CH638173A5 - Process for preparing benzylamine derivatives - Google Patents

Abstract

Compounds of the formula A1 are obtained by reacting ketones of the formula C with methyl Grignard compounds. The cis epimers are obtained either directly or following removal of the trans epimer which is formed concomitantly, and then used. The substituents X, R<1> and R<2> can be converted into other substituents which ensure that the substances are equally useful. The compounds I, and their pharmacologically usable acid addition salts, are suitable for use as analgesics for vertebrate animals. <IMAGE>

Description

The present invention relates to the production of benzylamine derivatives with a pharmacological, in particular analgesic, effect.

US Pat. No. 2,767,185 describes a process for the preparation of certain aminocycloalcohols of the formula

G

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R-CH NRg

J ®

© CH-CHOH V (CH2 / n

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reacted with a methyl Grignard compound, separated off any trans-epimer formed and, if desired, converted a free base (AI) obtained with an acid into a pharmacologically acceptable acid addition salt.

2. The method according to claim 1, characterized in that a compound of the formula (AI) obtained, in which X represents an alkoxymethoxy radical, is hydrolyzed to a corresponding compound with X = hydroxy.

3. The method according to claim 1, characterized in that a compound of the formula (AI) obtained, in which X = -OH, is converted into such a compound by etherification, in which X = alkoxymethoxy having up to 8 carbon atoms in the alkoxy radical.

4. The method according to claim 1, characterized in that a compound of the formula (AI), wherein X = -OH, is converted by esterification into a corresponding compound with X = alkylcarbonyloxy having up to 8 carbon atoms in the alkyl radical.

5. The method according to claim 1, characterized in that alkylating a compound obtained, wherein R2 is methylamino, to a corresponding compound with R2 = N-alkyl-N-methylamino having up to 8 carbon atoms in the alkyl radical.

6. A process for the preparation of a compound of formula AI as shown in claim 1, wherein R1 is an alkyl radical having up to 8 carbon atoms, characterized in that the compound of formula Al with R1 = H according to the process of claim 1 manufactures and etherifies the OH group.

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in which n is an integer from 3 to 5, R is a phenyl radical and -NR12 is one of the following secondary amino groups:

N-methyl-N-alkylamino, N-methyl-N-aralkylamino, piperidino, morpholino, pyrrolidino and N'-alkyl-piperazi-no. These compounds, which were prepared by reacting benzal cycloalkanones with corresponding amines and subsequent reduction, were obtained as mixtures of two epimeric racemic modifications, i.e. as mixtures of the racemates of the compounds which, with regard to the configurations on the asymmetric carbon atoms 2 and 3, are referred to as the ice and transient. Numerous compounds in which -NR12 denotes a piperidino or N'-alkylpiperazinorest have been broken down into the two racemic modifications without identification. The two additional epimeric racemic modifications that are theoretically possible due to the reverse configuration at the asymmetric carbon atom 1 were not obtained. As a field of use, the usability of the N'-alkylpiperazine compounds as intermediates in the preparation of corresponding hexahydro-benzhydryl-piperazines, whose quaternary ammonium salts are said to be effective spasmolytics, was specified in the above patent. This usefulness is also described in more detail for the trans-epimer in US Pat. No. 2,748,126.

By Baltzly, et al., J.A.C. S. 77, 624 (1955) also described the reaction of secondary amines with benzalcyclanones, which give aminocyc-lanones in the subsequent reduction. The cited literature reference also contains the melting points of the ice and trans epimers of piperidino and N'-alkylpiperazino-benzyl-cyclohexanols. By Rüssel et al., J.A.C. S. 77, 629 (1955) became the method for

638 173

Determination of the configuration of the epimeric piperidino and N-alkyl-piperazino-benzylcyclohexanols described.

When C-phenyl-nitron is added to cyclopentene or cyclohexene, the corresponding isoxazolidine is obtained, and in the case of cyclopentene, the reduction gives an a-

Methyl-aminobenzylcyclopentanol (Huisgen, et al, Chem. Ber. 101, 2043 (1968). The stereochemistry at the a-carbon atom was not explained.

The present invention relates to the preparation of compounds of the formula

(CH

in which R1 is hydrogen, lower alkyl or lower alkyl-carbonyl, R2 is a lower alkylamino, N-lower alkyl-N-methylamino, N-phenyl-lower alkyl-N-methylamino; 1-pyrrolidinyl, 4-morpholino, N-lower alkenyl-N-methylamino, N-cycloalkylmethyl-N-methylamino or N-oxo-N-lower alkyl-N-methylamino radical, X hydrogen, the hydroxyl group, a lower alkoxy -, Niederalkoxymethoxy- or Niederalkylcarbonyloxyrest or a halogen atom and n represent an integer from 3 to 6, wherein the cyclo-alkane ring may be further substituted, and their pharmacologically acceptable acid addition salts. The compounds can be used as analgesics for warm-blooded animals. “Lower” stands for residues that contain up to 8 carbon atoms.

The compounds of the formula I are in the form of the free bases colorless to yellow oils or solids which are practically insoluble in water and generally soluble in organic solvents such as ether, benzene, hexane, acetone and pyridine. In the form of the acid addition salts, the compounds are generally white to off-white crystalline solids with marked solubility in water. Infrared, ultraviolet and nuclear magnetic resonance spectra provide spectral data that confirm the above molecular structures. The mentioned physical properties and the elementary analysis of the products also confirm the assigned structures.

The compounds of formula I and their pharmacologically acceptable salts are active as analgesics in warm-blooded animals, as determined by standard tests.

The following compounds of the formula I are preferred with regard to their usability: cis-2- (a-dimethylamino-m-hydroxybenzyl) cyclohexanol; cis-2- (a-dimethylamino-m-methoxybenzyl) cyclohexanol; cis-2- (a-dimethylaminobenzyl) cyclohexanol; l-cis-2- (a-dimethylamino-m-hydroxybenzyl) cyclohexanol and their pharmacologically acceptable salts.

Preferred compounds of the formula I are furthermore epi-cis-2 (a-dimethylamino-m-hydroxybenzyl) cyclopentanol,

Epi-cis-2- (a-dimethylamino-to-hydroxy-benzyl) -cyclo-hexanol and their pharmacologically acceptable salts.

The method according to the invention is defined in claim 1 and initially leads to compounds (AI) in which R1 is hydrogen. Preferred embodiments of the method and also conversions of the substances obtained form the subject of dependent claims or dependent claims.

All products obtained can be converted into acid addition salts.

The product obtained in the process is generally in two epimeric forms, which can be separated according to conventional procedures before or after further treatments such as etherification or esterification.

Certain compounds of the formula AI can be converted into other compounds of the formula AI. Such processes are, for example, the etherification or esterification of a compound of the formula AI, in which 25 R1 is hydrogen, with the formation of a corresponding compound in which R1 is a lower alkyl or lower alkyl carbonyl radical, the etherification or esterification of a compound of the formula AI, in which X is a hydroxyl group to form a corresponding compound in which X is lower alkoxy, lower alkoxymethoxy or lower alkylcarbonyloxy; hydrolysis of a compound of formula AI, wherein X is lower alkoxy methoxy, to form a corresponding compound, wherein X is the hydroxyl group; hydro-hydrolysis of a compound of the formula AI, in which R2 is an N-benzyl-N-lower alkylamino radical, to form a corresponding compound in which R2 is a lower alkylamino radical; treating a compound of formula AI wherein R2 is an N-lower alkyl-N-methyl-40 amino group with a peracid, e.g. m-chloroperbenzoic acid, to form a compound of formula AI wherein R2 is an N-lower alkyl-N-methylamino -N-oxide means the alkylation of a compound of the formula AI, in which R2 is the methylamino radical, with a lower 45 alk-2-enylhalide to form a corresponding compound in which R2 is an N-lower alkenyl-N-methylamino radical, and Alkylation of a compound of formula AI in which R2 is the methylamino group to form a compound in which R2 is an N-lower-50-alkyl-N-methylamino-, N-cycloalkylmethyl-N-methylamino- or N-phenyl-lower alkyl- N-methylamino radical means, for example by acylation and subsequent reduction of the carbonyl group to the methylene group.

The invention also relates to a process for the preparation of pharmacologically acceptable acid addition salts of the compound of the formula I, which is characterized in that the free base I is treated with a pharmacologically acceptable acid.

The starting materials required for the process according to the invention are known or can be obtained by procedures known per se.

In particular, the ketone of formula (C) can be obtained by reacting a cycloalkanone in the presence of a base with a benzaldehyde to give a benzal compound and adding a secondary amine to it to form a compound (C), e.g. B. according to the following scheme:

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638173

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KOH

OCH.

Ï (CH3'2 CH—

The starting materials, i.e. the cycloalkanones and the benzaldehydes, are known or can be prepared from known compounds by processes familiar to the person skilled in the art, see for example Edwards et al., J. Chem. Soc., (c) 411 (1967).

The reaction of these compounds in the presence of an aqueous base such as potassium hydroxide leads to the correspondingly substituted benzalcycloalkanones III. The reaction temperature is not critical, but the condensation is expediently carried out at the reflux temperature and is carried out under nitrogen to achieve optimum yields. The product can be isolated from the reaction medium by standard methods, for example by extraction with an organic solvent such as diethyl ether, followed by washing, drying and distilling off the solvent. When the residue is distilled, the product is obtained in the form of an oil. The benzalcycloalkanone thus obtained is then reacted with the corresponding amine in a non-reactive solvent such as diethyl ether to form the corresponding benzylcycloalkanone C. This reaction is used OCH.

carried out moderately at room temperature in a pressure bottle, preferably using an excess of amine. As soon as the time required to ensure an optimal yield of benzylcycloalkanone has elapsed, the reaction mixture or also the isolated addition product is further reacted according to the invention, namely by treating the benzylcycloalkanone C with a methyl Grignard reagent, e.g. with methylmagnesium-25 bromide, using the usual conditions for the grignaration of ketones, for example refluxing in ether for several hours. The cis-epimer is obtained mixed with the trans-epimer and the two can be separated according to the methods given below.

The product usually obtained in the form of an oil generally comprises two epimeric forms, which are then separated.

The compounds obtained according to the invention have three asymmetric carbon atoms, which are shown in the following formula:

Theoretically, they should be available in eight optically active forms and four racemic modifications. However, not all of these modifications are obtained in the above process and the product consists essentially of a mixture of only two racemic modifications (i.e. two epimeric forms and their enantiomers). The aminoketones C occurring as an intermediate have two centers of asymmetry and can theoretically exist in two racemic modifications. So jCH 1

however, until the aminoketones are left in the reaction system leading to their formation for a considerable period of time, for example three days or more, only one epimer is isolated. In the methylating reduction of the car bonyl group, a new asymmetry center is formed, which leads to two epimeric racemic modifications CH3HB-cis ss and CH3HB-trans, which can be represented as follows:

C1S

In the present description, the expression “ice” denotes the epimer with the CH3HB-cis relationship when applied to compounds produced according to the invention.

The ice and trans epimers obtained in the above manner can be separated by known methods, e.g. by fractional crystallization or preferably by chromatography. The compounds are expediently separated by chromatography on aluminum oxide Woelm, for example neutral activity, grade III, in a column prepared with benzene / hexane in a ratio of 1: 1. The elution can be carried out using systems such as benzene / hexane and then benzene / ether, or benzene / hexane and then benzene and then benzene / ether. The trans isomer is eluted first, usually in the first solvent mixture, and the cis form is eluted in the second solvent.

It is also effective to use a column made of chloroform with Woelm alumina, from which the trans-epimer is first eluted with chloroform or with chloroform containing 5-10% acetone, followed by elution of the cis component with methanol after passing the column cut off just above the cis component. The cis component is made visible with UV light. Of course, the optimal chromatographic systems depend on the respective connections to be separated. However, the choice of the optimal system for each case lies within the range of usual professional skills. The cis and trans configurations can be distinguished using a narrower NMR signal for the cis compound.

Although the above illustration of the process according to the invention relates only to the preparation of a compound of the formula AI, in which R1 is hydrogen, R2 is the dimethylamino group and X is the m-methoxy group, it is obvious to the person skilled in the art that any substituted compounds within the scope of the present invention Invention can be obtained in an analogous manner. Thus, compounds can be prepared in which X is hydrogen, the hydroxyl group, a lower alkoxy or lower alkoxymethoxy radical or a halogen by using the appropriately substituted benzaldehyde in the first stage. In addition, compounds in which R2 is a lower alkylamino group, an N-lower alkyl-N-methylamino, N-lower alkenyl-N-methylamino, N-cycloalkylmethyl-N-methylamino, N-phenyl-lower alkyl-N-methylamino -, 1-pyrrolidinyl or 4-morpholino means, prepare by using the appropriately substituted primary or secondary amine in the second reaction stage. Compounds which have an N-oxo-N-lower alkyl-N-methylamino radical as substituents R2 are obtained by reacting the corresponding products with R2 = N-lower alkyl-N-methylamino with a peracid, such as, for. B. treated m-chloroperbenzoic acid. Compounds in which R1 is a lower alkylcarbonyl radical can be obtained by treating corresponding products with R1 = hydrogen with the anhydride or chloride of a lower alkylcarboxylic acid. Compounds in which X represents a lower alkylcarbonyl radical are obtained by reacting products with X = hydroxyl with such acylating agents. Compounds in which the substituent R1 is a methyl group can be obtained by treating the compounds with R1 = hydrogen with a strong base such as butyllithium and methyl iodide. In addition to the synthesis from the correspondingly substituted benzaldehydes, compounds in which X is the hydroxyl group can also be obtained according to a preferred procedure by acidic hydrolysis of the corresponding product in which X is an alkoxymethoxy radical

638 173

is. Compounds with X = hydroxy can be converted into the corresponding methoxy compounds by treatment with diazomethane, or in compounds with alkoxy substituents X, by reacting with the corresponding alkyl halide in the presence of a base. The person skilled in the art has no difficulty in carrying out these modifications.

Although compounds in which R2 is a lower alkylamino radical can also be prepared using a primary amine, it has been found that using a primary amine results in a reaction which is less stereospecific than the reaction described for the secondary amines. The result is the second possible epimer in this step in appreciable amounts, while reducing the yield of the desired epimer in the last process step. For this reason, a modification of the above general process is also preferred in the synthesis of the corresponding secondary amines. According to this modified procedure, the benzal-cyclohexanone (II) formed in the first precursor is reacted with a benzyl-lower alkylamine to form the corresponding a- (N-benzyl-N-lower alkylamino) -benzylcycloalkanone, which then becomes cycloalkanol in the manner already described is reduced methylating. Hydrogenolysis of this compound, for example with 10% palladium / carbon in the presence of an acid such as acetic acid, gives the desired a- (lower alkyl-amino) -benzylcycloalkanol. The latter compounds can also be used as intermediates in other syntheses of compounds in which R2 is an N-lower alkyl-N-methylamino, N-lower alkenyl-N-methylamino, N-cycloalkylmethyl-N-methylamino or N- Phe-nyl-lower alkyl-N-methylamino residue. In this variant of the process, the a- (lower alkylamino) benzylcycloalkanol is reacted with a carboxylic acid halide (for example with acetyl chloride if the substituent R2 is the N-ethyl-N-methylamino radical) and the intermediate is reduced, for example with lithium aluminum hydride, with receives the desired end product. A product whose substituent R2 is an N-lower alkenyl-N-methylamino radical can be prepared by alkylating the corresponding compound with R2 = methylamino with a lower alken-2-yl halide. A special process for the preparation of compounds with R2 = dimethylamino consists in the reaction with ethyl chloroformate or with N, N'-carbonyldiimidazole, whereby an N-methyl-carbäthoxyurethan or a cyclic urethane is obtained, which after reduction, for example with Lithium aluminum hydride, which gives the desired product.

In the present description and claims, lower alkyl is understood to mean a straight-chain or branched hydrocarbon radical having 1 to 8 carbon atoms, such as, for example, the methyl, ethyl, n-propyl, isopropyl radical or the like. The term “Niederal-kenyl” covers monoalkenes with 2 to 8 carbon atoms, which can be straight-chain or branched. “Cycloalkyl” is understood in particular to mean cyclic hydrocarbon radicals having 3 to 6 carbon atoms, examples being the cyclopropyl radical, cyclobutyl radical and the like. cited. A “phenyl-lower alkyl” radical is preferably understood to mean a phenyl radical bonded via an alkyl radical with 1 to 4 carbon atoms, very preferably the benzyl radical.

Of course, the cycloalkanone and cycloalkene starting materials can carry other substituents that are not affected by the process, e.g. Methyl or methoxy groups, chlorine atoms, trifluoromethyl groups and the like.

To achieve an analgesic effect in warm

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638 173

The compounds can be administered to hematopoiesis in various dosage forms orally or parenterally. The dose depends on the particular compound, the severity and type of pain and the animal to be treated. For large animals (about 70 kg body weight) and oral administration, doses between about 2 and about 40 and preferably about 10 and about 25 mg are used every four hours as needed. When administered intramuscularly, the dose is about 1 to about 20 mg if necessary. Ideally, therapy should be started with lower doses, after which the dosage is increased until the desired analgesic effect is achieved.

To produce dose units, the active ingredient is incorporated into conventional dosage forms for oral administration, such as tablets, capsules or liquid preparations, such as elixirs and suspensions, which contain colorants, flavors, stabilizers and taste-masking substances. To prepare oral dosage forms, the active ingredient can be diluted with various tabletting aids such as starches, calcium carbonate, lactose, sucrose or dicalcium phosphate in order to simplify tabletting and encapsulation processes. Smaller amounts of magnesium stearate are suitable as lubricants.

The compounds obtained according to the invention can be used in the form of the free bases or in the form of pharmacologically acceptable acid addition salts. These salts can be obtained by reacting the free base with an equivalent amount of acid, the acid addition salt having to be practically non-toxic under the conditions of use. Examples of suitable salts are the hydrochloride, hydrobromide, furamate, maleate, succinate, sulfate, phosphate, tartrate, acetate, citrate and the like. For parenteral administration, the compounds are expediently used in the form of their pharmaceutically acceptable acid addition salts. These salts are water soluble and can easily be incorporated into preparations suitable for injection.

Preparation A m-methoxymethoxybenzalcyclohexanone 167 g (1.0 mol) of m-mefhoxymethoxybenzaldehyde and 318 ml (3.0 mol) of cyclohexanone are boiled under reflux for 4 hours under nitrogen with a solution of 50 g (0.89 mol) of potassium hydroxide in 11 water . After cooling, the oily phase is extracted twice with ether. The ether solution is washed 3 times with water, then with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is distilled, the product obtained as a yellow oil (132 g), Kp0 3 = 173-116 ° CXmax EtOH 287 mu (s 13 100); vKBr 1685,1600, 1580 cm- '. NMR (CDC13): 5 5.2 (2H singlet, -0CH20), 3.48 (3H singlet, -OCH3).

Example cis-2- (a-dimethylamino-m-hydroxybenzyl) -1-methylcyclohexanol fumarate A solution of 100 g (0.4 mol) of m- (methoxy-meth-oxy) benzalcyclohexanone (see preparation A) in 100 ml of ether is cooled in a pressure bottle to -5 ° C, treated with 100 ml dimethylamine and left overnight at room temperature. Then the reaction mixture is concentrated, the residue is dissolved in ether and washed twice with water (the washing solutions are discarded), then extracted twice with dilute hydrochloric acid and with water. The combined acidic extracts are washed with ether and then made basic with ice-cold sodium hydroxide solution. Extracting with ether gives 96.5 g of the dimethylamino adduct (I.R. SAT only Oxo-Peak). 96 g of the adduct in 400 ml of ether are added to a 3 molar solution of methyl magnesium bromide in ether (250 ml) over the course of 30 minutes, then the mixture is refluxed for 90 minutes, after which the mixture remains at room temperature overnight. After treatment with 75 ml of ice-cold saturated ammonium chloride solution, 50 g of basic material are isolated in the same way as the methylamine adduct and chromatographed on 1.7 kg of clay (Woelm grade III neutral). The benzene / hexane (1: 2) and benzene fractions elute the trans-2- (a-dimethylamino-m-methoxymethoxybenzyl) -l-methylcyclo-hexanol (I) as an oil NMR (CDC13): 82.05 (6H Singlet, N (CH3) 2), 1.12 (3H singlet CH3-C (OH) =) ppm. Benzene with increasing amounts of ether changes the cis-2- (a-dimethylamino-m-methoxymethoxybenzyl) -l-methylcyclo-hexanol (II) as an oil, NMR (CDC13): 82.26 [H singlet, N (CH3 ) 2), 1.15 (3H singlet CH3-C (OH) =) ppm eluted. The stereochemical assignments are based on the NMR spectrum of the POCl3-pyridine dehydration products. These show that 1 gives only an A2-01efin, while II leads to an À1 olefin as the main product, together with smaller amounts of the A2 compound. In the acidic hydrolysis, the trans compound I gives the trans-2- (a-dimethylamino-m-hydroxybenzyl) -l-methyl-cyclohexanol with a melting point of 151-153 ° C. and a fumarate of 177-179 ° C. 10.0 g of the cis compound II in 50 ml of tetrahydrofuran are treated with 12.5 ml of 4.7 M isopropanolic hydrogen chloride and left to stand overnight. After the solvent has evaporated off, the residue is triturated with ammonia and ether, the ether extract is washed with water and saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gives the highly crystalline cis-2- (a-dimethylamino-m-hydroxybenzyl) -1-methoxycyclohexanol with a melting point of 175-177 ° C, a fumarate with a temperature of 199-203 ° C (decomposition). Analysis:

Found: C: 62.92; H: 7.69; N: 3.88.

Calculated for C16H25N02 • C4H404:

C: 63.30; H: 7.70; N: 3.69%.

NMR (DMSO) 82.2 (6H singlet, N (CH3) 2), 0.65 (eH singlet CH3-C (OH) =) ppm.

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Claims (3)

638 173 2nd PATENT CLAIMS 1. A process for the preparation of a compound of For in the cis form, essentially free of the trans-epimer, wherein R1 is hydrogen, R2 is an alkylamino, N-alkyl-N-methylamino, N-phenylalkyl-N-methylamino -, N-alkenyl-N-methylamino, 1-pyrrolidinyl, 4-morpholino or N-cycloalkylmethyl-N-methylamino radical, X is hydrogen, hydroxyl, alkoxy, alkoxymethoxy or alkylcarbonyloxy or halogen and n is an integer of 3 to 6, where the alkyl, alkenyl and alkoxy radicals mentioned have up to 8 carbon atoms and the cycloalkyl ring of the formula AI can carry further substituents, and their pharmacologically acceptable acid addition salts, characterized in that a corresponding compound of the formula C. (C) lCVn 7. A process for the preparation of a compound of formula AI as shown in claim 1, wherein R1 is an alkylcarbonyl radical having up to 8 carbon atoms in the alkyl radical, characterized in that the compound of formula Al with R1 = H according to the method Claim 1 produces and the OH group esterified accordingly. 8. A process for the preparation of a compound of formula AI as shown in claim 1, wherein R2 is the N-oxide of an N-alkyl-N-methylamino radical, characterized in that the compound of formula AI with R2 = N-alkyl-N -methylamino by the process according to claim 1 and then reacting this compound with a peracid. 25th