NO754028L - - Google Patents

Description

Procedure for the production of new organic compounds.

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

in which

IL means hydrogen, alkyl with 1 - h carbon atoms, alkoxy with 1 - h carbon atoms, fluorine, chlorine or hydroxy and

R2 means alkyl with 1 - h carbon atoms, alkenyl with 3-7 carbon atoms or alkynyl with 3-7 carbon atoms, whose unsaturated bond is not in the ct position of the nitrogen atom to which the alkenyl or alkynyl group is attached, cycloalkyl with 5-7 carbon atoms, with cycloalkyl with 2>-7J carbon atoms monosubstituted alkyl with 1-h carbon atoms, hydroxyalkyl with 2- h carbon atoms, whose hydroxy group is separated from the nitrogen atom to which the hydroxyalkyl group is bonded by at least 2 carbon atoms, a group (CR^p-CO -Ah, hyori

p is an integer from 1 to 3 and

A means alkyl with 1-k carbon atoms or alkoxy with 1-h carbon atoms, or

R^ and R^_ mean hydrogen, alkyl with 1 - h carbon atoms, alkoxy with 1 carbon atoms or halogen and

either X stands for a single bond, the vinylene or carbonyl group and n stands for an integer from 1 to 55

or X means a group of the series -O-, -S-, -SO-, -SO2- or -NR^ and n is an integer from 2 to 5, R^ standing for hydrogen, phenyl, alkyl with 1 - h carbon atoms or aTkanoyl with 2 - h carbon atoms.

Possible alkyl or alkoxy residues preferably contain 1 or 2, especially 1 carbon atom.

R2 preferably means hydrogen, alkyl, alkoxy, fluorine or chlorine.

R0 preferably stands for the above-defined groups alkyl, alkenyl,

hydroxyalkyl, -(CH ) -COA or

Standing R2

for the hydroxy alkyl group defined above, this preferably contains 2 or 3 carbon atoms. Stands for a group (CH^p-COA, p preferably means the number 2 or 3. If R2 stands for the cycloalkyl-alkyl group defined above, this residue preferably means cyclopropylmethyl.

A preferably stands for an alkyl group.

X preferably stands for a single bond or a group of the series -O-, -S-, -SO^- or -CO-, especially for a single bond or a carbonyl group. If X stands for a single bond or vinylene, n preferably means a whole number from 1 - h. Stands for X

for a group of the series -O-, -S-, -SO-, -SO2~, -CO- or -NR^-, n preferably means the number 2 or 3. If R^ stands for alkanoyl with 2- h carbon atoms, contains this residue preferably 2 or 3 carbon atoms.

R^ preferably means hydrogen, halogen or an alkyl group.

R^_ preferably stands for hydrogen. If R^ and/or R^ stand for halogen, these residues mean fluorine, chlorine or bromine, preferably fluorine or

■ chlorine.

The peculiarity of the method according to the invention is that

a) in the 1-position of compounds of formula II

in which R^ has the above meaning, a group R^ is introduced

with the above meaning or

b) for the preparation of compound of formula Ia,

in which R;j" means hydrogen, alkyl with 1 - h carbon atoms, alkoxy with 1 -*f . carbon atoms, fluorine or chlorine and

E means hydrogen, alkyl with 1-3 carbon atoms, cycloalkyl with

3-7 carbon atoms, with cycloalkyl with 3-7 carbon atoms monosubstitu-

pea alkyl with 1-3 carbon atoms or a group

where m means an integer from 0 to h and R^ and R^ has the above meaning,

is reduced in compounds of formula III

in which R;j" has the above-mentioned meaning and D means alkoxy with 1 - h carbon atoms or has the meaning given for E, a COD group to a CH E group.

2

The method according to the invention can be carried out analogously to known methods.

In procedure a), one goes, e.g. forward under the conditions

for an alkylation of a secondary amine. Method a) is therefore referred to in the following as alkylation. The compounds of formula II are alkylated, e.g. y, eå reaction with a compound of formula V

in which R^ has the above-mentioned meaning and Y stands for a residue that can be cleaved by an SN^ reaction, or with other known alkylating agents, e.g. with a compound obtainable from a compound ,%éd . formula V by cleavage of HY. Y means e.g. the acid residue of a reactive ester, e.g. halogen such as chlorine, bromine or iodine, preferably chlorine or bromine, or the acid residues of an organic sulphonic acid, e.g. an alkylsulfonyloxy acid residue such as methylsulfonyloxy, or an arylsulfonyloxy acid residue such as phenylsulfonyloxy or p-tolylsulfonyloxy.

The alkylation of the compounds of formula II with the compounds of formula V is conveniently carried out in an organic solvent, e.g. in an amide of an aliphatic carboxylic acid such as e.g. dimethylformamide or in an aromatic hydrocarbon such as toluene. It is advantageous to work in the presence of a basic condensation agent, e.g. an alkali metal carbonate such as potassium carbonate. The reaction temperature can vary between room temperature to approximately 120°C and one preferably works at the reflux temperature.

Suitable compounds, which can be obtained from a compound of formula V by cleavage of HY, are, among other things, a, p-unsaturated carbonyl compounds, for the introduction of a residue (CH^^-COA

or

in which A, R^and R^ have the above-

said meaning, and 1,2-alkylene oxides for the introduction of a 2-hydroxyalkyl group. The reaction of compounds of formula II with oc,S-unsaturated carbonyl compounds such as methyl vinyl ketone or acrylic acid, lower alkyl ester, conveniently takes place in a suitable organic solvent, e.g. glacial acetic acid, a lower alkanol such as methanol, ethanol and under stirring. The reaction temperature can vary between room temperature and the reflux temperature for the reaction mixture, preferably the reaction mixture is heated to approximately 20 - 80°C.

In the reaction of the compounds of formula II with 1,2-alkylene oxides, the reaction temperature can vary between approximately -10 and 100°C.

Groups of the residue R2, as under the conditions of the method

a) are not inert, can be protected and cleaved after introduction of the protected residue R^in the 1-position of the compounds of formula

II. Thus, one can e.g. obtain final compounds of formula Ib

where r means an integer from 1 to ? and L , R-, and R* have the above-mentioned meaning, in that a residue in which r, R^ and R^ have the above-mentioned meaning, in the form of a catal analogous to the methods described above 1 is introduced in the 1-position by a compound with formula II and from the protected end compounds thus obtained, e.g. with formula VI-

wherein Rp r, R^ and R^ have the above meaning and either R^

and R^' means alkyl with ^-k■ carbon atoms. or R^and R^.' together stand for an alkyl residue with 2 h carbon atoms, the protecting group or the protecting groups are split off.

If in the compound of formula I the carbon atom in the residue R^, which is in the a-position to the nitrogen atom, bears a hydrogen atom and is R^inated under the conditions for a reductive alkylation, then this residue can also be obtained by reductive alkylation of the compounds of formula II with aldehydes or ketones corresponding to R^. The reductive alkylation can be carried out according to known methods, e.g. hydrogenolytic or according to Leuckart-Wallach.

Procedure b) can be carried out analogously to those for reduction

of tert-amides, respectively N,N-disubstituted ureotanes to tert-amines known methods. The compounds of formula III are reduced, e.g. with possibly complex metal hydrides or diborane.

As metal hydrides, aluminum hydrides such as e.g. aluminum hydride, dialkyl aluminum hydrides, lithium aluminum hydride or lithium aluminum/aluminum chloride suitable.

In general, the reduction is conveniently carried out in a solvent that is inert under the reaction conditions. Suitable solvents are e.g. open or cyclic ethers, e.g. tetrahydrofuran.

The reduction can be carried out at approximately room temperature to approximately 100°C, e.g. at about 30°C to boiling temperatures of the reaction mixture. In the reduction of tertamides of formula III, one preferably works at approximately ho - 60°C, in the reduction of the urethanes of formula III preferably at the boiling temperature of the reaction mixture.

If a chlorine or bromine substituent is present in the compound of formula III, aluminum hydride or a dialkyl aluminum hydride is suitably used as the metal hydride, but also diborane.

Method b) is particularly suitable for the reduction of an N-alkoxycarbonyl group to the N-methyl group as well as for the introduction of the cyclopropylmethyl group.

The compounds of formula I can be present in free form as a base or in the form of addition salts with acids.

Acid addition salts can be prepared from the free bases in a known manner and vice versa, e.g. Bis-base-naphthalene-1,5-disulfonate or hydrogen malonate.

The compounds with formulas II and III are new and can be prepared analogously with known methods.

The compounds of formula IIa

in which R^" has the above-mentioned meaning, can for example be prepared by removing an alkoxycarbonyl protecting group from the compounds of formula Illa

in which r| has the above meaning and alk stands for alkyl with 1-k carbon atoms.

Ether cleavage of a compound of formula IIa, wherein r| means alkoxy with 1-h carbon atoms, with e.g. Lewis acids or with alkali metal hydride mercaptan such as sodium hydride/methyl mercaptan gives the corresponding hydroxy derivative.

The compounds with formula Illa can e.g. produced using

of a Grignard synthesis from the compound of formula IV, wherein alk has the above meaning. The turnover proceeds stereo-specifically.

The N-acylation, respectively N-formulation of the compounds by formejyl gives the corresponding NCOD derivatives of formula III, in which E has the meaning indicated.

The compounds of formula IV in which alk means ethyl are known. The other compounds of formula IV can be prepared analogously to this compound.

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

The compound of formula I in free form or in the form of their physiologically tolerable addition salts with acids, hereinafter referred to as substances of formula I, has an interesting pharmacodynamic

property, and can therefore be used as medicine.

They exhibit an antiarrhythmic effect, and because of this effect they are suitable for the treatment of heart rhythm disturbances.

For use as anti-arrhythmics, the substances of formula I, in which R is hydrogen, 3-methoxy, β-methyl, β-fluorine or β-chloro, as well as the substances of formula I, in which R ^ means methyl, allyl, a group (CH^)-CO-CH^, wherein p has the above meaning, phenylalkyl of 7-10 carbon atoms, phenoxyalkyl of 8-9 carbon atoms, 3-p-chlorophenylthiopropyl, 3-p-chlorophenylsulfonyl -

propyl or a group

wherein r has the above meaning, R 1 means hydrogen, fluorine, chlorine or methyl and R 2 means hydrogen or methyl.

The substances with formula I also exhibit an antidepressant effect, and are due to this effect suitable for the treatment of depression.

For use as antidepressants, the substances of formula I in which R 2 is chloro as well as the substances of formula I in which R 2 is methyl, allyl or 2-hydroxyethyl are particularly suitable.

The substance can be used in the form of preparations, e.g. a solution or a tablet which can be prepared according to known methods, using usual auxiliary and carrier substances.

In the following examples, all temperature indications are in °C and are uncorrected.

Example 1; (3aRS, hSR, 7aRS)-hexahydro-1-phenethyl-M-phenyl-^-indolinol

(method a)

1^.8 g of (3aRS,<I>fSR,7aRS)-hexahydro-If-phenyl-if-indolinol, 18.9 g of phenethyl bromide and 18 g of potassium carbonate are heated for 15 hours under reflux in 170 ml of dimethylformamide. After cooling, evaporation is carried out and they are shaken with water/ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated (melting point of the hydrogen malonate 133-135°C from ethanol/ethyl acetate).

The starting product was produced in the following way:

a) Phenylmagnesium bromide (prepared from ^f0 g of bromobenzene and 5 g of magnesium) is reacted with 30 g of cis-hexahydro-^-oxo-1-indoline-carboxylic acid ethyl ester in tetrahydrofuran. After h hours of stirring at room temperature, 100 ml of 2N hydrochloric acid and 200 ml of ether are added to the reaction mixture. The organic phase is separated, washed with water and dried over sodium sulphate. After evaporation of the ether, (3aRS,^SR,7aRS)-hexahydro-^-hydroxy-1+-phenyl-1-indoline-carboxylic acid ethyl ether remains as an oil. b) 30 g of (3aRS,<!>+SR,7aRS)-hexahydro-<l>+-hydroxy-<l>+-phenyl-1-indoline-carboxylic acid ethyl ester are dissolved in 300 ml of methanol, and after addition of 300 ml of 10N sodium hydroxide is stirred overnight at boiling temperature. After cooling, extract thoroughly with methylene chloride. The methylene chloride phase is extracted with 2N tartaric acid solution, the usual tartaric acid solution is made alkaline again and extracted with methylene chloride. After normal work-up of the organic phase, (3aRS,<l>+SR,7aRS)-hexahydro-If-phenyl-^--indolinol is obtained (melting point of hydrogen naphthalene-1,5-disulfonates 228 - 230°C from ethanol.

Example 2: (3aRS ,^-SR, 7aRS )-p-fluoro-^f-(hexahydro-^-hydroxy-^--m-methoxy enyl-1-indolinyl )butyrof enone

(method a)

6g of (3aRS,^-SR,7aRS)-hexahydro-<l>+-m-methoxyphenyl-<1>+-indolinol is heated with 3 g of 2-(3-chloropropyl)-2-p-fluorophenyldloxolane for 1 hour at 150 °C. The solidified melt (3aRS,>+SR, 7aRS)-1-(3-(2-p-fluoro-phenyl-1,3-dioxolan-2-yl)-propyl m-methoxyphenyl-h-indolinol is adjusted alkaline with 2N sodium hydroxide and extracted thoroughly with methylene chloride. The oily residue obtained after normal work-up is dissolved in 165 ml of acetone and removed with 16.5^1 2N hydrochloric acid for ^-8 hours at room temperature. After evaporation to dryness , the compound mentioned in the title crystallizes from ethanol/ether as a hydrochloride with a melting point of 168 - 170°C.

Example 3: (3aRS,*fSR,7aRS )-1+-p-chlorophenyl-hexahydro-1-methyl-^f-indolinol

(method b)

15 g of (3αRS,1+SR,7αRS)-1+-p-chlorophenylhexahydro-1+-hydroxy-1-indoline-carboxylic acid ethyl ester and k-g of lithium aluminum hydride in 100 ml of tetrahydrofuran are heated for 15 hours under reflux. Excess lithium aluminum hydride is decomposed by the addition of water. Partitioning between water and ether gives, after separation and normal work-up of the organic phase, the compound mentioned in the title, as an oil (melting point of the base 98 to 101°C from ether/petroleum ether).

Example h: (3aRS,<!>+SR,7aRS)-if-p-chlorophenyl-1 -cyclopropyl-S®iY.i~^®^S5§^y.^S2z<1>±liG^2ii22i

(method b)

To a solution of 1.3 g of lithium aluminum hydride in 30 ml of tetrahydrofuran is added a solution of 5,2 (3aRS,1+SR,7aRS)-1+-p-chlorophenyl-1-cyclopropyl-carbonylhexa-hydro-^f prepared during heating: indolinol in 30 ml of tetrahydrofuran. The mixture is stirred for 30 min. at 50°C, decomposed with saturated ammonium sulfate solution and filtered. The evaporated filtrate is added to a concentrated solution of naphthalene-1,5-disulfonic acid. After addition of ether, bis (3aRS,^-SR,7aRS)-If-p-chlorophenyl-1-cyclo.propyl-methylhexahydro-^-indolinol)naphthalene-1,5-disulfonate crystallizes with melting point 2h- 0 - 2h2 °C.

The starting material can be produced in the following way:

To a solution of 7.2 g (3aRS,>+SR,7aRS)-1+-p-chlorophenyl-hexahydro-^--indolinol and 2.5 ml of pyridine in 30 ml of methylene chloride, at o - 10° a solution is added dropwise of 2.7<*>+ g of cyclopropanecarboxylic acid chloride. The mixture is then stirred for 1 hour at room temperature, then shaken successively with ~\0% tartaric acid solution, sodium bicarbonate and saturated sodium chloride solution, dried over sodium sulfate and evaporated, as (3aRSj^-SR^aRS )-If-p-.chlorophenyl- 1-Cyclopropyl-carbonyl-hexahydro-β-indolinol with melting point 167 - 169* is obtained.

In an analogous way, by proceeding from the corresponding compounds with formula II (method a) or with formula III (method b), the following compound with formula I is obtained:

Claims (3)

1. Process for the preparation of new compounds of formula I in which FL means hydrogen, alkyl with 1-h carbon atoms, alkoxy with 1-k- carbon atoms, fluorine, chlorine or hydroxy and R^ means alkyl with 1 carbon atom, alkenyl with 3-7 carbon atoms or alkynyl with 3-7 carbon atoms, whose unsaturated bond is not in the a-position to the nitrogen atom to which the alkenyl or alkynyl group is bound, cycloalkyl with 5-7 carbon atoms, with cycloalkyl with 3-7 carbon atoms, monosubstituted alkyl with 1 carbon atoms, hydroxy alkyl with 2-k carbon atoms, whose hydroxy group is separated from the nitrogen atom to which the hydroxyalkyl group is bound by at least 2 carbon atoms, a group -(CH2 )p -CO-A, wherein p is an integer from 1 to 3 and A means alkyl with 1 - k carbon atoms or alkoxy with o 1 - h- carbon atoms or a group in which R^ and R^ mean hydrogen, alkyl with 1-k carbon atoms, alkoxy with 1 carbon atom or halogen and either X stands for a single bond, the vinylene or carbonyl group and n stands for an integer from 1 to 55 or X means a group of the series -0-,-S-,-SO-, -S02~ or -NR^ -and n means an integer from 2 to 5? as R^. stands for hydrogen, phenyl, alkyl with 1 - h carbon atoms or alkanoyl with 2 - k carbon atoms, and acid addition salts thereof, characterized by ata) in the 1-position of a compound of formula II in which R^ has the above-mentioned meaning, a group R^ with the above-mentioned meaning is introduced, orb) for the preparation of a compound of formula Ia in which R^" means hydrogen, alkyl with 1 - h carbon atoms, alkoxy with 1 - h carbon atoms, fluorine or chlorine and E b;e,tyr hydrogen, alkyl with 1 - 3 carbon atoms, cycloalkyl with 3-7 carbon atoms, with cycloalkyl with 3-7 carbon atoms, monosubstituted alkyl with 1 - 3 carbon atoms or a group where m means an integer from 0 to k and R^ and R^ has the above meaning, is reduced in connection with formula III in which R.j has the above-mentioned meaning and D means alkoxy with 1 - h carbon atoms or the meaning given for E, a COD group to a CH^ E group, and the thus obtained compounds of formula I are recovered as a base or as acid addition salts. 2. Process as stated in claim 1 for the production of (3aRS, <l> +SR, 7aRS )-hexahydro-1-phenethyl-^-phenyl-^f-indolinol, characterized in that a) in the 1-position of (3aRS,IfSR,7aRS )-hexahydro-1+-phenyl-^-indolinol introduces the phenethyl group or b) in (3aRS, <l> +SR,7aRS)-hexahydro-If-phenyl-1-phenacetyl- <i> +-indolinol reduces the benzylcarbonyl group. 3. Process as stated in claim 1 for the preparation of (3aRS,1+SR,7aRS)-If-p-chlorophenylhexahydro-1-(2-hydroxyethyl)-If-indolino: characterized by the at^i> 1 position of (3aRS, ^-SR^aRS)-If-p-.chlorophenylhexahydro-^-indolinol the 2-hydroxy-ethyl group is introduced. h. Process as stated in claim 1 for the preparation of (3aR£>y ^-SR,7aRS )-1 -allyl-^-p-chlorophenylhexahydro-^--indolinol, characterized in that the ally group is introduced in the 1-position of ( 3aRS,1+SR,7aRS)-^-p-Chlorophenylhexahydro-^--indolinol.