DE1470160C - 2-chloro-9-piperazinopropylidene-thioxanthenes and a process for their preparation - Google Patents

Description

The invention relates to 2-chloro-9-piper-azinopropylidenthioxanthenes of the general formula I

CH-CH ₂ -CH ₂ -N

in which R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and A is Represents alkylene group having 1 or 2 carbon atoms, their cis and trans forms and their salts with acids.

The compounds of the invention are useful in the chemotherapy of mental diseases and especially for controlling states of excitement. In addition, these compounds are very effective to prevent nausea.

The process for the preparation of the compounds of the general formula I is characterized in that that in a conventional manner 2-chloro-9- (3-bromopropylidene) thioxanthene or optionally its cis or trans form with a piperazine of the general formula II,

HN

NR ₂

(H)

wherein R _{2 is} the group - A-CO - NH-R or - COOC ₂ H ₅ , converts, saponifies obtained 2-chloro-9 - [3 - (4 - carbäthoxypiperazino) - propylidene] - thioxanthene in the presence of potassium hydroxide, the 2-chloro-9- (3-piperazinopropylidene) thioxanthene obtained with a compound of the general formula III a or III b,

CH ₂ = CH-CO-NH-R (DIa)

40

X-A-CO-NH-R

(HIb)

wherein X denotes a halogen atom, causes it to react and, if appropriate, then one obtained in this way Converts base into a salt with an acid and / or a obtained cis-trans isomer mixture separates into the trans and cis isomers by fractional crystallization.

The 2-chloro-9- (3-bromopropylidene) thioxanthene required as the starting compound is obtained by reacting 2-chlorothioxanthenone with an alkoxypropyl bromide by means of a Grignard reaction, so that the 2-chloro-9-hydroxy-9- (3-alkpxy ;. propyl) thioxanthene. This compound is then treated with aqueous concentrated hydrobromic acid treated while gaseous hydrogen bromide is passed through the reaction mixture.

Its cis and trans isomers are fractionated by Obtained crystallization from isopropyl ether.

The reaction of 2-chloro-9- (3-bromopropylidene) -thioxanthene with a compound of the general formula

N-A-C-NH-R

(I)

H-N

N-A-C-NH-R

can be using an about 50% strength ^e ri excess of monosubstituted piperazine and potassium carbonate in amyl alcohol perform. A preferred procedure is to reflux with methyl ethyl ketone or dimethylformamide and using a more than 100% excess of monosubstituted piperazine of potassium carbonate.

The reaction of the bromopropylidene compound with carbethoxypiperazine is carried out with an excess of the same in methyl ethyl ketone by heating under reflux, followed by an acid extraction. The product is then treated with 4N potassium hydroxide in 80% strength ^em ethanol, so that the piperazino-propylidene compound is obtained. The conversion of the piperazino-propylidene compound into the end product according to the invention is carried out by reaction with a compound of. general formula III a or III b causes. A suitable solvent is dimethylformamide. The reaction is carried out from about 12 to 180 hours at temperatures of about 25 to 85 ⁰ C. _^:;

The 2-chloro-9 - [3 - (4 - carbamoylalkyl - piperazino) - propylidene] thioxanthenes obtained in one of the above ways can be converted into acid addition salts in a manner known per se. For example can the base in absolute alcohol or another suitable solvent such as diethyl ether or acetone and the selected acid added. Mineral acid addition salts and organic acid addition salts, z. B. Salts of salt, hydrogen bromide, nitric, sulfur, phosphorus, vinegar, lemon, Tartaric, lactic, maleic acid and the like can be prepared in this or other suitable manner.

Of course, for the preparation of the acid addition salts, preference is given to using acids which, when combined with the free base, form salts whose anions are relatively harmless in therapeutic doses of the salts, so that the advantageous physiological properties inherent in the free base are not affected by the Side effects attributable to anions are impaired. However, if the products are salts of toxic acids, they can be easily removed by treatment with a strong base, e.g. B. diluted. Sodium hydroxide, convert to the free base. : ■ ■: ■

The preferred novel psychotherapeutic agents of the present invention are highly effective in the treatment of emotional excitement. The dosage depends on several factors dependent, e.g. B. on the extent of the emotional excitement, whether it is mild or serious. Tablets or capsules, which contain 2.5, 5, 10, 25 or 100 mg of the therapeutic agents according to the invention are expedient Dosage units.

The effectiveness of the compounds according to the invention was determined by symptomatology, antagonism compared to amphetamine, increase in

trium - 5 - (1 - cyclohexen -1 - yl) -1,5 - dimethyl barbiturate induced sleep time and reduction in rectal temperatures in mice, through experiments on Elimination of conditioned reflexes (conditioned avoidance tests) in rats, through symptomatology and prevention vomiting induced by apomorphine in dogs and by sympromatology shown in monkeys.

It was z. B. found that the 2 - chloro-9 - [3 - (4 - N - methylcarbamoylmethyl - piperazino) propylidene] thioxanthendimaleate (Mixture of the cis and trans isomers) about three times as effective as N - dimethylaminopropyl - 3 - chlorophenothiazine hydrochloride (»Chlorpromazine«) and trans-2-chloro-9 - (3-dimethylaminopropylidene) -thioxanthene (Chlorprothixen) is. . .

It has been found that one of the isomers which is the dimaleate with a melting point of 157 to. 159 ⁰ C (decomposition) forms, 6 to 10 times as effective as the other isomer and 3 to 5 times as effective as the isomer mixture is,

A study of the prevention of nausea in dogs, the compounds being administered intravenously, showed that the _{nausea prevention (ED 50} -WeIt) of cis-2-chloro-9- [3- (4-N-methylcarbamoylmethyl-piperazino) - propylidene] thioxanthene is about three times as large as a mixture of the cis and trans isomers. The prevention of nausea (ED ₅₀ value) of cis-2-chloro-9- {3- [4- (2 - N - methylcarbamoylethyl) - piperazino] - propylidene} thioxanthene z. B. was about 5 to 8 times stronger than the cis-trans mixture.

Test report

All of the following data were based on the methods described in ίο Psychopharmacologia (Berl), 12, pp. 142 to 157 (1968), described experimental methods determined.

Connection A:.

trans-2-chloro-9- {3- [4- (2-N-methylcarbamoylethyl) -piperazino] -propylidene} -thioxanthene- dimaleat.

Connection B:,

cis / trans -2-chloro-9- [3- (4-carbamoylmethyl-piperazino) -propylidene] -thioxanthene-dimaleate.

.

Connection C:

trans -2-chloro-9- [3- (4-N-methylcarbamoylmethylpiperazino) propylidene] thioxanthene dimaleate. 1. Toxicity in male albino rats and mice (Charles River C-DJ), rat weight 53 to 87 g, the mice 19 to 25 g. : ■

Ver
binding Laboratory animal orally Mode of administration LD ₆₀
(mg / kg) 'A' Albino mice i.p. (1% - ^w äßrige suspension) 278 A. Albino mice orally (0.5% suspension in Ringer's L.) 150 A. Albino rats Lp. (5% aqueous suspension) 580 A. Albino rats orally (2 ° / ₀ suspension in Ringer-L.) 120 B. Albino mice Lp. 180 -B ■ "■. ' Albino mice Lp. 150 Chlorpromazine Mice Lp. 165 Chlorpromazine Rats '62

2. Amphetamine antagonism in mice:
Administration: L p.

• _; Connection A.

Chlorpromazine

45

+++ (1.0 mg / kg) ++ (1.0 mg / kg)

+++ (0.5 mg / kg)
(Scale: + weak; ++ moderate; +++ pronounced.)

3. Antiemetic effect in dogs, ED ₅₀ μg /,. kg, Lp: ·; · ^;

- connection A

362 ± 15.9

Chlorpromazine

900 to 1000

4. Attempts to cancel the conditioned reflexes (conditioned avoidance test) in rats: ED ₆₀ mg / kg, Lp.

Connection '

IBI

1.0. ± 0.1

about 5

1.2 ± 0.1

Chlorpromazine

3.2 to 10

5. Effect on apomorphine-induced vomiting in dogs, ED ₅₀ (mg / kg ip) to block emesis:

connection

0.1 to 0.3

0.1 to 0.2

Chlorpromazine

about 0.7

According to the method according to the invention cis and trans isomers are produced. It is true that the isomeric mixtures show therapeutic properties of the of the same nature as the pure isomers, but the effectiveness of the one pure isomer was in all examined cases larger than in the other. In addition, the less effective isomer can be used in convert the more effective, e.g. B. by adjusting the equilibrium using acid and then fractional crystallization, and is therefore effective as an intermediate.

. The following examples serve to illustrate the invention.

5 6

B e i s ρ i e 1 1 heated under reflux for 12 hours. After finished

Heating to reflux removes the solvent

2-Chloro-9- [3- (4-carbamoylmethyl-piperazino) - vacuum distillation removed. The product, 2-chlorine

propylidene] thioxanthene dimaleate 9 - [3 - (4 - carbäthoxypiperazino) - propylidene] - thio-

5 xanthene, is dissolved in 125 ecm of ether, and the ethereal

A solution of 3.52 g (0.01 mol) of 2-chlorine extract is washed twice with 50 ecm of water each time. 9- (3-bromopropylidene) -thioxanthene and 4.3 g (0.03 mol) of the ether extract is mixed twice with 50 ecm of 1 n-salza-piperazinylacetamide each time Treated in 100 ecm of methyl ethyl ketonic acid to make an acid extraction of the Prowird Heated under reflux for 12 hours. To effect the product of the solution. The separated organic medium is removed by vacuum distillation. The io layer is produced twice with 50 ecm of water each time is extracted with 25 ecm of ether, and the wash. The washing water is made with the hydrochloric acid ether extract is combined twice with 50 ecm of water extracted and twice with 25 ecm of ether each time to wash. The ether extract is washed twice with 50 ecm each time, and the separated aqueous layer is Treated in hydrochloric acid to make the product extra- by adding 20% sodium hydroxide solution here. The separated organic layer is made two-15 alkaline. The carbethoxy compound will washed times with 50 ecm of water each time. The wash is extracted with ether, and the extract is made with water water is combined with the hydrochloric acid extracts and washed. The solvent is made by distillation Washed twice with 25 ecm of ether each time and removed them. The carbethoxy compound will separate about 12 hours aqueous layer is made by adding a with 4N potassium hydroxide with heating on the back-20% Sodium hydroxide solution made alkaline. Treated 20 flow in 80% ethanol, so that you get 2-chloro-Das The crude product is extracted with ether, and the 9- (3-piperazinopropylidene) -thioxanthene is obtained. The extract is washed with water and dried over a mixture of 2.8 g of 2-chloro-9- (3-piperazinopro-

dried free magnesium sulfate. The solution pylidene) thioxanthene and 1.14 g of acrylamide in 30 cm medium are removed by distillation. The product dimethylformamide ig ^he received 48 hours at 60 ° C gewird in 70% yield as the free base. 25 stirs. The reaction mixture is poured into water

The free base is converted into the dimaleate, poured, and the product is extracted with ether, by adding the base in 10 parts by weight of isopropanol. After washing with water, the ether layer is dissolves, the solution is treated with a solution of 2 molar equivalents twice with 50 ecm 1 η-hydrochloric acid each time to get the to extract valent maleic acid in 10 parts by weight of isopropanol basic product. The severed one treated, the crystalline precipitate through Fil- 30 organic layer is treated twice with 50 ecm of water Trier removed and the precipitate washed from an iso. The wash water is mixed with the hydrochloric acid propanol-water mixture recrystallized. The di-extracts are combined and twice with 25 ecm ether each time Maleate melts at 160 to 162 ° C., and the separated aqueous layer is washed

The 2-chloro required as starting compound by adding 10% sodium carbonate solution 9 - (3 - bromopropylidene) - thioxanthene is made alkaline as follows. The reaction product is with made to measure: ether is extracted, and the extract is mixed with water

A mixture of 0.4 mol of 3-t-amyloxypropyl washes and dried over sodium sulfate. The magnesium bromide and 0.2 mol of 2-chlorothioxanthenone solvent are removed by distillation. The In 1200 ecm of anhydrous ethyl ether, the oil produced for 24 hours is treated with charcoal heated to reflux. Decolorized after re-heating in isopropanol.

The reaction mixture is flowed with 2000 ecm of the free base is converted into the dimaleate,

Ammonium chloride solution (20 g of ammonium chloride in by adding the base in 10 parts by weight of isopropanol 100 ecm of water). The ether phase is detached, the solution is separated with a solution of 2 molar equivalents, washed with water and dried. According to valent maleic acid in 10 parts by weight of isopropanol Evaporation of the ether gives crude 2-chloro-treated 45, the crystalline precipitate by FiI-9-hydroxy-9- (3-t-amyloxypropyl) -thioxanthene, which is removed and the precipitate is recrystallized from a water-methanol mixture purified by recrystallization from isopropyl ether. The Di will and then a melting point of 109 to 110 ° C maleate is obtained in 38% yield and having. The product is aqueous with 1600 ecm melts at 175 to 177 ° C (decomposition), concentrated hydrobromic acid (48 ° / o) 1 hour 50

heated to reflux, during which time Example 3

gaseous hydrogen bromide by the reaction * - 2-chloro-9- {3- [4- (2-N-methylcarbamoylethyl) -

mixed headed. 4 liters of water are added to the mixture of piperazino] propylidene thioxanthene dimaleate

added, and the raw product is extra- ^{J with ether}

here. The ether extract is mixed with water and sodium. The procedure of Example 2 is repeated, bicarbonate solution washed and dried. The one being stoichiometric instead of acrylamide Ether is evaporated and the oily residue is converted into equivalent amounts of N-methylacrylamide recrystallized from an ether-petroleum ether mixture, turns. The melting point of the dimaleate is so that 2-chloro-9- (3-bromopropylidene) thioxanthene 174 to 177 ° C. with a melting point of 64 to 65 ° C. is obtained. 60 Example4

B e i s ρ i e 1 2 2-chloro-9- [3- (4-N-methylcarbamoylmethyl-

piperazino) propylidene] thioxanthene dimaleate

2-chloro-9- {3- [4- (2-carbamoylethyl) piperazino] - ". ". , _, _ "_ ,, _n ...

propylidene} thioxanthene dimaleate Em mixture of 3.57 g of 2-ChIo ^ - 3-piperazmo-

^J 65 propyhden) thioxanthene, 4.28 g a-chloro-N-methyl-

A solution of 0.01 mol of 2-chloro-9- (3-bromoacetamide and 2.76 g of potassium carbonate in 30 ecm of di-

propylidene) thioxanthene and 0.03 mol carbethoxymethylformamide is 25 hours at room temperature

piperazine in 100 ecm methyl ethyl ketone is stirred about ratur. The reaction mixture is in water

poured, and the product is extracted with ether. After washing with water, the ethereal layer is treated twice with 50 ecm 1 η-hydrochloric acid each time in order to remove the extract basic product. The separated organic layer is mixed with the hydrochloric acid extracts combined and washed twice with 25 ecm of ether each time and made alkaline with 10% sodium carbonate solution. The reaction product is extracted with ether, and the extract is washed with water and dried over sodium sulfate. The solvent is removed by distillation. The resulting oil is decolorized by treatment with charcoal in isopropanol, which contains a trace of carbon disulfide. The free base can be converted into the dimaleate by adding it to 10 parts by weight of isopropanol dissolves the solution with a solution of 2 molar equivalents of maleic acid in 10 parts by weight of isopropanol treated, the crystalline precipitate removed by filtration and the precipitate from a Water-acetonitrile mixture recrystallized. The dimaleate is obtained in 67% yield and melts at 141 to 143 ° C (decomposition).

The free base is in chloroform to the maxima in the infrared spectrum a characteristic peak at 1680 cm ^"1; this indicates the presence of the amide carbonyl group of the Ulträviolettspektrum the free base showing X _ma x 325 ηιμ and X _max 270 πιμ;. This indicates the presence of Δ 9 double bond.

CH ₂ -CH ₂ -N

NO'

O
π R ' Melting point
of the dimaleate
. (° C) Il
- C
O
Il -CH ₂ Il
- C - NHCH ₂ CH ₃ 148 to 150 - CH ₂ - NHCH (CH ₃ ) _a 165 to 167

Example 6

2-chloro-9- {3- [4- (1-N-methylcarbamoylethyl) piperazino] propylidene} thioxanthene dimaleate

Example 7

2-Chloro-9- [3- (4-N-methylcarbamoylmethylpiperazino) propylidene] thioxanthene dihydrochloride

The hydrochloric acid addition salt of 2-chloro-9- [3- (4 - N - methylcarbamoylmethyl - piperazino) - propylidene] thioxanthene is prepared by mixing an acetone solution of the free base with an aqueous Mixing solution that has a stoichiometrically equivalent

ίο contains amount of hydrochloric acid, and the solution obtained evaporates. The hydrochloride is obtained as a crystalline solid.

Examples

cis -2-chloro-9- [3- (4-N-methylcarbamoylmethylpiperazino) propylidene] thioxanthene dihydrobromide

A solution of 4.19 g of the free base from Example 4 in 100 ecm of 95% strength aqueous isopropanol is mixed with 2 ecm of concentrated hydrobromic acid. While the solution is slowly being cooled, 1 g of a crystalline salt separates out with a melting point of 231 to 232 ^° C. (decomposition). The compound is separated off by filtration and recrystallized from 95% strength aqueous isopropanol and melts at 236 to 238 ° C. (decomposition). A test by thin layer chromatography shows that the product contains less than 5% of the trans-Ispmereri.

B e i s ρ i e 1 5

The procedure of Example 4 is repeated, using instead of α-chloro-N-methylacetamide stoichiometrically equivalent amounts of other suitable N-substituted -chloro- or bromoacetamides are used. There were the following 2-chloro-9 substituted on the nitrogen atom of the carbamoylmethyl radical - [3 - (4 - carbamoylmethyl - piperazino) - propylidene] thioxanthenes receive:

40

45

55 B e i s ρ i e 1 9

trans -2-chloro-9- [3- (4-N-methylcarbamoylmethylpiperazino) propylidene] thioxanthene dipicrate

. The mother liquor obtained after filtering off the dihydrobromide from Example 8, which is 0.04 mol of a mixture of about 70%. contains trans and 30% cis isomers, becomes with a half. Equivalent (0.04 mol) of picric acid added. The resulting precipitate is filtered and recrystallized twice from 80% aqueous dimethylformamide. The Dipikrat obtained melts at 220-221 ⁰ C and the trans isomer containing less than 5% of the cis isomer. The analysis for C ₂₃ H ₂₆ ClN ₃ OS 2C ₆ H ₃ N ₃ O ₇ resulted in:

Calculated, found N 14.2%;
N 14.1%.

Example 10

cis-2-chloro-9- [3- (4-N-methylcarbamoylmethyl-. piperazino) -propylidene] -thioxanthari'dipicrate:

■ This isomer is obtained by mixing a solution of the free base: added in 70% strength aqueous dimethylformamide ^s i with two molar equivalents of picric acid (isomer ratio 1: 1). The compound has a melting point of 223 to 224 ^° C. (decomposition). The analysis for C ₂₃ H ₂₆ ClN ₃ OS · 2C ₆ H ₃ N ₃ O ₇ resulted in: ^: ·: .. ^: ■: ■ .v ■■ '[■

Calculated
found

N 14.2%;
N 14.1%.

This compound is prepared according to the procedure described in Example 4, but in this case 2-chloro-9- (3-piperazinopropylidene) thioxanthene is reacted with α-chloro-N-methylpropionamide. The dimaleate has a melting point of 176 to 177 ⁰ C.

. ·· "Example" 11

trans -2-chloro-9- [3- (4-N-methylcarbamoylmethylpiperazino) propylidene] thioxanthene dimaleate

The trans-dipicrate of Example 9 is converted to the free base by adding a 60% solution of the trans dipicrate in aqueous methanol

109 512/387

Amberlite No. Ir-45 (Rohm & Haas: a weakly basic polyamine anion exchange resin based on polystyrene) directs. The trans isomer of the free base is dissolved in 10 parts by weight of isopropanol. the A solution of 2 molar equivalents of maleic acid in 10 parts by weight of isopropanol is added to the solution. The resulting precipitate is filtered off and recrystallized from a water-acetonitrile mixture, so that the trans-dimaleate is obtained, which melts at 157 to 159.degree. The analysis for

resulted in:

Calculated
found

C ₂₃ H ₂₆ ClN ₃ OS ^ C ₄ H ₄ O ₄

... C 56.4%, H 5.2%, N 6.4%;
, .. C 56.2%, H 5.5%, N 6.1% ..

Example 12

trans -2-chloro-9- {3- [4- (2-N-methylcarbamoylethyl) piperazino] propylidene} thioxanthene

A solution of 3.31 g of trans-2-chloro-9- (3-bromopropylidene) -thioxanthene and 3.25 g of l- (N-methylcarbamoylethyl) piperazine in 75 ecm acetone is 16 hours heated to reflux. When finished, the solvent is evaporated and it becomes 100 ecm Water added. The mixture is made alkaline with sodium bicarbonate. The product is used three times extracted with 40 ecm of methylene chloride each time, and the extract is washed with 75 ecm of water. The methylene chloride extract is treated twice with 50 ecm 1 η hydrochloric acid each time and with a 10% solution made alkaline by sodium carbonate. The product is extracted three times with 100 ecm of methylene chloride each time and the extract is dried over sodium sulfate. The solvent is evaporated, whereby 2.5 g (60% yield) of a product with a

10

Melting point at 159 to 161 ⁰ C remain behind. The product is recrystallized from a mixture of 3 parts of isopropyl ether and 1 part of methylene chloride and melts at 166 to 167 ^° C. Thin-layer chromatography shows that the product contains less than 10% of the cis isomer.

Example 13

cis-2-chloro-9- {3- [4- (2-N-methylcarbamoylethyl) -
^xu piperazino] propylidene} thioxanthene

The procedure of Example 12 is repeated using cis-2-chloro-9- (3-bromopropylidene) thioxanthene. The crystalline product obtained has a melting point of 145 to 147 ^° C.

The cis and trans isomers of 2-chloro-9- (3-bromopropylidene) thioxanthene required as starting compounds for Examples 12 and 13 are obtained by adding 16.2 g of isomer mixture (1: 1) to 100 ecm of isopropyl ether there and cools ^{to 0 0 C.} The cis isomer is filtered and recrystallized from isopropyl ether. It melts at 82 to 86 ° C. The analysis for Ci ₆ H ₁₂ BrClS showed:

Calculated
found

0.54.6%, H 3.4%;
0.54.8%, H 3.5%.

The addition of η-hexane to the mother liquor remaining after the removal of the cis isomer leads to the result to precipitate the trans isomer with a melting point of 85 to 87 ° C.

Claims (3)

Patent claims: 1. 2-chloro-9-piperazinopropylidene-thioxanthenes of the general formula I. CH-CH ₂ -CH ₂ -N -Cl N-A-C-NH-R in which R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and A is an alkylene group having 1 or 2 carbon atoms represents their cis and trans forms and their salts with acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in a conventional manner 2-chloro-9- (3-bromopropylidene) thioxanthene or optionally its cis or trans form with a piperazine of the general formula II, 60 HN NR ₂ (H) wherein R _{2 is} the group - A - CO - NH - R or --COOC ₈ H ₅ , the 2-chloro-9- [3- (4-carbäthoxypiperazino) propylidene] thioxanthene obtained is saponified in the presence of potassium hydroxide, the obtained 2-chloro-9- (3-piperazinopropylidene-thioxanthene with a compound of the general formula III a or III b, CH ₂ = CH - CO - NH - R (III a)
X —A —CO —NH-R (HIb) wherein X denotes a halogen atom, causes it to react and, if appropriate, then one obtained in this way Converts base into a salt with an acid and / or a obtained cis-trans isomer mixture separates into the trans and cis isomers by fractional crystallization. 3. trans -2-chloro-9- {3- [4- (2-N-methylcarbamoylethyl) piperazino] propylidene} thioxanthene and its salts with acids.