DE1037459B - Process for the preparation of 1-aza-6 - [(tertiary-amino) -alkylamino] -thioxanthones - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of a low molecular weight in the 6-position 1-Aza-2,4,9-trimethyl-thioxanthones containing (tertiary-amino) -alkylamino groups as well as their salts. Under a low molecular weight (tertiary amino) alkylamino group is to be understood in particular as one whose alkylene radical contains at most 3 carbon atoms and in the tertiary amino group of which the nitrogen atom is attached to two aliphatic radicals each with a maximum of 4 carbon atoms, in particular to corresponding alkyl groups. Furthermore, the tertiary amino group for example also be a morpholino, piperidino or pyrrolidino group.

The new compounds can also contain other substituents. First and foremost concerns the present invention is the preparation of 1-aza-2,4,9 - trimethyl - 6 - diethylaminoethylamino - thioxanthone and its salts.

The compounds according to the invention are pronounced in relation to schistosomes and amoebas Effect on and can be used as a remedy for human schistosomiasis and amoebiasis. she have compared to the l-aza-6-diethylaminoethylamino-9-methyl-thioxanthone known from British patent specification 700124 particularly valuable properties. The following comparative tests with 1-aza-2,4,9 resulted - trimethyl - 6 - diethylaminoethylamino - thioxanthone and the above-mentioned known l-aza-6-diethylaminoethylamino-9-methyIthioxanthone with cercariae of Schistosoma mansoni subeutan by injection of for every 100 living larvae infected white mice, l-aza-2,4,9-trimethyl-6-diethylaminoethylamino-thioxanthone was twice as effective.

A. Test method

White mice are infected subeutanely with about 100 Schistosoma mansoni cercariae. During from 6 to 8 weeks, the larvae mature on their migration through different parts of the body and settle in the mesenteric veins of the animals towards the end of the specified period. Here they produce Eggs that are deposited in large quantities in the liver and also appear in the feces. This is where they become microscopic verifiable. Your vitality is checked in the miracid hatch test, i. H. in a slip test of eggs. At the end of the experiment (8th to 10th week) the mice are dissected to detect worms and eggs. The preparations to be tested are given to the animals during the 1st week post infection, beginning with 2 hours administered orally before infection.

B. Results

The new compounds are obtained if 1 -Aza ^^^ - trimethyl-thioxanthones, which are in the 6-position Method of manufacture

of 1 - aza-6- [(tertiary -amino) -alkylamino] -

thioxanthones

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

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

Claimed priority:
Switzerland from December 23, 1955

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

(Switzerland),
have been named as inventors

25th preparation l-aza-2,4,9-tri-
methyl-6-di-
ethylamino
ethylamino
thioxanthone l-aza-6-diethyl-
amino-ethyl
amino-9-methyl-
thioxanthone 30th Minimal effective Dose for 100% worm freedom in mg / kg SO 100 Toxicity LD ₅₀ 6 times application > 500 > 500 OD orally in mg / kg 1000 <1000 Therapeutic index <0.1 <0.2 approximate > 0.05 > 0, l judgement 40 the effect very good Well

contain a reactive esterified oxy group or an amino group, with a low molecular weight Alkylamine or a reactive ester of a low molecular weight alkanol in a manner known per se converts, wherein the low molecular weight alkyl radical of the alkylamine or of the alkanol in each case still contains a tertiary amino group or a radical which can be converted into it and in compounds obtained with a radical which can be converted into a tertiary amino group, this after per se known processes converted into such and optionally obtained salts into the free bases or free Converts bases into their salts. So you can l-azo-2,4,9-trimethyl-thioxanthones, those in the 6-position are a chlorine atom

809 599/551

have, with low molecular weight (tertiary-amino) -alkylamines, such as diethylaminoethylamine, implement. On the other hand, such l-aza ^ AQ-trimethyl-thioxanthones, which have an amino group in the 6-position, with a tertiary-amino-low molecular alkyl halide, such as Diethylaminoethyl chloride, implement. In the gradual transfer, z. B. the tertiary amino group be replaced in these reactions by an oxy group, which is then subsequently esterified in a reactive manner, e.g. B. with hydrochloric acid, and then exchanged for a low molecular weight tertiary amino group, z. B. by reaction with the corresponding secondary amine.

The reactions are 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, in the open or carried out under pressure in a closed vessel.

Depending on the procedure, the new compounds are obtained in the form of their bases or salts. From the salts the free amine bases can be obtained in a manner known per se. The latter, in turn, can be obtain salts through reaction with acids that are suitable for the formation of therapeutically useful salts, z. B. of hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic acid, Propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, Oxyethanesulfonic acid, benzene or toluenesulfonic acid or therapeutically active acids.

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

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

example 1

9 g of l-aza ^^^ - trimethyl-o-chloro-thioxanthone are refluxed in 40 cm ^{3 of} NN diethylethylenediamine for 5 hours at 160X. The excess diamine is distilled off in vacuo, the residue is dissolved in 200 cm ³ 10% acetic acid, the solution is filtered through diatomaceous earth and the filtrate is made basic with ammonia.

The base which precipitates is taken up in methylene chloride and the base is isolated after washing with water. The l-aza-2,4,9-trimethyl-6-diethylaminoethylamino-thioxanthone crystallizes from alcohol the formula

CH.

NH-CH ₂ -CH ₂

-N (C ₂ H ₅ ),

CH ₃

in golden yellow, fine flakes, mp = 118 to 118.5 ⁰ C. The hydrochloride produced in the usual else W ^T forms orange yellow prisms, mp = 228-229 ⁰ C.

The 1-aza-2,4,9-trimethyl-6-chloro-thioxanthone used as the starting material can be made in the following ways:

33 g of 2-chloro-3-cyano-4,6-dimethyl-pyridine are mixed with the anhydrous sodium compound from 31.7 g of 2-methyl-5-chloro-thiophenol in 150 cm ^{3 of} absolute dioxane with stirring in a nitrogen atmosphere for 10 hours refluxed. Then the table salt is suctioned off over diatomaceous earth and the filtrate is evaporated

ίο and the residue taken up in methylene chloride. The methylene chloride solution is washed with dilute sodium hydroxide solution and water, dried and evaporated and the residue is recrystallized from methanol. The 4,6 - dimethyl - 3 - cyano -2 - (5 '- chloro-2' -methyl - phenylmercapto) pyridine melts g at 101-102 ⁰ C. Yield 48th 28.35 g of the nitrite are in 250 cm ³ 80 ° / _? sulfuric acid with stirring for 6 hours at 140 heated to 15O ⁰ C. It is then cooled to 0 to 1O ⁰ C is added dropwise a concentrated, aqueous solution of 10 g of sodium nitrite while stirring below the liquid surface. Then the ice-cooling is removed and warmed to reach room temperature in 1 hour to 50 to 6O ⁰ C. At this temperature, stirring is continued for about 2 hours until the evolution of gas has ended. The mixture is then poured onto ice, adjusted to a ρπ value of 4 with concentrated ammonia and the carboxylic acid which precipitates out as a yellowish plastic mass is filtered off. It is dissolved in dilute soda solution while warming, the solution is filtered off from some insoluble by-product and reprecipitated with acetic acid.

The 4,6-dimethyl-3-carboxy-2- (5'-chloro-2'-methyl-phenylmercapto) pyridine melts, recrystallized from dilute alcohol, at 155-156 ⁰ C. Yield 22.45 g.

22 g of this carboxylic acid are heated in 400 g of polyphosphoric acid for 6 hours to 160 to 17O ⁰ C. The melt is poured onto ice, made basic with concentrated ammonia while cooling, and the precipitated reaction product is taken up in methylene chloride. The l-aza-2,4,9-trimethyl-6-chlorothioxanthone is recrystallized from dioxane / alcohol and forms yellow flakes with a melting point of 162 to 163 ° C. Yield 18.3 g.

Example 2

5 g of l-aza-2,4,9-trimethyl-6-chlorothioxanthone are refluxed with 30 cm ^{3 of} N, N-diethyl-propylenediamine- (l, 3) for 5 hours. After distilling off the excess diamine in vacuo, the residue is treated with 200 cm ³ 10 ° / ₀ acetic acid is heated, the solution of some insoluble by-product suction filtered through diatomaceous earth and made the orange yellow filtrate with 2N sodium hydroxide solution alkaline. The precipitating base is taken up in ether, the ether solution is washed with water, dried with sodium sulfate and evaporated.

The remaining brown-red oil (5.6 g) slowly crystallizes through and is recrystallized from ether / petroleum ether; Yield 4.5g. The l-aza-2,4,9-tri-methyl-6-diethylaminopropylamino-thioxanthone thus obtained the formula

CH, ^w NH-CH ₉ -CH ₉ -CH ₉ -N '.

CoHe

CH _S

* N '

CH,

melting at 62-63 ⁰ C. The hydrochloride obtained in the usual manner melts at 235 ° to 236 ° C.

Example 3

5 g l-aza ^ AQ-trimethyl-o-chloro-thioxanthone with 10 cm ³ of N - (/ - aminoethyl?) -Morpholine heated for 6 hours in an oil bath to 18O ⁰ C. The mixture is ^{dissolved warm in 30 cm 3 of} glacial acetic acid and the solution is ^{diluted with 270 cm 3 of} hot water while shaking. Undissolved by-product is then filtered off with suction over diatomaceous earth and the clear, yellow-red filtrate is made weakly alkaline drop by drop with 2η sodium hydroxide solution while stirring and cooling with ice. The base which precipitates in crystalline form is filtered off with suction, washed with water and, after drying, recrystallized from alcohol in vacuo. The thus obtained l-aza ^^^ - trimethyl-o-morpholinoäthylamino-thioxanthone of the formula

refluxed. After working up as in Example 3, the solution from the acetic acid is diluted with Sodium hydroxide solution, base precipitated in crystalline form (3.1 g) was recrystallized from alcohol. The 1-aza-2,4,9-trimethyl-6-dimethylaminoethylamino-thioxanthone thus obtained the formula

CH.

NH-CH ₉ -CH ₀ -N

, CH ₅

"CH,

CH.

NH-GH «—CHp-N '

CH,

CH, -.,

CH ₃

forms fine, yellow needles with a F. = 133 to 135 ^° C. Yield 5.5 g. The hydrochloride obtained in the usual way crystallized from alcohol / ether in yellow needles, mp = 258 to 26O ⁰ C.

Example 4

5 g of l-aza ^^^ - trimethyl-o-chloro-thioxanthone are mixed with 25 cm ^{3 of} N, N-dimethyl-ethylenediamine for 6 hours

forms brown-yellow leaflets from F. = 136 to 137 ⁰ C.

Example 5
20th

9.65 g of l-aza ^^^ - trimethyl-ö-chloro-thioxanthone be with 11g N ~ butyl-N - (- oxyäthyl /?) -Ethylenediamine and a trace of copper powder heated for 18 hours 160 to 170 ⁰ C. After working up as in Example 3, the base precipitated from the dilute acetic acid solution with sodium hydroxide solution is taken up in ether, the ethereal solution is washed with water, dried and evaporated. The residue (6.3 g of crystalline base) is recrystallized from ether / petroleum ether. The l-aza-2,4,9-trimethyl-6 - [(N - /? - oxyethyl-N-butyl-amino) -äthylamino) - thioxanthone of the formula obtained in this way

CH ₃ V NH-CH ₉ -CHo-N. , C ₄ H ₉

C H "- CHoOH

CH,

"N S

CH,

forms fine, yellow needles from F. = 109 to HO ⁰ C. The hydrochloride melts, recrystallized from alcohol / ether, at 137 ⁰ C; it contains 1 mole of crystal water.

Example 6

2 g of l-aza-2,4,9-trimethyl-6- (ß-oxyäthylamino) thioxanthone are heated with 25 cm ^{3 of} phosphorus oxychloride for 2 hours on a boiling water bath. The excess phosphorus oxychloride is then distilled off in vacuo, the residue is dissolved in hot 5 η hydrochloric acid, the solution is filtered through diatomaceous earth and then made basic with concentrated aqueous ammonia with the addition of ice. The precipitated crude l-aza-2,4,9-trimethyl-6 - (/ 3-chloräthylamino) -thioxanthon is heated in the steel tube with 200 cm ³ 17% alcoholic dimethylamine 15 hours at 90 to 10O ⁰ C. It is then evaporated to dryness, the residue is dissolved in 15 cm ^{3 of} hot glacial acetic acid, ^{diluted with 150 cm 3 of} water and the flocculated impurity is filtered off over diatomaceous earth. The l-aza-2,4,9-trimethyl-6-dimethylaminoethylamino-thioxanthone is precipitated from the filtrate with 2N sodium hydroxide solution. Washed with water and dried in vacuo give 1.7 g of crystalline 1-aza-2,4,9-tri-methyl-6-dimethylaminoethylamino-thioxanthone. Recrystallized from methanol, it melts at 135 to 137 ° C. and does not result in any depression with the product described in Example 4.

The 1-aza-2,4,9-trimethyl-6 - (/ I-oxyäthylamino) -thioxanthone used as starting material can be obtained by boiling 5 g of 1-aza-2,4,9-trimethyl-6-chlorothioxanthone for 20 hours can be obtained with 60 cm ^{3 of} ethanolamine with the addition of 1 g of copper powder. The reaction mixture is ^{diluted with 500 cm 3 of} water, the precipitated product is filtered off with suction, washed with water and recrystallized from a large amount of alcohol. This gives 4 g of 1-aza-2,4,9-trimethyl-6 - (/? - oxyäthylamino) thioxanthone as fine, golden yellow, shiny needles with a temperature of 193 to 195 ° C.

55

Example 7

1 g l-aza ^^^ - trimethyl-o-amino-thioxanthone is heated for 1 hour at 140 to 15O ⁰ C and 1 cm ³ Chloräthyldiäthylamin. The solid reaction product is dissolved warm in 2N hydrochloric acid, the solution is filtered with charcoal and made alkaline with 2N sodium hydroxide solution. The precipitated base is filtered off with suction, washed with water, dissolved in 100 cm ^{3 of} 10% acetic acid for further purification, the solution is filtered clear through diatomaceous earth and the base is then precipitated in crystalline form by adding 2N sodium hydroxide solution dropwise while stirring and cooling with ice. Yield 0.6g. Recrystallized from isopropanol, the thus obtained l-aza-2,4,9-trimethyl-6-diäthylaminoäthylamino-thioxanthone melts at 116 to 118 ⁰ C and is with the method described in Example 1, product no depression.

The l-aza-2,4,9-trimethyl-6-amino-thioxanthone used as the starting material can be heated to 150 to 150% by heating l-aza ^^^ - trimethyl-o-chloro-thioxanthone with concentrated aqueous ammonia in a steel pipe for 6 hours 160 ° C can be obtained with the addition of a small amount of copper powder. The l-aza-2,4,9 trimethyl-6-amino-thioxanthone crystallized from alcohol in lustrous golden yellow leaflets, mp = 189-191 ⁰ C.

Example 8

5 g l-aza ^. ^ - trimethyl-o-chloro-thioxanthone are mixed with 10 g Ν, Ν-di-n-butyl-ethylenediamine IO hours at 160 to 17O ⁰ C heated. The mixture is then ^{heated on a water bath with 100 cm 3} of 2N hydrochloric acid, insoluble

Sucked off IO lichem and made the yellow-red, acidic filtrate alkaline with potassium carbonate. The base, which precipitates out as a brownish-red, viscous oil, is filtered off with suction, taken up in ether, the ethereal solution is washed several times with water, dried and evaporated. The brown-red oil that remains crystallizes in yellow needles with a temperature of 60 to 63 ° C when acetone is added. The base is dissolved in acetone, the calculated amount of 1N hydrochloric acid is added and the deep red solution is completely evaporated to dryness. The residue is dissolved in absolute, hot alcohol, the solution is strongly concentrated and then absolute ether is added until crystallization begins. The hydrochloride of l-aza-2,4,9-trimethyl-6-dibutylaminoethylamino-thioxanthone of the formula

(CH ₂ ) ₃ - CH ₃

CH, Y NH-CH ₂ -CH ₂ -Ν;

CH

• HC1

CH,

crystallizes in orange-yellow prisms with a mp = 211 to 213 ° C. Yield 4.8 g.

Example 9

5 g l-aza ^^^ - trimethyl-o-chloro-thioxanthone be with 13 g of 2-amino-l- [N-ethyl-N- (2'-oxyäthyl) -amino] -propane 15 hours at 160 ⁰ C. heated. The reaction mixture is worked up as in Example 8. The base, which is obtained directly in crystalline form from the ethereal solution, is recrystallized from acetone. The golden yellow 1-aza-2,4,9-trimethyl-6 - [_ l '- (N-ethyl-N-2 "-oxyethyl-amino) -propyl- (2') -amino] -thioxanthone of the formula

CH,

40

45

CH ₃

melts at 103 to 105 ⁰ C.

That in the usual way

melts at 198 to 199 ⁰ C.

produced hydrochloride

Claims (6)

Patent claims: 1. A process for the preparation of l-aza-6 - [(tertiary amino) alkylamino] thioxanthones, characterized in that one l-aza ^^^ - trimethyl-thioxanthones, which or a reactive esterified oxy group in the 6-position Contain an amino group, is reacted with a low molecular weight alkylamine or a reactive ester of a low molecular weight alkanol in a manner known per se, the low molecular weight alkyl radical of the alkylamine or of the alkanol in each case also containing a tertiary amino group or (CH ₂ J ₃ -CH ₃ contains a radical which can be converted into it 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 ^^^ - trimethyl-thioxanthones, which contain a reactive esterified oxy group in the 6-position, with low molecular weight Reacts oxyalkylamines, reactive esterifying the free oxy group and the compounds thus obtained can react with low molecular weight secondary amines. 3. \ ^r learn according to claim 1, characterized in that the starting materials used are those alkylamines or alkanols whose alkylene radical contains at most 3 carbon atoms and in whose tertiary amino group the nitrogen atom is bonded to two aliphatic radicals each having at most 4 carbon atoms. 4. The method according to claim 2, characterized in that such oxyalkylamines, their alkylene radical Contains at most 3 carbon atoms, and those secondary amines in which the nitrogen atom is attached two aliphatic radicals each with a maximum of 4 carbon atoms is bound to be used as starting compounds. 5. The method according to claim 1, characterized in that diethylaminoethylamine or a reactive Diethylaminoethanol esters can be used as starting compounds. 6. The method according to claim 2, characterized in that the oxyalkylamine and ethanolamine secondary amine diethylamine is used. Considered publications:
British Patent No. 700 124. © "09 599/551 8.5"