, 4- (4-bromobutoxy) xanthone is obtained by reacting 5.3 g of 4-hydroxyxanthone (literature cited) with 11.2 g of 1,4-dibromobutane in a solution of 1.7 g of potassium hydroxide in 100 ml of methanol similarly as described for a similar substance in the previous example. The desired intermediate was obtained in a yield of 4.9 g (57%), m.p. 95-98 ° C (ethanol).

The starting 4-hydroxyxanthone can be obtained in a new way as follows: A mixture of 7.7 g of 4-methoxyxanthone (Ullmann F., Zlokosoff H .: Ber. Dtsch. Chem. Ges. 38, 2111, 1905) and 26 g of pyridinium chloride is heated with stirring. 45 min in a 230 ° C bath. A similar treatment to that described in Example 1 gives 6.9 g of crude product which is dissolved in 400 ml of boiling ethanol, filtered with activated carbon and the filtrate is filtered. partly evaporates: 5.8 g (81%) of 4-hydroxyxanthone crystallized on standing, melting at 243-245 ° C.

Example 6

4- (4- (n-butylamino) butoxy) thioxanthone

To a solution of 3.6 g of 4- (4-bromobutoxy) thioxanthone in a mixture of 50 ml of ethanol and 5 ml of benzene is added 3.3 g of n-butylamine and the mixture is refluxed for 8 hours. The solvents were evaporated in vacuo, 10 ml of 10% sodium hydroxide solution was added to the residue, and the product was extracted with benzene. Work-up of the extract gave 3.3 g of crude material, which was dissolved in 15 ml of ethanol and acidified with a solution of hydrogen chloride in ether. The hydrochloride of the title compound is obtained in a yield of 3.5 g which crystallizes from a mixture of methanol and ether and melts at 174-177 ° C.

Example 7

4- (4-cyclohexylaminobutoxy) thioxanthone

To a warm solution of 3.6 g of 4- (4-bromobutoxy) thioxanthone in 40 ml of ethanol was added 5.0 g of cyclohexylamine, and the mixture was refluxed for 9 hours with stirring. After standing for several days, the mixture is filtered, the filtrate is evaporated in vacuo, 50 ml of 10% sodium hydroxide solution are added to the residue, and the product is extracted with benzene. The base is transferred from the organic solvent to an aqueous solution by shaking with an excess of 3M-HCl, the hydrochloride solution obtained is separated, quenched with aqueous ammonia and the base is extracted with benzene. Treatment of the extract yields a crude product which crystallizes on standing; 3.2 g (84%), m.p. Mp 83-85 ° C (cyclohexane). Neutralization with hydrogen chloride gives the hydrochloride which crystallizes from methanol and melts at 210-213 ° C.

Example 8

4- (2-hydroxy-3- (2-propylamino) propoxy) thioxanthone

To a solution of 1.2 g of isopropylamine in 15 ml of ethanol is added dropwise a solution of 1.8 g of 4- (2,3-epoxypropoxy) thioxanthone in 80 ml of ethanol at 60-70 ° C. The mixture was stirred and refluxed for 2 hours, evaporated in vacuo, partitioned between water and warm benzene and the separated benzene solution was shaken with excess 3M-HCl. The resulting aqueous hydrochloride solution was separated and basified with aqueous ammonia, and the base was extracted with chloroform. The extract was worked up to give a crude product which was crystallized from 20 ml of ethanol; 1.6 g (74%), m.p. Mp 139-141 ° C. The hydrochloride obtained by neutralizing the base with hydrogen chloride in a mixture of methanol and ether crystallizes from this mixture of solvents and melts at 203-206 ° C.

The starting 4- (2,3-epoxypropoxy) thioxanthone used is a substance not yet described and can be prepared as follows: A mixture of 6.8 g of 4-hydroxythioxanthone, 21.6 g of 1-chloro-2,3-epoxypropane, 6.4 g of carbonate The reaction mixture was stirred at 80 ° C for 2 h and then refluxed in a 135 ° C bath for 1 h. The volatiles were removed in vacuo, the residue partitioned between water and chloroform, and the chloroform solution was dried and evaporated. The crude product obtained is dissolved in a mixture of 300 ml of ethanol and 50 ml of benzene, filtered through a layer of activated carbon, the filtrate is partially evaporated and left to crystallize in a refrigerator: 6.7 g (80%), m.p. 136 DEG-138 DEG C. (ethanol).

Claims (2)

OBJECT OF THE INVENTION in which X is a sulfur atom or an oxygen atom, n is 0, 1 or R 2 is hydrogen or even 2 hydroxyl, R is hydrogen or methyl and R is C 1 -C 4 alkyl or cyclohexyl, as well as their hydrochlorides.