NO754417L - - Google Patents

Description

Procedure for the production of new organic compounds.

The present invention relates to a method for the production of new organic compounds with formula I

in which

stands for hydrogen, an alkyl group with 1-6 carbon atoms,

a cycloalkyl group with 4-6 carbon atoms,

a hydroxyalkyl group of 2 to 5 carbon atoms whose hydroxy group is separated from the nitrogen atom by at least two

carbon atoms, an oxoalkyl group of 3 to 5 carbon atoms whose carbonyl group is separated from the nitrogen atom by at least one carbon atom, an alkanoyloxyalkyl group containing an alkanoyl radical of 2 to 10 carbon atoms and an oxyalkyl radical of 2 to 5 carbon atoms whose oxygen atom is separated from the nitrogen atom by at least 2 carbon atoms, or an alkoxycarbonylalkyl group containing an alkoxy acid residue of 1 to 4 carbon atoms and an alkylcarbonyl residue of 3 to 6 carbon atoms, whose carbonyl group is separated from the nitrogen atom by at least one carbon atom,

means hydrogen, chlorine or alkyl of 1-4 carbon atoms. and

R 3 means hydrogen, alkyl with 1 to 4 carbon atoms or halogen

with an atomic number of 17 to 35,

where at most two of the substituents R^, R2 and R^ represent hydrogen,

and acid addition salts thereof.

Alkyl or alkylene groups contained in the residue R^ can be straight-chain or branched.

If R^ stands for an alkyl group defined above, this preferably contains 1 to 4, especially 1 to 3 carbon atoms and constitutes especially methyl, ethyl. or isopropyl. A functional group contained in the residue R^ is preferably separated from the nitrogen atom by 2 or 3 carbon atoms. If R^ stands for a hydroxyalkyl group, this preferably contains 2 or 3 carbon atoms. Examples of preferred hydroxyalkyl groups are 2-hydroxyethyl and 3-hydroxypropyl. If R^ stands for a previously defined oxoalkyl group", this preferably contains a CH^-CO group and constitutes, for example, the acetonyl or 4-oxopentyl group. If R^ constitutes an alkanoyloxyalkyl group, the oxyalkyl residue bound to the nitrogen atom preferably contains 2 or 3 carbon atoms. The alkanoyl residue can, for example, constitute an acetyl or heptanoyl group. As examples of well-suited alkanoyloxyalkyl groups, acetoxyethyl or heptanoyloxyethyl are mentioned. If R^ constitutes an alkoxycarbonylalkyl group, the carbonylalkyl residue bonded to the nitrogen atom preferably contains 3 or 4 carbon atoms. methoxy or ethoxy Examples of suitable alkoxycarbonylalkyl groups are ethoxycarbonylethyl and ethoxycarbonylpropyl.

The substituent R^ preferably stands for an alkyl group with 1 more

3 carbon atoms or a hydroxyalkyl group of 2 to 3 carbon atoms.

R2 preferably means hydrogen. Such a substituent R is preferably arranged in the 2-position of the benzocycloheptathiophene shell. If R 2 denotes an alkyl group defined above, this preferably contains 1 to 2 carbon atoms and is especially methyl.

t

R3 preferably means hydrogen. Such a substituent R 3 is preferably arranged in the 6- or 7-position, especially in the 7-position of the benzocycloheptathiophene shell and preferably constitutes chlorine. If R^ stands for alkyl as defined above, this preferably contains 1 to 2 carbon atoms and is especially methyl.

Particularly preferred are such compounds of formula I in which R1 means an alkyl group with 1 to 3 carbon atoms or a hydroxyalkyl group with 2 to 3 carbon atoms, whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms, R2 means hydrogen and R^ stands for hydrogen or chlorine, as preferred is arranged in the 7-position vav the ring shell.

The peculiarity of the method according to the invention for the production of the new compounds of formula I and their acid addition salts is that

a) for the preparation of compounds of formula Ia

wherein R2 and R^ have the above meaning and R-^<1> stands for hydrogen, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 4 to 6 carbon atoms, a hydroxyalkyl group of 2 to 5 carbon atoms, whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms or an oxoalkyl group with 3 to 5 carbon atoms, if the carbonyl group is separated from the nitrogen atom by at least one carbon atom, compounds of formula II are condensed

wherein R 2 and R 3 have the above-mentioned meaning and R^means

hydrogen or lower alkyl, with compounds of the formula

III

wherein R^<1> has the above meaning or

b) for the preparation of compounds of formula Ic.

in which R 2 and R 1 have the above meaning and R 11 stands for

an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 4 to 6 carbon atoms, a hydroxyalkyl group with 2 to 5

. carbon atoms, whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms, an oxoalkyl group with 3 to 5 carbon atoms, whose carbonyl group is separated from the nitrogen atom by

at least one carbon atom, or an alkoxycarbonylalkyl group, which contains an alkoxy acid residue with 1 to 4 carbon atoms or a carbonylalkyl residue with 3 to 6 carbon atoms, whose carbonyl group is separated from the nitrogen atom by at least one carbon atom,

compounds of formula Ib are alkylated

where R ? and R-, has the above-mentioned meaning, or c) for the preparation of compounds of formula le in which R2 and R^ have the above-mentioned meaning, A means an alkylene group with 2 to 5 carbon atoms and R^ stands for an alkyl group with 1 to 9 carbon atoms, compounds of formula Id are acylated

wherein I^/R 3 and A has the above meaning,

and the obtained compounds of formula I are optionally transferred in their acid addition salts.

The condensation reaction of the compounds of formula II with the compounds of formula III can take place in ways known per se in the presence of a water or alcohol splitting agent. The compounds of formula II, in which R. means hydrogen, can be used in the enol form or the keto form isomeric to it. Lewis acids or preferably strong inorganic or organic acids are suitable as water- or alcohol-releasing agents. If the reaction is carried out in the presence of a strong inorganic or organic acid,

equivalent amounts of these acids are preferably used and the reaction is carried out at an elevated temperature, preferably at temperatures between 50 and 250°G. Examples of suitable acids include mineral acids such as sulfuric acid or organic acids such as benzenesulfonic acid or p-toluenesulfonic acid. Water or alcohol, which is formed during the reaction, can be removed directly during the reaction by distillation, preferably under reduced pressure, e.g. a pressure between 10 and 100 torr.

According to an appropriate embodiment, e.g. an anhydrous salt, e.g. the p-toluenesulfonate of a compound of formula III with a compound of formula II and the mixture is preferably heated under reduced pressure. The reaction temperature is, if R4 means hydrogen, preferably between 150 and 250°C, and if R4 means lower alkyl, preferably between 100 and 200°C. If the reaction takes place in the presence of a Lewis acid, it is carried out in an organic solvent that is inert under the reaction conditions, e.g.

an aromatic hydrocarbon such as benzene at elevated temperature is preferred

at the boiling temperature of the reaction mixture. Titanium tetrachloride or tin tetrachloride are preferably used as Lewis acids.

The alkylation of the compounds of formula Ib according to process variant b) can be carried out in ways customary for the alkylation of secondary amines per se, e.g. the compounds of formula Ib can be reacted with compounds of formula IV in a manner known per se

wherein R-^<11> has the above meaning and X stands for the acid residue of a reactive ester, preferably ±. for halogen or an organic sulfonic acid residue. The reaction preferably takes place in an organic solvent inert under the reaction conditions at temperatures between approx. 20°C and the boiling temperature of the reaction mixture, preferably in the presence of a basic condensing agent, e.g. an organic amine such as triethylamine or an alkali metal carbonate,

or in the presence of an excess of a compound of formula Ib. As a solvent, e.g. lower alcohols, halogenated hydrocarbons or dimethylformamide. Compounds, of formula Ic, which do not contain any groups which can be reduced by mild catalytic hydrogenation and in which to the carbon atom of the residue which is present. in .; The ^- position to which the nitrogen atom is bound at least one hydrogen atom can also be obtained by reduction

alkylation. The reductive alkylation, which is particularly suitable for

v production of compounds of formula Ic, in which R^<11>means cycloalkyl with 4 to 6 carbon atoms, takes place by reductive reaction with a corresponding aldehyde or ketone. The reductive alkylation can take place by catalytic hydrogenation under mild reaction conditions, preferably in the presence of a palladium catalyst, e.g. palladium/charcoal (5 or 10%) or palladium/barium sulfate. As a solvent, e.g. lower alcohols such as ethanol or dimethylformamide. For the preparation of compound of formula Ic, in which R^<11> stands for a previously defined alkoxycarbonylalkyl group, whose carbonyl group is separated from the nitrogen atom by at least 2 carbon atoms, the alkylation is preferably carried out by addition of corresponding acrylic acid derivatives according to the method of Michael. The Miehael addition of acrylic acid derivatives to compounds

with formula Ib can be carried out in a manner known per se in an organic solvent inert under the reaction conditions, preferably a cyclic ether such as dioxane, preferably in the presence of a basic catalyst, e.g. an organic ammonium hydroxide such as benzyltriethylammonium hydroxide. The reaction temperature can lie between room temperature and the boiling temperature of the reaction mixture, preferably between 40 and 50°C. For the preparation of compounds of formula le, in which R-^11 stands for a hydroxyalkyl group defined above, whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms, the compounds of formula Ib can also be reacted in a manner known per se with corresponding epoxides.

The acylation of the compounds of formula Id according to process variant e) can take place according to methods known per se, e.g. by reaction with corresponding acid halides, preferably chlorides, or corresponding acid anhydrides. If acid anhydrides are used as acylating agent, the reaction is carried out under mild reaction conditions, e.g. at temperatures between -10 and 50, preferably between 0 and 10°C. When using acid halides as acylating agent, the reaction is preferably carried out in the presence of an acid binding agent, e.g. an organic base such as pyridine, optionally with the addition of an organic solvent inert under the reaction conditions. The pH value for the reaction mixture is preferably between 5 and 14, especially between 7 and 8.

The compounds of formula I which can be preserved by the method according to the invention can be in the form of the free bases or their acid addition salts. The free bases can be transferred in a manner known per se into their acid addition salts and vice versa. Thus, the compounds of formula I can e.g. with inorganic acids such as hydrochloric acid or with organic acids such as fumaric or maleic acid to form acid addition salts. As enamines can be cleaved in an aqueous medium by an excess of protons, the acid addition salts of the compounds of formula I are preferably recovered in an anhydrous medium under

•use of equivalent amounts of acid.

The output connections can be obtained in the following way:

a<1>) the compound of formula IIa

in which and has the above meaning, can e.g. is produced by the ether groups in compounds of formula Hb in which R2 and R^ have the above meaning and R^1 means lower alkyl, in a manner known per se, is transferred into hydroxy groups. The obtained compounds of formula IIa usually exist partly in their keto form. b') compounds with formula Ilb can e.g. is obtained by reducing compounds of formula V in which and and R^<1> have the above-mentioned meaning. The reduction can e.g. is carried out using a mixture of aluminum chloride and lithium aluminum hydride in an organic solvent that is inert under the reaction conditions. c') compounds of formula V can be obtained in a manner known per se, in that compounds of formula VI

in which R 2 and R 2 have the above meaning, are brominated using N-bromosuccinimide, the dibrominated reaction products obtained in the 9- and 10-positions of the ring reaction are reacted with

an alcohol with the formula R^OH, in which R^1 has the above meaning and hydrobromic acid is then split off.

d<1->) compounds of formula VI can be obtained in a manner known per se, e.g. analogous to the one in Heiv. Chim. Aeta 49, 214-234 (1966) described method, starting from corresponding 2-/2-(2-thienyl)ethyl7benzoic acid derivatives.

To the extent that the production of the starting compounds is not described, these are known or can be produced according to per se known methods, respectively analogous to those described here or analogous to per se known methods.

The compounds of formula I and their physiologically tolerable acid addition salts are distinguished by interesting pharmacological properties and can consequently be used as pharmaceuticals.

Thus, in animal experiments for neuroleptics, the compounds show typical properties and inhibit e.g. the spontaneous motility of mice.

Due to the aforementioned effects, the compounds of formula

In finding use as a neuroleptic and used in psychiatry

for the treatment of psychotic disorders.

As drugs, the compounds of formula I and their physiologically tolerable acid addition salts can be contained together with common pharmaceutical excipients in galenic preparations such as e.g. tablets, capsules or solutions. These galenic preparations can be prepared according to methods known per se.

In the following examples which illustrate the invention,

all temperature indications in °C.

Example 1; lziå^ Z^^ 2^ j.^ £Y] Sl2h^ l2t:^^ j. 2z& t:i2t.^ zlL9. ZYll

.43 g of N-methylpiperazine in 100 ml of methanol is added to a solution of 83.0 g of p-toluenesulfonic acid monohydrate in 250 ml of methanol, evaporated under reduced pressure and the evaporation residue is dried under a water jet vacuum (approx. 15 torr) for 1 hour at 150°C. The tosylate obtained is pulverized after cooling, mixed with 50.v6)g of 10-methoxy-4-H-benzo/4",5J7-cyclohepta/1,2-b7thiophene and heated for 30 minutes at 160°C and then for 1.5 hours under reduced pressure (approx. 15 torr) at 160° C. After cooling to room temperature, 250 ml of chloroform and 250 ml of 20% NaOH are added to the solid reaction mixture, the chloroform phase is separated and the aqueous solution is further extracted with chloroform. The combined organic solutions are washed with water, dried over potassium carbonate and evaporated. The obtained crude title compound is recrystallized from isopropanol. M.P. 147 - 151°C.

The starting material is obtained in the following way:

a) to a mixture of 300 ml abs. ether, 28.9 g of anhydrous aluminum chloride and 7.2 g of lithium aluminum hydride are added during

20 minutes at 20 r- 25°G in portions 30 g of 10-methoxy-4H-benzo/4,SjTcyclohepta/C 2-b_7thiophen-4-one and it is then stirred for 1 hour at room temperature. It is then added drop by drop at 20°C

while cooling 300 ml ethyl acetate and then 150 ml 25%

NaOH. The organic phase is decanted from the soft mass of inorganic material and evaporated. The evaporation residue is recrystallized from methanol. In this way, 10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophene is obtained.

Temp. 94 to 96°C.

Example 2: lii^H-b^nzo^ASZcyk^ohepta

10 g of 4H-benzoZ4",57cycloheptaZl,2-b7thiophen-10 (9H)-one, 41.3 g of N-methylpiperazine and 200 ml of benzene are placed in a flask and 78.5 g of p-toluenesulfonic acid monohydrate are added. The suspension is then evaporated in vacuo and the evaporation residue is heated for 5 hours at 200°C oil bath temperature under water jet vacuum (15 torr). After cooling to about 50°C, 300 ml of 3N NaOH and 500 ml of benzene are added to the reaction mixture and dissolved with stirring. The organic phase is then separated, washed with water, dried over sodium sulfate and evaporated.In this way, the crude compound mentioned in the title (base) is obtained which, after recrystallization from isopropanol, melts at 147 to 151°C.

The starting material is obtained in the following way:

a) 32.75 g of 10-methoxy-4H-benzo/5,5_7cyclohepta/T,2-b7thiophene are boiled under reflux for 1 hour in 300 ml N hydrochloric acid and 300 ml

methanol. It is then cooled and the product is filtered off. The crystallisate is recrystallized from isopropanol. In this way, pure 4H-benzo[4,5-7cyclohepta[1,2-b]thiophene-10 (9H)-one is obtained which melts at 117 to 119°C.

Analogously to examples 1 and 2, the following compounds can also

with formula Ia is obtained by reaction of corresponding piperazin derivatives with formula III with corresponding 4H-benzo,/3,5j7cyclohepta/1,2-bithiophene derivatives with formula II

Example 3: 4 = 14H-benzo/li5ZcYklohep.ta/Ii2-b

To the suspension of 8.0 g of 1-(4H-benzo/3,57cyclohepta/1,2-b7thiophen-10-yl)-piperazine (for the preparation see example 1) and 2.6 g of sodium bicarbonate in 20 ml of ethanol are added dropwise, over 30 minutes a solution of 3.3 g of isopropyl bromide in 5 ml of ethanol at room temperature, the reaction mixture is heated for 4.5 hours at boiling temperature and evaporated under reduced pressure. The residue is dissolved in 100 ml of water and 300 ml of methylene chloride, the organic phase is separated, washed with water and saturated sodium chloride solution, dried over magnesium sulphate

and evaporated. The compound obtained in the title is transferred in methanol to its hydrogen fumarate. Smp.: Cleavage

from 226°G (from methanol).

Analogous to example 3, those in example 2 and in the examples can also

2 C to 2 L said compounds of formula Ic are obtained by alkylation of corresponding 4-(4H-benzo[3,5-7cyclohepta]1,2-b7thiophen-10-yl)piperazine derivatives of formula Ib.

Example 4: lzi2^ l2IZ^ Z^^^ 2/^ j.^ 22Y} Sl2\ l§^^/ Åj. 2:Z^ 7z^ i2i§Uzl9. Z

<yl>)_<->4-CYclopentylpiperazine.

A solution of 6.0 g of 1-(7-chloro-4H-benzo[4",57cyclohepta[1,2-£i7-thiophen-10-yl)piperazine and 1.8 g of cyclopentanone in 75 ml of ethanol is hydrogenated in the presence of 0.5 g of 10 % palladium on charcoal at 50° C and 5 ato hydrogen pressure. After absorption of the theoretical amount of hydrogen (time approx. 5 hours) the catalyst is filtered off, the solution is evaporated to dryness and the compound mentioned in the title remaining as a solid residue is crystallized from ether.

Temp. 169 - 170°C.

Analogous to example 4, especially the compounds of formula Ic mentioned in examples 2 A and 2 I can also be obtained by reductive alkylation of the corresponding 4-(4H-benzo</>4, 5_7cycloheptaZ<T>, 2-b7-thiophene-10- yl)piperazine derivatives of formula Ib.

Example 5: 1-2-acetoxyethyl]-4-4H-benzo

thiophene^lO^YiiPiES^Szin

To the solution of 2.0 g of 4-(4H-benzo/4",57cyclohepta/1,2-b7thiophen-10-yl)-1-piperazineethanol in 20 ml of anhydrous pyridine is added dropwise at room temperature 0.48 g of acetyl chloride, the reaction mixture is further stirred for 6 hours at room temperature and poured into 100 ml of water.

The resulting solution is extracted with benzene, the benzene solution is washed with water, dried over magnesium sulphate and evaporated. The compound mentioned in the title is crystallized from the obtained residue of ether/petroleum ether. Temp. 14 0 to 141°C.

Analogous to example 5, the following compounds of formula le can also be obtained by aylation of the corresponding hydroxy compound of formula Id with the corresponding acid derivative.

Claims (1)

Process for the preparation of new compounds of formula I in which stands for hydrogen, an alkyl group with 1-6 carbon atoms, a cycloalkyl group of 4 to 6 carbon atoms, a hydroxyalkyl group of 2 to 5 carbon atoms, whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms, or an oxoalkyl group of 3 to 5 carbon atoms, whose carbonyl group is separated from the nitrogen atom by at least one carbon atom, an alkanoyloxyalkyl group, " containing an alkanoyl residue of 2 to 10 carbon atoms and an oxyalkyl residue of 2 to 5 carbon atoms, whose oxygen atom is separated from the nitrogen atom by at least two carbon atoms, or an alkoxycarbonylalkyl group containing an alkoxy acid residue of 1 to 4 carbon atoms and an alkylcarbonyl residue of 3 to 6 carbon atoms , whose carbonyl group is separated from the nitrogen atom by at least one carbon atom, R 2 means hydrogen, chlorine or alkyl with 1 to 4 carbon atoms and R 3 means hydrogen, alkyl of 1 to 4 carbon atoms or halogen with an atomic number of 17 to 35, wherein at most two of the substituents R 1 , R 2 and R 2 mean hydrogen and acid addition salts thereof, characterized by ata) for the preparation of compound of formula Ia in which R2 and R^ have the above meaning and R^1 stands for hydrogen, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 4 to 6 carbon atoms, a hydroxyalkyl group of 2 to 5 carbon atoms, whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms, or an oxoalkyl group with 3 to 5 carbon atoms, whose carbonyl group is separated from the nitrogen atom by at least one carbon atom, compound of formula II is condensed wherein R 2 and R 1 have the above-mentioned meaning and R 1 means hydrogen or lower alkyl, with a compound of formula III wherein R^<1> has the above meaning, or b) for the preparation of compound of formula Ic in which R_ and R^ have the above meaning and R^<11> stands for an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 4 to 6 carbon atoms, a hydroxyalkyl group with 2 to 5 carbon atoms whose hydroxy group is separated from the nitrogen atom by at least two carbon atoms . at least one carbon atom, compounds of formula Ib are alkylated where R ? and R^ has the above meaning, or c) for the preparation of compound of formula le in which R2 and R^ have the above meaning, A means an alkylene group with 2 to 5 carbon atoms and R,- stands for an alkyl group with 1 to 9 carbon atoms, acylated compound of formula Id in which , R^ and A have the above meaning, and the obtained compounds of formula I are transferred, if desired, in their acid addition salts.