DE1037458B - Process for the preparation of 1-aza-6-tertiary-amino-low-molecular-alkyl-amino-9-methyl-thioxanthones - Google Patents

Description

GERMAN

The present invention relates to a process for the preparation of l-aza-2-low molecular alkyl-6- (tertiary amino-low molecular alkylamino) -9-methyl-thioxanthones, especially of l-aza-2-low molecular alkyl - 6 - (di- low molecular alkylamino low molecular alkylamino) -9-methyl-thioxanthones and their salts.

The new compounds can also contain other substituents, in particular one low molecular weight alkyl group in position 4. Primarily, the present invention relates to one Process for the preparation of l-aza-2-low molecular alkyl - 6 - diethylaminoäthylamino - 9 - methyl - thioxanthone, as from l-aza-2-methyl-o-diethylaminoethylamino-9-methyl-thioxanthone, and their salts.

The compounds according to the invention have a pronounced tendency towards schistosomes and amoebas Effect on and can be used as a remedy for human schistosomiasis and amoebiasis. They have compared to the l-aza-6-diethylaminoäthylamino known from British patent specification 700 124 -9- methyl thioxanthone particularly valuable properties. The following comparison tests with 1-aza-6-diethylaminoethylamino-2,9-dimethyl-thioxanthone resulted and the above-mentioned known 1 - aza-6 - diethylaminoäthylamino - 9-methyl - thioxanthone with cercariae of Schistosoma mansoni subcutaneously by injecting about 100 live animals each Larvae infected white mice in various doses and applications for at least 2 to 5 times superior effect of l-aza-6-diethylaminoäthylamino - 2,9-dimethyl-thioxanthone.

1. Method of testing the schistosomacid activity of compounds of the azathioxanthone series

White mice weighing about 20 g of both sexes are infected with Schistosoma cercariae mansoni infected subcutaneously by injecting around 100 living larvae each. Treatment of the so infected mice is carried out daily using a gavage at the specified dose and period (see table). It should be noted that treating the mice at this early stage of infection is a test method with more difficult conditions of action for chemotherapeutic agents, compared for example to Treatment from the sixth week of infection.

The evaluation of the treatment results is carried out by counting those in the mesenteric vein system detectable mature worm pairs in the tenth week after infectionem. In the table overleaf is the Worm infestation included in the group average.

The new compounds are obtained if one l-aza ^ -lower molecular alkyl ^ -methyl-thioxanthones, which in the 6-position is a reactive esterified one

for the production of l-aza-6-tertiaryamino-low molecular alkylamino-9-methyl-thioxanthones

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority:
Switzerland from August 19, 1955 and July 13, 1956

Dr. Jean Druey, Riehen, and Dr. Konrad Maier, Basel.

(Switzerland),
have been named as inventors

Oxy group or an amino group contain, in a known manner with a low molecular weight Reacts alkylamine or a reactive ester of a low molecular weight alkanol, the low molecular weight alkyl radical of the alkylamine or of the alkanol in each case a tertiary amino group or contains a radical which can be converted into it, and in compounds obtained with a radical Amino group convertible radical, these are converted into such a radical by processes known per se, and converting any salts obtained into the free bases or free bases into their salts.

So you can l-aza ^ -lower molecular alkyl ^ -methyl-thioxanthones, which have a chlorine atom in the 6-position, with tertiary-amino-low molecular alkylamines, z. B. Diethylaminoäthylamin implement. On the other hand, one can such l-aza-2-low molecular alkyl-9-methyl-thioxanthones, which have an amino group in the 6-position, with a tertiary-amino-low molecular alkyl halide, such as diethylaminoethyl chloride to implement. In the gradual transfer, z. B. the tertiary amino group in these reactions must be replaced by an oxy group, which is then subsequently esterified in a reactive manner, z. With hydrochloric acid, and then exchanged for the tertiary amino group, e.g. B. by Reaction with the corresponding amine.

809 599/550

3 4

2. Comparison of the Schistosomacid Effect

dose number of
Treatments period number of
at the end of
tenth week
dissected mice Effect: reduction link mg / kg by mouth the worm number
(Average of
dissected mice)
in percent
the untreated 10 6 times first week 7th control I.
l-aza-6 - (/ 9-diethyl- 50 6 times post infectionem 7th 50% aminoethylamino) - 100 6 times 12th 100% 2,9-dimethyl- 100 »/ Ό thioxanthone 75 1 time 3 hours 10 ante infectionem 80 ¹ V ₀ 100 6 times third week 6th post infectionem 50% II 10 6 times first week 10 l-aza-6- (jS-diethyl- 50 6 times post infectionem 6th 0% aminoethylamino) - 100 6 times 8th 35% 9-methyl- 100% thioxanthone 75 1 time 3 hours 8th ante infectionem 50% 100 6 times third week 6th post infectionem 16% - - - 5 untreated 0%

The reactions are carried out in a manner known per se in the presence or absence of diluents and / or condensing agents and / or catalysts at ordinary or elevated temperature carried out in an open or in a closed vessel under pressure.

Depending on the procedure, the new compounds are obtained in the form of their bases or salts. From the The free amine bases can be obtained from salts in a manner known per se. From the latter in turn can be achieved by reaction with acids which are suitable for the formation of therapeutically useful salts win salts, such as hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, Rhodanic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, Methanesulfonic acid, ethanesulfonic acid, oxyethanesulfonic acid, benzene or toluenesulfonic acid or of therapeutically effective acids.

The starting materials are known or can be prepared in a manner known per se.

The new compounds can be used as remedies, e.g. B. in the form of pharmaceutical preparations, use find which they or their salts in mixture with one for enteral, parenteral or topicale Application of suitable pharmaceutical organic or inorganic, solid or liquid carrier material contain.

The invention is described in more detail in the following examples.

example 1

13.8 g of l-aza-2,9-dimethyl-6-chlorothioxanthone are gently refluxed at 160 ° C. ^{in 60 cm 3 of diethylaminoethylamine for 5 hours.} The excess diamine is then distilled off and the residue is ^{treated with 100 cm 3 of} 10 percent acetic acid.

The solution is shaken out with a little ether, separated from the ether layer and after filtering made basic with coal with potassium carbonate. The free base is extracted with ether. The ethereal solution leaves the yellow, crystallized base after washing with water, drying and evaporation. the end Alcohol is the l-aza-2,9-dimethyl-6-diethylaminoethylamino-thioxanthone of the formula

NH-CH ₂ -CH ₂ -N (C ₂ H ₅ ),

Preserved in golden yellow needles with a temperature of 83 to 84 ° C.

Yield 16g. The hydrochloride obtained in the usual way forms yellow needles from F. 229 to 229.5 ° C.

The 1-aza-2,9-dimethyl-6-chloro-thioxanthone used as the starting material can be made in the following ways:

64 g of 2-chloro-3-cyano-6-methyl-pyridine are refluxed for 16 hours ^{with 83.5 g of anhydrous sodium compound of 2-methyl-5-chlorothiophenol in 500 cm 3 of dioxane.} Then sodium chloride is filtered off with suction, the residue is dissolved in methylene chloride after evaporation and the solution is washed with water, dried and evaporated. The residue, 6-methyl-3-cyano -2 - (5'-chloro-2'-methyl-phenylmercapto) -pyridine with a melting point of 110 ° to 111 ° C., is recrystallized from methanol. Yield: 98 g.

27.45 g of the nitrile are ^{heated to 140 to 150 ° C. in 200 cm 3 of} 80 percent sulfuric acid for 12 hours. Then, it is poured onto ice, made basic with 10 N sodium hydroxide to a _pH value of 3 and extracted with methylene chloride. When distilled off, the methylene chloride leaves behind crystalline o-methyl-3-carboxy-2 - (5'-chloro-2'-methyl-phenylmercapto) -pyridine with a melting point of 167 ° to 169 ° C. Yield: 24 g.

29.35 g of this carboxylic acid are heated to 140 to 150 ° C. ^{in 150 cm 3 of concentrated sulfuric acid for 2 hours.} It is then poured onto ice, made alkaline with 10 N sodium hydroxide solution and extracted with methylene chloride. The residue obtained after distilling off the methylene chloride is converted from dioxane

10

crystallized. The l-Aza ^^ - dimethyl-o-chloro-thioxanthone Melts at 204 to 206 ° C. Yield: 21.4 g.

Example 2

12.5 g of crude 1-aza-2-isobutyl-6-chloro-9-methyl-thioxanthone are refluxed with 50 cm ^{3 of} diethylaminoethylamine for 6 hours. The excess diamine is then distilled off in vacuo and the residue is dissolved in 200 cm ^{3 of} 10 percent acetic acid. The orange-yellow solution is made alkaline dropwise with 2 η sodium hydroxide solution while stirring and cooling with ice, the golden-yellow base precipitating in crystalline form. The l-Aza ^ -isobutyl-ö-diethylarnmoäthylamino ^ -methyl-thioxanthone of the formula

C NH-CH ₂ -CH ₂ -N (C ₂ H ₅ J ₂

CH ₃
CH ₁

CH-CH ₂ -V

N S

melts at 88 ° C. Yield: 15 g.

In the usual way, the base is dissolved in alcohol for the preparation of the hydrochloride, with the calculated one Amount of alcoholic hydrochloric acid are added and the solution is concentrated. The hydrochloride crystallizes in golden yellow, matted needles from 195 to 196 ° C.

The 1-aza-2-isobutyl-6-chloro-9-methyl-thioxanthone used as the starting material can be made in the following ways:

19.45 g of 2-chloro-3-cyano-6-isobutyl-pyridine are refluxed with 18.8 g of the sodium compound of 2-methyl-5-chlorothiophenol in 300 cm ^{3 of} anhydrous toluene for 20 hours. Then, the toluene solution is treated with water, separated, washed with 2N sodium hydroxide £ jj brine and water, and the toluene abdestil- ^a

lates. The 6-isobutyl-3-cyano-2- (5'-chloro-2'-methyl-phenylmercapto) -pyridine thus obtained distills at _{boiling point} 158 ° C. in the form of an almost colorless oil. Yield: 16.5 g.

15.8 g of this nitrile are ^{heated to 140 to 150 ° C. with 150 cm 3 of} 80 percent sulfuric acid for 5 hours. Then, the mixture is poured onto ice, adjusted with concentrated ammonia under ice cooling to a p _H value of 3 to 4 and filtered off with suction the precipitated carboxylic acid. To clean it, it is dissolved warm in dilute, excess sodium bicarbonate solution, the solution is filtered with charcoal and the acid is precipitated again with 2N hydrochloric acid. 15.1 g of crude 6-isobutyl-3-carboxy-2- (5'-chloro-2'-methyl-phenylmercapto) -pyridine are obtained in this way. The pure product, recrystallized several times from dilute alcohol, melts at 157 to 158 ° C.

14 g of this carboxylic acid are mixed with 300 g of polyphosphoric acid Heated to 140 to 150 ° C for 5 hours. Then the mixture is poured onto ice and that Reaction product extracted with methylene chloride. The methylene chloride solution is diluted with soda solution and washed with water and leaves on evaporation of the l-Aza ^ -isobutyl-o-chloro ^ -methylthioxanthone as a brownish oil, which slowly crystallizes. Yield: 13.25 g. The product will processed further without further purification.

CH ₃ is then distilled off in vacuo, the residue is dissolved in 50 cm ³ lOprozentiger acetic acid, the solution is filtered with charcoal and then made with 2 N sodium hydroxide to a _pH value of eighth The precipitated base is taken up in ether, the ether solution is washed with water, dried and evaporated. The l-aza-2,9-dimethyl-6-dimethylaminopropylamino-thioxanthone of the formula obtained in this way

NH-CH ₂ -CH ₂ -CH ₂ -N (CH ₃ ) S

CH,

melts, recrystallized from acetone, at 95 to 96 ° C. The hydrochloride obtained in the usual way melts at 226 to 228 ° C. Yield: 7.3 g.

Example 4

6.88 g of l-aza-2,9-dimethyl-6-chlorothioxanthone are refluxed with 50 cm ^{s of} morpholino-ethylamine for 12 hours. After the excess base has been ^{distilled off, the residue is dissolved warm in 200 cm 3 of} 10 percent acetic acid, the solution is filtered with charcoal and, after cooling, the base is precipitated in crystalline form by dropping dilute sodium hydroxide solution while cooling with ice and stirring. The precipitate is filtered off with suction, washed neutral with water and dried in vacuo. The 1-aza-2,9 - dimethyl - 6 - morpholino - ethylamino - thioxanthone of the formula

O NH-CH ₂ -CH ₂ -N <

Example 3

6.88 g of l-aza ^^ - dimethyl-o-chloro-thioxanthone are melted with 50 cm ^{3 of} dimethylaminopropylamine for 11 hours and refluxed. The excess of diamine 70 136.5 ° C.

CH ₃

Recrystallized acetone, at 135.5 to

The hydrochloride prepared in the usual way crystallizes from water - acetone in yellow, matted Needles from 280 to 282 ° C. Yield: 6 g.

Example5

1.28 g of 1 - aza - 2,9 - dimethyl - 6 - aminothioxanthone are heated with 1 cm ^{3 of} chloroethyl diethylamine in an oil bath at 140 to 150 ° C. for 1 hour. The mixture is then dissolved in dilute hydrochloric acid, the yellow-red solution, after filtration through charcoal, is made basic with ammonia and the precipitate is filtered off with suction. The residue on the suction filter is ^{treated with 80 cm 3 of} 5% strength acetic acid and the orange-yellow solution is freed from insoluble constituents by filtration over diatomaceous earth. The filtrate is made basic with dilute ammonia, the precipitating base is taken up in ether, the ether solution is washed several times with water, dried with sodium sulfate and the ether is distilled off. There remain 1.2 g of an orange-yellow oil, which crystallizes from acetone petroleum ether in yellow, matted needles with a melting point of 83 to 84 ° C. The l-aza-2,9-dimethyl-6-diethylaminoethylamino-thioxanthone thus obtained gives no depression in the mixed sample with the 1-aza-2,9-dimethyl-6-diethylaminoethylamino-thioxanthone described in Example 1.

The 1-aza-2,9-dimethyl-6-aminothioxanthone used as the starting material can be made in the following ways:

2.75 g of l-aza ^^ - dimethyl-o-chlorothioxanthone are heated with 150 cm ^{3 of} aqueous ammonia (27%) and 0.3 g of copper powder in the tube at 150 to 160 ° C. for 6 hours. The solid fractions are filtered off with suction, washed with water and then treated with concentrated hydrochloric acid. Almost everything goes into solution; a small amount of insoluble material is filtered off on a glass funnel. The filtrate is made basic with concentrated ammonia with the addition of ice, the precipitated yellow base, 1-aza-2,9-dimethyl-6-aminothioxanthone, filtered off with suction, washed neutral with water and dried in vacuo. It is then recrystallized from alcohol. Yield 1.5 g; F. 173 to 174 ° C.

B e i s ρ i e 1 6

2.75 g of l-aza ^^ - dimethyl-o-chloro-thioxanthone are refluxed for ^{15 hours with 30 cm 3 of} ethanolamine with the addition of 0.5 g of copper powder. After cooling, the crystal slurry is diluted with V2 1 water and the reaction product, 1 - aza-2,9 - dimethyl - 6 - oxyäthylamino-thioxyanthone, filtered off with suction, washed neutral with water and dried. It is obtained from a lot of alcohol in yellow, shiny needles with a temperature of 216 ° C. Yield 2.8g.

2.8 g of l-aza ^^ - dimethyl-o-oxyäthylamino-thioxanthone are heated with 25 cm ^{3 of} phosphorus oxychloride on a water bath at 90 to 100 ° C. for 2 hours. The excess phosphorus oxychloride is then distilled off in vacuo, the residue is dissolved in concentrated hydrochloric acid, the solution is filtered with charcoal and the chlorination product is precipitated from the filtrate with the addition of ice with concentrated ammonia. The precipitate is filtered off with suction, washed with water, ^{briefly boiled with 300 cm 3 of} ethanol and the alcoholic solution is filtered off to remove little insolubles. The alcoholic solution is then ^{mixed with 25 cm 3 of} diethylamine and heated to 125 ° C. in the tube for 12 hours. The yellow-brown solution is evaporated, the residue is ^{heated with 100 cm 3 of} 10% acetic acid, the solution is filtered with charcoal and made basic with ammonia. The precipitate is filtered off with suction, dissolved again in 5% acetic acid for purification, the solution filtered with charcoal is made basic with sodium hydroxide solution and the product which precipitates out is extracted with ether. Upon evaporation, the ether solution leaves behind the - aza - 2,9 - dimethyl - 6-diethylaminoethylamino thioxanthone described in Example 1 as a yellow oil which crystallizes from ether petroleum ether in yellow needles.

Claims (6)

Patent claims: 1. Process for the preparation of l-aza-6-tertiary - amino - low molecular weight alkylamino-9-methyl thioxanthones, characterized in that 1 - aza -2 -lower molecular alkyl-9-methyl-thioxanthones, which contain a reactive esterified oxy group or an amino group in the 6-position, in a manner known per se with a low molecular weight alkylamine or a reactive one Reacts ester of a low molecular weight alkanol, the low molecular weight alkyl radical of the alkylamine or the alkanol in each case still has a tertiary amino group or one which can be converted into it Contains remainder, and in compounds obtained with one in a tertiary amino group The remainder which can be converted is converted into such a remainder by processes known per se and, if appropriate converts obtained salts into the free bases or free bases into their salts. 2. The method according to claim 1, characterized in that that one l-aza-2-low molecular alkyl-9-methyl-thioxanthones, which contains a reactive esterified oxy group in the 6-position, reacts with low molecular weight oxyalkylamines which free oxy group reactively esterified and the compounds thus obtained with secondary Can react amines. 3. The method according to claim 1, characterized in that diethylaminoethylamine or a reactive esters of diethylaminoethanol can be used as starting compounds. 4. The method according to claim 1, characterized in that l-aza-2,9-dimethyl-thioxanthone, the contains a reactive esterified oxy group or an amino group in the 6-position, and diethylaminoethylamine or a reactive ester of diethylaminoethanol as starting compounds be used. 5. The method according to claim 2, characterized in that the oxyalkylamine and ethanolamine diethylamine can be used as the secondary amine. 6. The method according to claim 2, characterized in that l-aza-2,9-dimethyl-thioxanthone, the in the 6-position contains a reactive esterified oxy group, as a starting compound, as an oxyalkylamine Ethanolamine and, as the secondary amine, diethylamine can be used. Considered publications:
British Patent No. 700124. ® 809 599/550 4.