DE1199278B - Process for the preparation of homo-thioxanthene derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

Number:
File number:
Registration date:
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C07d

German class: 12q-26

1199 278
S75124IVb / 12q
August 1, 1961
August 26, 1965

The invention relates to a process for the preparation of homothioxanthene derivatives of the general formula

Process for the preparation of homothioxanthene derivatives

H — C — C — C — N

I i!

Ri R2 R ₃

R ₅ R ₄

in which Ri, R2 and R3 are hydrogen atoms or lower Denote alkyl groups, R4 and R5 each represent a methyl group or R5 a methyl group and R4 together with Ri or R2 the dimethylene radical or with R3 represent the trimethylene or the tetramethylene radical or their acid addition salts.

It has been found that the homothioxanthene derivatives of the general formula given above are characterized by a histamine-inhibiting effect. In addition, narcosis-potentiating, adrenolytic, antipyretic and hypothermic effects have been noted. The process products should to be used as a remedy.

For comparison tests, the U- (γ-dimethylaminopropylidene-homothioxanthene (compound I) (Examples 3 and 7) and the II- [l'-methylpiperidylidene- (4 ^/ )] - homothioxanthene (compound II) (Example 1) were compared to the one from the German Auslegeschrift 1 044 103 known 9- (γ-dimethylaminopropylidene) -thioxanthene (compound III) tested with regard to the histamine-inhibiting effect.

The experiments were carried out in such a way that guinea pigs 3 hours after subcutaneous Pretreatment with the substance to be examined (antihistamine) exposed to a histamine spray will. The histamine-inhibiting effect of the tested substance is numerically represented by the EDse (in mg / kg, see α), d. H. that dose, through the 50% of the animals are protected expressed.

Toxicity: The mean lethal dose DL50 was determined, i.e. H. the dose at which 50% of the Animals (mouse) perish after oral administration of the preparations. The results are in the Table I below compiled.

Applicant:

Sandoz A. G., Basel (Switzerland)

Representative:

Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Ernst Jucker, Ettingen;

Dr. Adolf J. Lindenmann, Basel;

Dr. Fulvio Gadient, Birsfelden (Switzerland)

Claimed priority:
Switzerland of August 26, 1960 (9684),
of October 25, 1960 (11 895),
dated June 1, 1961 (6432) link Inhibition of histamine asthma
ED ₅₀ mg / kg, sc toxicity
DL ₅ U mg / kg,
oral (mouse) 2
Table I. I.
II
III 0.46
0.30
0.85 600
410
320

The values found show that to achieve an equally strong inhibition of histamine asthma from process product I an approximately 1.85 times smaller dose and from process product II even a dose that is 2.83 times smaller than that of comparative preparation III is required, i.e. i.e., the substances I and II are about 1.85 and 2.83 times more histamine-inhibiting than III.

The two process products I and II are also less toxic than the comparative preparation. I is about 1.9 times and II about 1.3 times more tolerable than the comparison substance.

509 658/477

In addition, the histamine-inhibiting effect was determined on the isolated guinea pig small intestine. The well-known antihistamine was used as the reference substance for the histam-inhibiting effect, 1-methyl-4-amino-N'-phenyI-N '- (2'-thenyI) -piperidine (thenalidine).

The results obtained are shown in Table II.

Table II

common formula

Hai-Mg-CH-CH-CH-N-R ₅

R ₁ R ₂ R ₃ R4

in the Ri to R5 have the above meaning and Hai means a chlorine, bromine or iodine atom, converts the reaction products to homothioxanthenol derivatives the general formula

-S-CH ₂

R. > (Example 5) 0 Histamine-
inhibition
Thenalidine
= 100 toxicity
DL50 mg / kg,
oral (mouse) CH - CH ₂ CH ₂ - N (CH ₃ ) ₂
(Examples 3 and 7) r-CH ₃ CH - CH ₂ - 200 to 300 600 / ^ N-CH ₃ I.
CH ₃
(Example 6) 200 410 (Example 1) Thenalidine PTT 200 900 400 500 100 290

45

50

The values in this table show that the tested process products at an approximately 1.4 to 3.1 times lower toxicity have a significantly stronger histamine-inhibiting effect than the reference substance.

The homothioxanthene derivatives of the general formula given above are prepared by that one homothioxanthone of the formula

-S-CH ₂

R ₅

HC

Ri Ra R3

with an organomagnesium compound that hydrolyses, this optionally separates into the stereoisomeric forms, then with dehydrating Treated agents and the compounds obtained optionally in their acid addition salts convicted.

The method is carried out, for example, that a Grignard solution, which consists of a copper-magnesium alloy or from magnesium turnings in an anhydrous open-chain or cyclic ether, such as diethyl ether or tetrahydrofuran, under Add a few drops of methyl iodide, ethyl bromide or ethylene bromide and a trace of iodine Addition of a solution of a corresponding basic substituted alkyl halide has been prepared is, mixed with homothioxanthone, the mixture to complete the reaction a few more Time at 0 to 50 ° C, then the reaction mixture in the cold with aqueous ammonium chloride solution hydrolyzed, the mixture with a water-immiscible organic solvent extracted and this removed after drying the extract. This as an intermediate product Homothioxanthenol derivative obtained is either directly or optionally after purification further processed by crystallization.

The elimination of water is achieved, for example, by heating the homothioxanthenol dissolved in glacial acetic acid made with concentrated hydrochloric acid. Phosphorus oxychloride and thionyl chloride are also suitable for this purpose or zinc chloride. The process product is isolated in the form of the free base, or it can optionally can also be obtained as acid addition salts.

Such salts are e.g. B. those with inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid, or with organic acids such as acetic acid, malic acid, oxalic acid, fumaric acid, Maleic acid, tartaric acid, naphthalene-1,5-disulfonic acid.

The homothioxanthone to be used as the starting material can be obtained by cyclization of S-benzylthiosalicylic acid chloride or 2- (phenylmercaptomethyl) benzoyl chloride by means of aluminum chloride or from 2- (phenylmercaptomethyl) benzoic acid using concentrated sulfuric acid or Polyphosphoric acid or boron trifluoride ethyl etherate getting produced. The production of the starting materials is not part of the subject matter of the invention.

The following examples illustrate the invention. Melting and boiling points are uncorrected here.

example 1

11- [1'-methyl-piperidylidene- (4 ')] -homothioxanthene

a) A Grignard solution which has been prepared by adding 4.2 g of iodine-activated copper-magnesium alloy (according to G i 1 m a n) covered with a little tetrahydrofuran, then with 0.5 ecm Ethylene bromide is added, followed by a solution of 20.1 g of 1-methyl-4-chloropiperidine when the reaction starts in 20 ecm of tetrahydrofuran can be added dropwise to the extent that the solvent boils, and then the reaction mixture is heated to boiling for a further 2 hours and is added dropwise a solution of 13.5 g of homothioxanthone in 50 ecm '5 Tetrahydrofuran is added and the mixture is heated to boiling for 2 hours. Then the obtained reaction mixture is cooled, poured into a solution of 45 g of ammonium chloride and 300 ecm of water, the whole thing diluted with 300 ecm of ether and filtered through highly purified diatomaceous earth. The ether phase then becomes separated, the aqueous part shaken twice with 200 ecm of ether each time, the combined ethereal solutions are washed with water, then dried over magnesium sulfate, and then is removed the solvent. The semi-crystalline residue obtained is recrystallized from acetone. There are 12.2 g of pure II- [l'-methyl-piperidyl- (4 ')] - II-hydroxy-homothioxanthene obtained from m.p. 184 to 187 ° C.

A solution of 5.0 g of the 11- [I'-methyl-piperidyl- (4 ') I-11-hydroxy-homothioxanthens obtained in 50 ml of glacial acetic acid is heated to boiling with 20 ml of concentrated hydrochloric acid for 1 hour. Then the solvent is removed under a pressure of 15 mm, the residue is made alkaline with 20% sodium hydroxide solution and extracted three times with 100 ecm of ether each time. The ether extract is washed with water, dried over magnesium sulfate, then the ether solution is concentrated to about 50 ecm and saturated with hydrogen bromide. The ether is then distilled off and the remaining oil is taken up in ethanol, the ll- [l'-methylpiperidylidene - (4 ')] - homothioxanthene - hydrobromide precipitating in crystalline form in the cold. After recrystallization from ethanol, the compound melts at 265 to 27O ⁰ C with decomposition. The yield is 4.0 g.

b) The homothioxanthone used as the starting substance was produced as follows:

To 32, 85 ° Og / cent phosphoric acid are added under vigorous stirring at 80 to 100 ⁰ C 46.5 g of phosphorus pentoxide. Within 5 minutes, is added to the resulting polyphosphoric acid in portions with 15.0 g of 2- (Phenylmereaptomethyl) benzoic acid and the mixture is stirred for 30 minutes at 100 ⁰ C. Then the reaction mixture is poured still hot with stirring to 250 g of ice and 200 ecm benzene diluted. After filtration through highly purified diatomaceous earth, the benzene solution is separated off and the aqueous phase is extracted with 100 ecm benzene. The combined benzene extracts are extracted twice with 50 ecm 2 η sodium hydroxide solution, washed neutral with water and dried over magnesium sulfate. After removing the solvent in vacuo, the crystalline residue is dissolved in boiling ethanol, cleaned with animal charcoal and the solution cooled. After crystallization from ethanol, the compound melts at 84 to 86 ^° C. The yield is 23.4 g.

Example 2

1H / Hr-methyl-piperidyl- (2 ') - ethylidene]} - homothioxanthene

A Grignard solution which has been prepared by overlaying 8.4 g of iodine-activated copper-magnesium alloy (according to G i 1) with a little tetrahydrofuran, then adding 0.5 ecm of ethylene bromide, then adding a solution of when the reaction starts 48.8 g of 1- [1'-methylpiperidyl- (2 ')] - 2-chloroethane in 50 ecm of tetrahydrofuran can be added dropwise in such a way that the solvent boils, and then the reaction mixture is heated to boiling for a further 2 hours, is added dropwise a solution of 27 g of horrothioxanthone in 90 ecm of tetrahydrofuran is added and the mixture is heated to boiling for 2 hours. The reaction mixture obtained is then cooled, poured into a solution of 90 g of ammonium chloride and 600 ecm of water, the whole thing is diluted with 500 ecm of ether and filtered through highly purified diatomaceous earth. Thereafter, the ether phase is separated, the aqueous portion extracted twice with 300 cc of ether and the combined ether solutions we ^r the washed with water, then dried over magnesium sulfate, and then the solvent is removed. The oily residue obtained is treated with 50 cc of acetone, the 1 l - {, tf [r-methylpiperidyl (2 ') - begins äthyip _r -11 -hydroxy-homothioxanthen crystallize. After recrystallization from acetone, the pure compound melts at 175 to 180 ^° C. The yield is 10 g.

A solution of 10.0 g of the 1 H ^ - [I '-Methyl - piperidyl - (2') - ethyl]} -11 - hydroxy - homothioxanthens obtained in 100 ecm of glacial acetic acid is heated to boiling with 40 ecm of concentrated hydrochloric acid for 1 hour . The solvent is then removed under a pressure of 15 mm, the residue is made alkaline with 2Q ° / c. Sodium hydroxide solution and extracted three times with 200 ecm of ether each time. The ether extract is washed with water, dried over magnesium sulfate, then the ether solution is concentrated to about 75 ecm and saturated with hydrogen bromide. The ether is then distilled off and the remaining oil is taken up in acetone, the II- {ß- [V- methyl - piperidyl - (2 ') - ethylidene]} - homothioxanthene hydrobromide precipitating in crystalline form in the cold. After recrystallization from acetone, the compound melts at 210 to 217 ° C. (with decomposition). The yield is 7.0 g.

Example 3
II- (γ-dimethylaminopropylidene) homothioxanthene

A Grignard solution made by adding 7.1 g of iodine-activated copper-magnesium alloy (according to G i 1 m a n) covered with a little tetrahydrofuran, then with 0.5 ecm Ethylene bromide is added, then a solution of 29.6 g of 3-dimethylamino-1-propyl chloride when the reaction starts in 30 ecm of tetrahydrofuran added dropwise in such a way that the solvent boils, and then the reaction mixture is heated to boiling for a further 2 hours, is added dropwise a solution of 20 g homothioxanthone in 60 ecm

Tetrahydrofuran is added and the mixture is heated to boiling for 2 hours.

The reaction mixture obtained is then cooled, poured into a solution of 75 g ammonium chloride and 500 ecm water, the whole thing is diluted with 700 ecm ether and filtered through highly purified diatomaceous earth, the ether phase is then separated off, the aqueous part is shaken out twice more with 200 ecm ether each time The combined ethereal solutions are washed with water, then dried over magnesium sulfate, and then the solvent is enueiTii. The oily residue obtained is mixed with 50 ecm of acetone, the II- (γ-dimethylaminopropyl) -11-hydroxy-homothioxanthene beginning to crystallize. The compound is turned over from acetone, it then melts at 130 to 132 ° C. The yield is 12.5 g.

A solution of 5.0 g of the II- (γ-dimethylaminopropyl) -i 1 -hydroxy-homothioxanthenes obtained in 50 ml of glacial acetic acid is heated to boiling with 20 ml of concentrated hydrochloric acid for 1 hour. Then the solvent is removed under a pressure of 15 mm, the residue is made alkaline with 20% sodium hydroxide solution and shaken three times with 100 ecm of ether each time. The ether extract is washed with water, dried over magnesium sulphate, then the ether solution is concentrated and the remaining oil is distilled at 170 "C under a pressure of 0.1 mm in an air bath, with 4.4 g of 1 l - (> - Dimethylaminopropylidenj-homothioxanthene oil This is converted with 1.27 g of oxalic acid into the oxalate, which, after recrystallization from methanol, ^{melts at 167 to 169 °} C. The yield is 5.12 g.

Example 4

11 - [I '-Methyl-pyrrolidyl- (3 "> methylene] -hoir.othioxanthene

A Grignard solution made by it. that 5.7 g of iodine-activated magnesium are covered with a little tetrahydrofuran, then 0.1 ecm of ethylene bromide is added, then a solution of 30.0 g of 1-methyl-pyrrolidyi- (3) -chloromethane in 30 ecm when the reaction starts Tetrahydrofuran is added dropwise in such a way that the solvent boils, and then the reaction mixture is heated to boiling for a further 2 hours, a solution of 29.9 g of homothioxanthone in 90 ecm of tetrahydrofuran is added dropwise at OC, and the mixture is then kept for 30 minutes at the same time Stirring temperature and then further treated according to the method described in Example 1, a). The ether extracts obtained are dried over magnesium sulfate, cleaned with animal charcoal, the solvent is removed and the residue obtained is distilled. Here, the ll- [l'-methylpyrrolidyl- (3 ') -methylj-11-hydroxy-homothioxanthene passes over in an air bath at 200 ° C. under a pressure of 0.15 mm. The yield is 22 g.

A solution of 7.0 g of the 11- [1'-methyl-pyrrolidyl- (3 ') -methyl] -11 obtained Hydroxy-homothioxanthens in 70 ecm glacial acetic acid is more concentrated with 21 ecm Hydrochloric acid is heated to boiling for 1 hour and the resulting mixture is then worked up analogously to Example 1, b). 4.75 g of crude 11- [1'-methylpyrrolidyl - (3 ') - methylene] - homothioxanthene (oil) obtained with 0.77 g of 98% fumaric acid in the neutral fumarate is transferred. After recrystallization from ethanol-acetone (1: 1) melts the neutral fumarate at 213 to 215 ° C.

Example5

1 l- {ß- [l ^/ -Methyl-pyrrolidyl- (2 ') -ethyIiden]} - homothioxanthene

A Grignard solution, which has been prepared by covering 4.2 g of iodine-activated magnesium with a little tetrahydrofuran, then adding 0.15 ecm of ethylene bromide, and then, when the reaction starts, a solution of 24.7 g of 1 - [I ' -Methyl-pyrrolidyl- (2 ')] -2-chloroethane in 25 ecm tetrahydrofuran can be added dropwise at such a rate that the solvent boils, and then the reaction mixture is heated to boiling for 45 minutes, is at 0 ⁰ C within 15 minutes a solution of 17.4 g of homothioxanthone in 45 ecm of tetrahydrofuran is added, the mixture is then stirred for 30 minutes at the same temperature and then treated further by the method described in Example 1, a). The combined ether extracts obtained are dried over magnesium sulfate, cleaned with animal charcoal, the solvent is removed and the oily residue obtained is treated with ethanol, one isomer of 1 H / I- [1'-methylpyrrolidyl- (2 ') - ethyl]} -11 -hydroxy-homothioxanthens begins to crystallize. After recrystallization from ethanol, the pure compound melts at 192 to 200 ^° C. The yield is 8.0 g.

The other isomer of 11 - {ß - [1 '- methyl - pyrrolidyl - (2') - ethyl]} - 11-hydroxy-homothioxanthene crystallizes from the mother liquor by adding a little pentane. After recrystallization from ethanol-pentane (2: 1), this isomeric form melts at 116 to 120 ^° C. The yield is 5.1 g.

A solution of 8.0 g of H - {/ 3- [r-methyl-pyrrole-

idyl- (2 ') - ethyl]} - l 1-hydroxy-homothioxanthene vom

F. 192 to 200 ⁰ C in 80 ecm glacial acetic acid is heated to boiling with 32 ecm concentrated hydrochloric acid for 1 hour. The solvent is then removed under a pressure of 15 mm, the residue is made alkaline with 2 η sodium hydroxide solution and extracted three times with 200 ecm of ether each time. The ether extract is washed with water, dried over magnesium sulfate, then the solvent is removed, and the oily residue obtained (7.0 g), which contains the crude 11 - {ß- [I '-methyl-pyrrolidyl- (2') - ethylidene ]} - 2-hornothioxanthene is converted into the acidic oxalate by adding 2.75 g of oxalic acid. After recrystallization from ethanol-acetone (9: 1), the acidic oxalate melts at 150 to 153 ^° C. The yield is 5.1 g.

In an analogous manner, when using the other isomeric form of m.p. 116 to 120 ⁰ C, the acidic oxalate of 11 ~ {ß- [r-methyl-pyrrolidyl- (2 ') - ethylidene]} - hornothioxanthens vom M.p. 150 to 153 ° C.

Example 6

11 - (γ-Dimethylaminopropylidene) homothioxanthene

A Grignard solution made by adding 9.5 g of iodine activated magnesium Covered with a little tetrahydrofuran, then mixed with 0.5 ecm of ethylene bromide, then on insertion the reaction a solution of 47.9 g of 3-di-

methylamino-1-propyl chloride in 90 ecm of tetrahydrofuran is added dropwise in such a way that the solvent boils, and then the reaction mixture is heated to boiling for a further hour, a solution of 40.1 g of homothioxanthone in 133 ecm of tetrahydrofuran is then added dropwise and Heated to the boil for 5 minutes. The reaction mixture obtained is then cooled, poured into a solution of 133 g of ammonium chloride in 880 ecm of water and the whole thing extracted with ι or 450 ecm of ether. The ether extract is then dried over magnesium sulfate, the solvent is distilled off and the semi-crystalline residue is melted in an oil bath at 150.degree. The dark brown UI it is distilled at 0.007 mm, »5 wherein proceed at 170 to 180 ⁰ C 45.5 g of oil, which is taken up in 160 cc of boiling ethanol and purified with animal charcoal. (Y-dimethylaminopropyl) -l 1-hydroxy-homothioxanthen from mp 130 to 132 ° C - on cooling of the purified solution at 20 ⁰ C, the 11 crystallized. The yield is 36.8 g.

26.1 g of the 1 l- (γ-dimethylaminopropyl) -11-hydroxy-homothioxanthen obtained are dissolved in 130 ecm of ethanol at the boiling point, followed by the solution cooled to 60 ° C and for 5 minutes with an ethanolic hydrochloric acid, prepared from 52 ecm of ethanol and 12.2 g of hydrogen chloride are added. The solution is then for 2 hours heated to reflux and then cooled to 15 ° C. After standing for two and a half hours, it becomes crystalline 11 - (γ-dimethylaminopropylidene homothioxanthene hydrochloride filtered off, washed with ethanol and dried in vacuo. F. 224 to 226 ° C. The Yield is 19.4 g.

35

Claims (1)

Claim: Process for the preparation of homothioxanthene derivatives of the general formula 40 45 HH / R ₅ c - c - c - n: \ τ in which Ri, R2 and R3 are hydrogen atoms or mean lower alkyl groups, R4 and R5 each represent a methyl group or R5 a methyl group and R4 together with Ri or R2 the dimethylene radical or with R3 the trimethylene or represent the tetramethylene radical, or their acid addition salts, characterized in that that in a known manner homothioxanthone of the formula 'S-CH ₂ with an organomagnesium compound of the general formula Hal - Mg - CH - CH - CH - N - R ₅ Ri R ₂ R ₃ in which R _x to R5 have the above meaning and Hal is a chlorine, bromine or iodine atom, converts the reaction products to homothioxanthenol derivatives of the general formula -S-CH ₂ R ₅ HO Ri R ₂ R ₃ hydrolyzed, this optionally separates into the stereoisomeric forms, then with dehydrating Treated agents and the compounds obtained optionally in their acid addition salts caught. Ri R ₂ R ₃ Considered publications: Reports of the German Chemical Society, 83, pp. 367 to 371 (1950). 5M65S. 477 8.65 Bundesdruckerei Berlin