DE2256392A1 - PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS - Google Patents

Description

Basel 'Case 100-3661

to the; Hers tell ung new h ^ e'teroc cll5cher_Verbi ηά un_gen_

The invention relates to a process for the preparation of new compounds of the formula I in which η is an integer from 0 to 3, R _{1 is} hydrogen, chlorine, bromine, fluorine, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio, R _{2 is} the cyano, a -COR ₃ - or a -COOR, group, in which R _{3 is} lower alkyl and R. is hydrogen or lower alkyl, and their acid addition salts and also includes the compounds of the formula I and their acid addition salts "

According to the invention, the new compounds of the formula I and their acid addition salts are obtained by mixing compounds of the formula II in which R, has the above meaning with compounds of the formula III in which R _{2 has the} above meaning and Z represents an X- (CH,) -CHR ₄ group, in which R ^ and η have the above meaning and X is the acid residue of a reactive ester, or a CH ₃ = CR. Group, in which R _{4 has the} above meaning, and the stable compounds of the formula I gev / ün-schtenfall converted into their acid addition salts.

In the compounds of the formula I the subscript is used. do t R, preferably for hydrogen. If R 1 is lower alkyl, then contains this alkyl group preferably has 1 to 4 carbon atoms and represents in particular the methyl group. In the radical R “ent-

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BATH ORIGINAL.

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Holding lower alkyl groups R ₃ preferably have 1 to 4 carbon atoms. The radical R _{2 is} preferably an alkylcarbonyl group. The substituent R, preferably represents hydrogen or chlorine. If R, stands for lower alkyl, this preferably contains 1 to 4 carbons, if R ^ stands for lower alkoxy or alkylthio, then these groups preferably contain 1 to 3 carbon atoms and are in particular Methoxy or methylthio.

The inventive reaction of compounds of the formula II with compounds of the formula III can be carried out, for example, in an organic solvent which is inert under the reaction conditions, preferably at an elevated temperature. For the addition of vinyl compounds of the formula IHa, in which R ₂ and R _{4 have the} above meanings, to compounds of the formula II, for example, lower alkenols such as ethanol are suitable as solvents and the reaction temperature is preferably at temperatures between about 60 and 100 °, in particular at Boiling point of the reaction mixture. The reaction of compounds of the formula II with compounds of the formula IUb ₇ in which R ₃ , R ₄ , η and X have the above meanings is preferably carried out in the presence of an acid-binding agent. Examples of suitable solvents which are inert under the reaction conditions are lower alkanols such as ethanol, chlorinated aliphatic hydrocarbons such as chloroform, aromatic hydrocarbons such as toluene or dimethylformamide. As an acid-binding agent, for example, alkali metal carbonates such as sodium or potassium carbonate or a tertiary nitrogen base such as triethylamine can be used. The reaction is preferably carried out at temperatures between about 50 ° and about 150 °, in particular at the boiling point of the reaction mixture. In the compounds of the formula ITIb, X is preferably chlorine, bromine, iodine or the acid radical of an organic sulfonic acid, for example the methylsulfonyloxy or p-toluenesulfonyioxy radical.

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The compounds of the formula I can be prepared in a manner known per se isolated from the reaction mixture and purified, the Free bases can be converted into their acid addition salts in the usual way convict and vice versa.

The starting compounds of the formula II can, for example be obtained by adding ketones of the formula IV, wherein R, Has the above meaning with the Grignard compound of the formula V converts, hydrolyzes the complex obtained, then splits off water and from the compounds thus obtained Formula VI, in which R- has the above meaning, the methyl group splits off in a manner known per se, e.g. by. Reaction with a compound of the formula VII and hydrolysis of the resultant Urethane.

The compounds of the formula I and their pharmacologically acceptable acid addition salts have not yet been described in the literature. They are distinguished by interesting pharmacodynamic properties and can therefore be used as medicaments. In particular, they have sleep-promoting properties. In the sleep experiment according to the method of G. Stille, H, Lauener and E, Eichenberger (Il Farmaco VoI, 26, 10, 603-625 [1971]) in rats, doses of approx. 1 to 10 mg / kg body weight po. to increase sleep. In doses of 0.1 to 3.0 mg / kg body weight i.v. _v . the substances cause an increase in the electrographic wake-up threshold in rabbits in a wake-up experiment using the method of G. Stille, H. Ackermann, E. Eichenberger and H. Lauener (Int. J. Neuropharmacol. _4, 375-391 [1965]),

Due to their sleep-promoting effects, the substances can be used to treat sleep disorders and restlessness «The doses to be used naturally vary depending on

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according to the type of substance, the administration and the condition to be treated. In general, however, the results will be satisfactory with a dose of approx. 0.7 to 10 mg / kg body weight, this dose can, if necessary, in 2 to 4 portions or can also be administered as a sustained release form. For larger mammals, the daily dose is around 50 to 500 mg. For example, contain for oral applications the partial doses are about 12 to 250 mg of the Compounds of the formula I in addition to solid or liquid carriers.

The substances also have muscle-relaxing properties. In doses of approx. 0.01 to 1.0 mg / kg body weight iv they cause a reduction in muscle tone in rabbits, as can be seen in measurements of the reflex muscle tone using the method of HJ Teschendorf, R. Kretzschmar and A. Ladous (Arch. exp. Pharmacol. 266 , 467-468 [197O]).

Due to their muscle-relaxing effects, the substances can used to treat muscle spasms. The doses to be used naturally vary depending on the type the substance, the administration and the condition to be treated. In general, however, satisfactory results are obtained with a dose of about 0.01 to 7 mg / kg body weight, If necessary, this dose can be administered in 2 to 4 portions or as a sustained release form. For larger mammals the daily dose is around 50 to 500 mg. For oral applications, these partial doses contain about 12 to 250 mg of the compounds of the formula I in addition to solid or liquid carriers.

The compounds of the formula I or their physiologically tolerable acid addition salts can be used alone as medicaments or administered in a suitable drug form with pharmacologically indifferent auxiliaries.

If the preparation of the starting compounds is not described, these are known or known per se

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Process or analogous to those described here or analogous can be produced by methods known per se.

In the following examples, which explain the invention in more detail, but are not intended to limit their scope in any way, all temperatures are given in degrees Celsius.

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Example 1: 9- (1-acetonyl-4-p.ip orid ylidene) thioxanthene

The solution of 10 g of 9- (4-piperidylidene) thioxanthene in 200 nil absolute ethanol is mixed with 8.6 g of sodium carbonate and 4 g of ChI or acetone added and refluxed for 1 hour. After cooling, the precipitate is filtered off and the alcohol solution evaporated to dryness. Precipitation and binding steam residue v / ground several times boiled with chloroform. The one after evaporation the crude title compound remaining crystalline from the chloroform extract is recrystallized twice from isopropanol. M.p. 141 to 143 °.

Example 2; ^ -Jl-JA

The solution of 20 g of 9- (4-piperidylidene) thioxanthone in 175 ml of chloroform is mixed with 18.2 g of anhydrous sodium carbonate and 14.2 g of 5-bromine-2-pentanone and refluxed for 15 hours reflected off, the filtrate being the hydrobromide of the title compound is obtained by evaporation and aen residue from ethanol crystallized. It is recrystallized again from ethanol and then melted at 222 to 225 ° with decomposition, which from the hydrobromide on the oily base The hydrochloride produced melts after crystallization from ethanol at 206 ° to 208 ° with decomposition.

Example 3:

To a suspension of 15.5 g of 2-chloro-9- (4-piperidylidene) thioxanthene and 12.6 g of sodium carbonate in 250 ml of chloroform drop; a solution of 9.9 g of 5-bromo-2-pentanone in 50 ml of Chlorofor.:. It is refluxed for 17 hours and shaken after cooling Water out, the chloroforric phase dries over magnesium sulfate,

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if it evaporates, the evaporation residue is transferred to a column of 250 g silica gel and eluted with chloroform containing 1% methanol. After evaporation of the eluate, the crude title compound remains. The title compound is quickly converted into the hydrochloride dissolved in acetone and the solution made weakly acidic with ethereal hydrogen chloride. The immediately precipitating hydrochloride the title compound is made from acetone, which contains 5% water, recrystallized. M.p. 222 to 226 °.

The starting material is obtained as follows:

To a solution of 17.6 g of ethyl chloroformate in 60 ml of absolute toluene are added dropwise to the solution of 17.7 g of 4- (2-chloro-thioxanthenylidene) -1-methylpiperidine at 90 ° over the course of 2 hours in 100 ml of absolute toluene. The mixture is then stirred for 15 hours at 12O °, the solution is evaporated in vacuo and the Residue with a solution of 28.0 g of potassium hydroxide in Boiled 200 ml of n-butanol under reflux for 1 hour. One cools down diluted with plenty of water and extracted with ether. The crude 4- (2- chloro-9-thioxanthenylidene) piperidine remaining after evaporation of the ether is processed further without further purification.

Analogously, the following connections can also be made by Um -

Formation of the corresponding 9- (4-piperidylidene) thioxanthene derivatives

of the formula II ■ lait corresponding Ilalogenalkylderi-

fathers are received:

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30th

TJ

m σ

OO I

ο to

Ν »

ro

IT
Βερ. j
N " ¹ * ' substance Halcgenalky! Derivative M.p. Remarks up to 153 ° Hydrochloride:
(Decomposition) !
4th 9- [1- (3-0xobutyi) -4-piperidy-
.lidön] thioxanthene 4-chloro-2-butanone M.p. . 151 up to 134 ° 5 9- [1- (3-oxopentyI) -4-piperidy-
liden] thioxanthene 5-bromo-3-pentanone M.p. . 132 up to 127 ° 6th 9- [1- (2-MGthoxycarbynylethyl) -
4-piperidylidene jthioxanthene 3-broropropicic acid
methyl ester M.p. . 125 up to 155 ° 7th 9- [1- (2-cyanoethyl) -4-piperi
dylidene] thioxanthene 3-bromopropionitrile M.p.
307 . 153 Hydrochlorids:
310 ° 8th 2-chloro-9- [l- (3-oxobutyl) -4-
piperidylidene] thioxanthene 4-chloro-2-butanone M.p. . of
until '. . 98 to 100 ° 9 9- (l-methoxycarbonyimethyl-4-
piperidylidene) thioxanthene Eromacetic acid methyl
esrer SlT.O
19S . of the hydrochloride:
up to 201 ° (decomposition) 10 9- [1- (5-0xohexyi) -4-piperi
dylidene] thioxanthene 6-bromo-2-hexanone Mp. Des
168-170 ° 11 9- [1- (2-methyl-3-oxobutyl) -4-
piperidylidene] thioxanthene
I. 4-chloro-3-methyl-2-
butanone

PO cn cn co co

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Example 12 i 9zlil. (3-OxobutYl) _- 4-2iperidYlidene] thioxanthene

To the solution of 10 g of 9- (4-piperidylidene) thioxanthene in 100 ml of absolute ethanol, 5.9 ml of methyl vinyl ketone are added dropwise at 70 ° with thorough stirring over a period of 10 minutes. The mixture is stirred for a further 1 hour at 70 °, then cooled to 0 ° and the _N- crystallized 9- [1- (3-oxobutyl) -4-piperidylidene] thioxanthene is filtered off. After crystallization from ethanol, it melts at 151-153 °.

The following compounds can also be prepared analogously by reacting the corresponding 9- (4-piperidylidene) thioxanthene derivatives of Formula II obtained with appropriate vinyl compounds v; earth:

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E.g.

substance

Vinyl compound

Remarks

L3

.14

15th

16 17

9_ [ι- (2-methyl-3-oxobutyl) -4-piperidyliae] thipxanthene

S- [1- (3-OxopentyI) -4-piperidy ~ liden] thioxanthone

9- [1- (2-mathoxycarbonylethyl) -

4-piperidylidene] thioxanthene

9- [1- (2-cyanoethyl) -4-piperidylidene] thioxanthene

2-Chloro-9- [1- (3-oxobutyl) -4-piperidylidene] thiox & nthene

Isopropenyl methyl ketone Ethyl vinyl ketone

Acrylic acid methyl ester

Acrylonitrile

Methyl vinyl ketone

Sinp. of the hydrochloride: 168-170 ° (decomposition)

Stxp. 132 to 134 °

M.p. 125 to 127 °

M.p. 153 to 155 '

. of the hydrochloride 307 to 310 °

CO CO NJ

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Example 18:

2-methylthio-9- (4-piperidylidene) thioxanthene and methyl vinyl ketone are implemented according to the procedure described in Example 12 and the title compound is converted into its hydrochloride with a melting point of 280 to 290 (decomposition from isopropanol).

The starting material can be obtained as follows:

a) To a Grignard compound prepared from 0.96 g of magnesium turnings and 5.34 g of N-methyl-4-chloropiperidine in 25 ml of tetrahydrofuran, 5.16 g of 2-methylthiothioxanthone are added at -5 °
added in portions and the 'reaction mixture a further 2
Stirred for hours without cooling. For work-up, it is poured onto 80 ml of 10% strength ammonium chloride solution and 40 ml of ether are added, crude 9-hydroxy-2-methylthio-9- (1-methyl-4-piperidyl) thioxanthene crystallizing out. The one when narrowing the with
The residue obtained from saturated sodium chloride solution, washed and dried, is combined with the crude crystals and the crude product is recrystallized from ethanol. M.p. 198 to 199 °.

b) 3.1 g of the product described above with 60 ml 5N hydrochloric acid refluxed for 1 hour. The hydrochloride which crystallizes out after the reaction solution has cooled down is

Slurried in water, the mixture with 2N sodium hydroxide solution under Made alkaline cooling and extracted with chloroform. After concentrating the washed with saturated sodium chloride solution and dried chloroform extract 2-Methylthio-9- (1-ethyl-4-piperidylidene) thioxanthene is made from

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Isopropanol recrystallized. M.p. 104-106 °.

c) 2-methylthio-9- (l-methyl-4-piperidylidene) thioxanthene is as described under Example 3 in 2-methylthio-9- (4-piperidylidene) thioxanthene transferred and processed further directly without cleaning. M.p. of the hydrochloride '293 to 297 ° (decomposition).

Example 19; 3-chloro _:: 9-Jl-j3-gxobutYl] _- 4-giperidYlidenl-

3-chloro-9- (4-piperidylidene) thioxanthene is according to the example 12 is reacted with methyl vinyl ketone and the resulting title compound converted into its hydrogen fumarate. M.p. 136 to 14 3 ° (decomposition).

The starting material is prepared analogously to Example 18 a) to 18 c):

a) 3-chloro-9-hydroxy-9- (l-methyl-4-piperidyl) thioxanthene, m.p. 182 to 183 °.

b) 3 ~ chloro-9- (l-methyl-4-piperidylidene) thioxanthene, the crude Compound is purified via its fumarate and further processed directly.

c) 3-chloro-9- (4-piperidylidene) thioxanthene, m.p. of the hydrochloride: approx. 290 ° (decomposition, from isopropanol / ethanolic hydrochloric acid)

Example 20: 2-MettYl-9-Jl-J3-oxobut ^ l) _- 4-gigeridYliden2;

2-methyl-9- (4-piperidylidene) thioxanthene and methyl vinyl ketone can be by the process described in Example 12 A ^ J RifÄbÄf η ¹ SBSfjfetzt

ORIGINAL INSPECTED

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and the title compound obtained is converted into its hydrochloride. M.p. 290 ° (decomposition).

The starting material can be obtained analogously to Examples 18 a) to 19 c) will:

a) 9-Hydroxy-2-methy1-9- (1-methyl-4-piperidyl) thioxanthene, m.p. . 189 to 191 °.

b) 2-methyl-9- (1-methyl-4-piperidylidene) thioxanthene, crude product processed directly.

c) 2-methyl-9- (4-piperidylidene) thioxanthene, m.p. of the hydrochloride: 275 to 285 ° (decomposition, from isopropanol / ethanolic hydrochloric acid) . '

The following compounds can also be prepared analogously to Example 3 by reaction from corresponding 9- (4-piperidylidene) thioxanthene derivatives of the formula II with corresponding haloalkyl derivatives are obtained:

eat co Ni Κ »

E.g.
No. substance Haloalkyl derivative M.p.
290 " Remarks of the hydrochloride:
(Decomposition) 280 to I.
until 21 2-methylthio-9- [1- (3-oxo-
butyl) -4-piperidylidene] thio
xanthene 4-chloro-2-butanone M.p.
202 " of the hydrochloride:
(Decomposition)
• 200 to 22nd 1
2-methylthio-9- [1-ij-oxo-
pentyl) -4-piperidylidene] -
thioxanthene I.
5-bromo-1-pentanone of the hydrochloride: 290 ° 5 23 2-methyl-9- [1- (3-oxobutyi) -
4-piperidylidene] thioxanthene 4-chloro-2-butanone M.p. of the hydrochloride:
(Decomposition) 235 to 24 2-methyl-9-Cl- (| -oxopentyl) -
4-piperidylidenithioxanthene L.
5-bromine - $ - pentanone M.p.
237 " of hydrogen fumarate:
up to 14 3 ° (decomposition) 10 25th 3-chloro-9- [1- (3-oxobutyl) -4-
piperidylidene] thioxanthene 4-chloro-2-butanone M.p.
136 of fumarates: 137
(Decomposition) 26th 3-chloro-9- [1- (l-oxopentyl) -
4-piperidylidene] thioxanthene ί
5-bromo-t-pentanone M.p.
139 "

Νλ K) cn <n co CD

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Z-R,

III

IIIb

II

CH ₂ = CH-R ₂

HIa

IV

MgBr

■ Ν

CH.

^R l VI

Cl-COOAlkyl VII

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Claims (3)

Patent claims: 1. Process for the preparation of new compounds of the formula I / where η is an integer from 0 to 3, R is hydrogen, chlorine, bromine, fluorine, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio, R_ is cyano, a -COR-- or a -C00R ₃ ~ Group in which R_ is lower alkyl and R. is hydrogen or lower alkyl, and their acid addition salts, characterized in that compounds of the formula II, II wherein R, has the above meaning, with compounds of the formula III, Z-R, III where R _{2 has the} above meaning and Z represents an X- (CH ₂ J-CHR ₄ group, where P. and η have the above meaning and X unites the acid radical; is a reactive ester, or a CH ₂ = CR. group, in which R. has the above meaning, stands, reacts and converts the compounds of the formula T obtained into their acid addition salts. 309822/120 7 100-3661 2. Compounds of the formula I, where η is an integer from 0 to 3, R, hydrogen, chlorine, bromine,, fluorine, trifluoromethyl, lower alkyl, lower alkoxy or lower alkyithio, R _{2 is} the cyano,
a "-COR-- or a -CGOR_ group, in which R- is lower alkyl, and R, is hydrogen or lower alkyl, and their acid addition salts. 3. Remedies characterized in that they have compounds of the formula I or their acid addition salts. 309022/1207