CH621328A5 - Process for the preparation of benzylamine derivatives - Google Patents

Abstract

Compounds of the formula I are obtained by reduction of ketones of the formula C. The cis-epimers are obtained and used directly or after removal of additionally formed trans-epimers. The substituents X, R<1> and R<2> can be converted into other substituents which guarantee the same utility of the substances. The compounds I and their pharmacologically utilisable acid addition salts are suitable as analgesics for vertebrates. <IMAGE>

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 



      PATENT ADDRESS
1.  Process for the preparation of compounds of the formula
EMI1. 1
 in the specified, essentially free of trans-epimer cis form, in which 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-cycloalkyl-methyl-N-methylamino radical, X is hydrogen, the hydroxyl group, an alkoxy, alkoxymethoxy or alkylcarbonyloxy radical or a halogen atom and n is an integer from 3 to 6, where the specified alkyl, alkenyl and alkoxy radicals have up to 8 carbon atoms and the cycloalkyl ring shown can carry further substituents, and their pharmacologically acceptable acid addition salts, characterized in that a corresponding compound of the formula
EMI1. 2nd
 reduced,

   separates any trans-epimer formed and, if desired, converts a free base (A) obtained with an acid into a pharmacologically acceptable acid addition salt. 



   2nd  A method according to claim 1, characterized in that reducing the compound of formula (C) with diborane. 



   3rd  Process according to claim 1, characterized in that a compound of formula (A) in which X represents an alkoxymethoxy radical is hydrolyzed to a corresponding compound with X = hydroxy. 



   4th  Process according to claim 1, characterized in that a compound of the formula A in which X = ZH is etherified to a corresponding compound in which X = alkoxymethoxy. 



   5.  Process according to claim 1, characterized in that a compound obtained in which R2 is methylamino is alkylated to a corresponding compound with R2 = N-alkyl-N-methylamino. 



   6.  Process according to claim 1, characterized in that a compound of formula (A) in which X = -OH is obtained is converted by esterification into a corresponding compound with X = alkylcarbonyloxy. 



   7.  Process according to claim 1 or 2, characterized in that a compound of formula C, in which X = alkoxymethoxy, R2 = dimethylamino and n = 4, is reduced. 



   8th.  Process according to claims 3 and 7, characterized in that a compound of the formula C, in which x = alkoxymethoxy, R2 = dimethylamino and n = 4, is reduced and then hydrolysed to form a compound of the formula A, in which X = hydroxy, R2 = Dimethylamino and n = 4.    



   9.  A process for the preparation of a compound of the formula A, as shown in claim 1, in which R1 represents an alkyl radical having up to 8 carbon atoms, characterized in that the compound of the formula A is prepared by the process according to claim 1 and the OH Group etherified. 



   10th  A process for the preparation of a compound of formula A 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 A is prepared by the process according to claim 1 and the OH Group esterified accordingly. 



   11.  A process for the preparation of a compound of formula A 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 A with R2 = N-alkyl-N-methylamino after the method according to claim 1 and then reacting this compound with a peracid. 



   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 aminocycloalkanols of the formula
EMI1. 3rd
 in which n is an integer from 3 to 5, R is a phenyl radical and -NR21 is one of the following secondary amino groups:
N-methyl-N-alkylamino, N-methyl-N-aralkylamino, pipe ridino, morpholino, pyrrolidino and N'-alkylpiperazino. 



  These compounds, which were prepared by reacting benzalcycloalkanones with corresponding amines and subsequent reduction, were obtained as mixtures of two epimeric racemic modifications, i.  H.  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 cis and trans.  Numerous compounds in which NR21 represents a piperidino or N'-alkylpiperazine radical 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. 

  The usability in the above patent specification of the usefulness of the N'-alkylpiperazine compounds as intermediates in the preparation of corresponding hexahydro-benzhydryl-piperazines was specified, the quaternary ammonium salts of which are said to be effective spasmolytics.  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) has also described the reaction of secondary amines with benzalcyclanones, which give aminocyclanones in the subsequent reduction.  The cited reference also contains the melting points of the cis and trans epimers of piperidine and N'-alkylpiperazino-benzyl-cyclohexanols.  Russel et al. , J. A. C. S.  77, 629 (1955) described the method for determining the configuration of the epimeric piperidino- and N-alkylpiperazino-benzylcyclohexanols. 



   When C-phenyl-nitrone is added to cyclopentene or cyclohexene, the corresponding isoxazolidine is obtained, and in the case of cyclopentene, the reduction gives an α-methylaminobenzylcyclopentanol (Huisgen et al. , Chem.  Ber. 



  101, 2 043 (1968).  The stereochemistry at the a carbon atom has not been explained. 



   The present invention relates to the preparation of compounds of the formula
EMI2. 1
 in which R1 is hydrogen, a lower alkyl or lower alkylcarbonyl radical, 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, X is hydrogen, the hydroxyl group, a lower alkoxy, lower alkoxymethoxy -, or lower alkylcarbonyloxy radical or a halogen atom and n represent an integer from 3-6, where the cycloalkane ring may be further substituted, and their pharmacologically acceptable acid addition salts.  The compounds can be used as analgesics for warm-blooded animals.   Low stands for residues that contain up to 8 carbon atoms. 



   The compounds of formula 1 are in the form of the free
Bases colorless to yellow oils or solids that 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 according to the invention: cis-2- (α-dimethylamino-m-hydroxybenzyl) cyclohexanol; cis-2 - (a -dimethylamino-m-methoxybenzyl) cyclohexanol; cis-2- (a-dimethylaminobenzyl) cyclohexanol; 1-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) cyclohexanol and their pharmacologically acceptable salts. 



   A general process for the preparation of the compounds of Formula A, i.e.  H.  of such compounds (1), wherein R1 =
H, and their pharmacologically acceptable acid addition salts, consists in the reduction of a compound of the formula
EMI2. 2nd
 in which R2, n and X are as defined above to form a compound of formula 1 in which R1 is hydrogen, optionally followed by etherification or esterification of the product to form a compound (1) in which Rl is a lower alkyl or lower Alkylcarbonylrest represents, and optionally conversion of the product into an acid addition salt. 



   Suitable reducing agents in this process are complex metal hydrides, e.g.  B.  Lithium aluminum hydride, sodium or potassium borohydride, lithium aluminum trimethoxy hydride or diborane.  The reduction can be carried out in a non-reactive organic solvent such as diethyl ether. 



   The product obtained in the reduction generally comprises two epimeric forms which can be separated by conventional methods before or after further treatments such as etherification or esterification. 



   Certain compounds of Formula I can be converted to other compounds of Formula I.  Such processes are, for example, the etherification or esterification of a compound of formula 1, in which R1 is hydrogen, to form a corresponding compound in which R1 represents a lower alkyl or lower alkylcarbonyl radical, the etherification or esterification of a compound of formula 1, in which X is a Is hydroxyl to form a corresponding compound in which X represents a lower alkoxy, lower alkoxymethoxy or lower alkylcarbonyloxy radical; hydrolysis of a compound of formula 1, wherein X is a lower alkoxymethoxy, to form a corresponding compound, where X is the hydroxyl group;

   hydrogenolysis of a compound of formula 1 in which R2 represents an N-benzyl-N-lower alkylamino radical to form a corresponding compound in which R2 represents a lower alkylamino radical; the treatment of a compound of formula 1 in which R2 represents an N-lower alkyl-N-methylamino radical with a peracid, for example m-chloroperbenzoic acid, to form a compound of formula 1 in which R2 represents an N-oxo-N- lower alkyl-N-methylamino means the alkylation of a compound of formula 1, wherein R2 is methylamino, with a lower alk-2-enyl halide to form a corresponding compound, in which R2 is an N-lower alkenyl-N represents methyl amino radical, and the alkylation of a compound of formula 1, in which R2 is the methylamino group, to form a compound,

   wherein R2 is an N-lower alkyl-N-methylamino, N-cycloalkylmethyl-N-methylamino or N-phenyl-lower alkyl-N-methylamino radical, 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 compounds of formula 1, which is characterized in that the free base I is treated with a pharmacologically acceptable acid. 



   The above and other manufacturing processes are explained in more detail below:
The following scheme A illustrates the reaction sequence for the preparation of a cis-aminobenzylcycloalkanol, especially cis-2- (o -dimethylamino-m-methoxybenzyl) cyclohexanol.      Scheme A
EMI3. 1

The starting materials of Scheme A, i.e.  H.  the cycloalkanones L and the benzaldehydes II 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 the compounds L and II 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 work 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 IV. 

  This reaction is expediently carried out 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 passed, the reaction mixture or also the isolated addition product is added to a suspension of a reducing agent, for example to a complex metal hydride, e.g.  B.  Lithium aluminum hydride, sodium or potassium borohydride, lithium aluminum trimethoxy hydride or diborane, working in a non-reacting organic solvent such as diethyl ether.  The mixture is then refluxed for several hours, during which the corresponding benzylcycloalkanol V is formed.  The product can be isolated in a known manner, for example by diluting the reaction mixture with aqueous base, e.g. 

  B.  3% sodium hydroxide solution, treated, the organic phase is separated from the solids and the aqueous phase, with dilute mineral acid, for.  B.  Hydrochloric acid, extracted, the aqueous acidic extract extracted with basic solvent such as ether, whereupon this extract is washed, dried and freed from the solvent.  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. 
EMI3. 2nd




   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 of the reduction consists essentially of a mixture of only two racemic modifications (i.e.  two epimeric forms and their enantiomers).  The intermediate aminoketones IV have two centers of asymmetry and can theoretically exist in two racemic modifications.  However, as long as the aminoketones are not left in the reaction system leading to their formation for a considerable length of time, for example for three days or more, only one epimer is isolated. 

  When the carbonyl group is reduced
EMI4. 1

In the present description, the term cis denotes the epimer with the HAHB-cis relationship when applied to compounds produced according to the invention.    



   The cis and trans epimers obtained in the above manner can be separated by known methods, e.g.  B.  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 a benzene / hexane 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, whereupon the elution of the cis component with methanol takes place after passing the column cut off directly 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. 



   It has been found that the above measures for separating the cis form are not always necessary.  If diborane is used to reduce the amino ketone, the cis-epimer is isolated practically free from trans form. 



   Although the illustration of the process according to the invention in Scheme A relates only to the preparation of a compound of the formula I in which R1 is hydrogen, RZ 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 amino group, an N-lower alkyl-N-methylamino, N-lower alkenyl-N-methylamino, N-cycloalkylmethyl-Nmethylamino, N-phenyl-lower alkyl -N-methylamino, 1-pyrrolidinyl or 4-morpholino means, produce by using the appropriately substituted primary or secondary amine in the second reaction stage.  Compounds which, as substituents R2, have an N-oxo-N-lower alkyl-N-my new center of asymmetry, which leads to two epimeric racemic modifications HAHB-cis and HAHB-trans, which can be represented as follows:
EMI4. 2nd
 have thylamino, are obtained by using the corresponding products with R2 = N-lower-alkyl-N-methylamino with a peracid, such as.  B.  m-chloroperbenzoic acid, treated. 

  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 alkylcarbonyloxy radical can be 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 appropriately 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.  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 of the process illustrated in scheme A. 



   Although compounds in which R2 is a lower alkylamino radical can also be prepared using the corresponding 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 stage in appreciable amounts while reducing the yield of the desired epimer in the last stage of the process.  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 benzalcyclohexanone formed in the first stage is reacted with a benzyl-lower alkylamine to form the corresponding a - (N-benzyl-N-lower alkylamino) benzylcycloalkanone, which is then reduced to the cycloalkanol in the manner already described .  The hydrogenolysis of this compound, for example with 10% palladium / carbon in the presence of an acid such as acetic acid, gives the desired CL - (lower alkylamino) 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 Is N-phenyl-lower alkyl-N-methylamino.  

  In this variant of the process, the CL - (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, whereby 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, carbäthoxy urethane or a cyclic urethane is obtained which, after reduction, for example with lithium aluminum hydride, gives the desired product results. 



   As already mentioned, the process according to Scheme A, which for the sake of simplicity is referred to below as the amine condensation process, leads to a mixture of the two epimeric racemic modifications, namely the cis and trans isomers (based on the two centers of asymmetry of the cycloalkane ring), from which the desired cis epimer is isolated.  The compounds obtainable in this way correspond to the following formula:
EMI5. 1

In the present description, connections of this configuration are considered normal and are therefore not given any further prefix.  The compounds obtainable by the procedure of Scheme B, which is referred to in the following description as the nitrone process, have exclusively the cis configuration with respect to the two centers of asymmetry on the cycloalkane ring. 

  However, it has been found that compounds are also formed which are diastereoisomers of the compounds with a normal configuration and which therefore must be epimers with the opposite configuration on the benzyl carbon atom. 



   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 or the like.  The term lower alkenyl includes monoalkenes with up 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, cyclobutyl and the like.  A phenyl-lower alkyl radical is preferably understood to mean a phenyl radical bonded via an alkyl radical having 1 to 4 carbon atoms. 



   Of course, the cycloalkanone and cycloalkene starting materials can carry further substituents that are not affected by the process, such as.  B.  Methyl or methoxy groups.  Chlorine atoms, trifluoromethyl groups and the like.  To achieve an analgesic effect in warm-blooded animals, the compounds can be administered orally or parenterally in various dosage forms. 



  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 40 and preferably 10 and 25 mg are used, as required every four hours.  When administered intramuscularly, the dose is about 1 to 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 customary dosage forms for oral administration, such as tablets, capsules or liquid preparations such as elixirs and suspensions, which contain colorants, aromas, stabilizers and taste-masking substances.  For the preparation of 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, fumarate, painter's, 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-methoxymethoxybenzaldehyde and 318 ml (3.0 mol) of cyclohexanone are refluxed 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, giving the product as a yellow oil (132 g), bp 0.3 = 173-176 "CA R 95aYX AtoH 287 new (E 13 100); vKBr 1685, 1600, 1580 cm-t-NMR ( CDCl3): 6 5.2 (2 H singlet, CH2O), 3.48 (3 H singlet, -OCH,).    



   Example 1 cis-2- (a -Dimethylamino-m-methoxybenzyl) cyclohexanol
A solution of 50 g (2.31 10-9 mol) of m-methoxybenzalcyclohexanone in 50 ml of ether is cooled to -5 ° C. in a pressure bottle and treated with 20 ml of dimethylamine (3 10-l mol).  The bottle is stuffed and left at room temperature for 16 hours.  The above reaction is carried out twice (the IR spectrum indicates that the mixture reaches an equilibrium concentration in which the ss dimethylaminoketone addition product is favored in a ratio of about 2: 1 compared to the m methoxybenzalcyclohexanone).  

  The combined reaction mixtures are added dropwise in a nitrogen atmosphere with stirring to a suspension of 20 g of lithium aluminum hydride in 1.2 l of ether, and the mixture is boiled under reflux for 4 hours.  The ice-cooled reaction mixture is then treated with 100 ml of 3% aqueous sodium hydroxide solution and filtered.  The precipitated solids are washed with boiling ether and the combined filtrates are concentrated to about 11.  The ether phase is extracted twice with excess dilute hydrochloric acid and then with water.  The combined aqueous extracts are back extracted with ether, then made basic with 50% sodium hydroxide and extracted twice with ether. 

  The ether phases are washed with saturated sodium chloride solution and concentrated to 50 g of an oil which, according to the gas chromatogram, consists mainly (96%) of 2 components.  32 g of the residue was chromatographed on Woelm alumina (900 g, neutral activity, grade III) in a column prepared with benzene / hexane (1: 1).  The main component trans-2- (α-dimethylamino-m-methoxybenzyl) cyclohexanol in an amount of 20 g is eluted by benzene / hexane fractions (1: 1 and 2: 1), NMR (CDCl3): 8 2.28 ( 6 H singlet N (CH3) 2), 3.0 (1 H doublet J = 3 cps CH N (Me) 2), 3.3-3.7 (1 H broad multiplet CH (OH)), 3.8 (3 H singlet OCH3) ppm. 



   Benzene / ether (4: 1 and 2: 1) fractions eluted 10 g of cis-2- (a -dimethylamino-m-methoxybenzyl) cyclohexanol, NMR (CDCl3): a 2.12 (6 H singlet N (CH3) 2 ), 3.44-3.66 (2 H multiplet CH (OH) and CH N (CH3) 2), 3.8 (3 H singlet -OCH3) ppm. 



   From hexane / methylene chloride, 10.5 g of hydrochloride of the trans-epimer of F.    203-206 C crystallized. 



  Analysis (air dry sample): Found: C 60.68 H 9.07 N 4.53 Calculated for Cl6H2602NCl H2O: C 60.46 H 8.88 N 4.41
The hydrochloride of the cis epimer from F.    205-208 C was crystallized from methanol / ether (8.6 g). 



  Analysis: Found: C 64.09 H 8.74 N 4.67 Calculated for C, 6H2602NCl (299.84): C 64.14 H 8.98 N 4.10
Example 2 cis-2 - (a -Dimethylamino-m-methoxybenzyl) cyclohexanol acetate, hydrochloride
3.0 g of cis-2- (a -dimethylamino-m-methoxybenzyl) cycloheanol (Example 1), 5 ml of acetic anhydride and 15 ml of pyridine were briefly warmed to effect solution, then the mixture was left overnight at room temperature .  The reaction mixture was then poured into dilute sodium hydroxide solution and extracted twice with ether. 



  The ether phases were washed twice with water, dried over potassium carbonate and concentrated.  Traces of pyridine were removed by azeotropic distillation with toluene, a crystalline residue being obtained; IR 1738, 1615, 1590 cm-1 NMR (CDCl3): b 1.96 (3 H singlet, CH3CO-O) * 2. 06 (6 H singlet, N (CH3) 2), 3.38 (2 H doublet J = 10. 5 cps CH NMe2), 3.77 (3 H singlet, CH30-), 4.51 (1 H multiplet W 1/2 H 8 cps) ppm. 



   The crystalline acetate was transferred directly to the hydrochloride from F.    235-237 C (foaming) converted.  The analysis sample was crystallized from acetone / methylene chloride. 



  Analysis: Found: C 63.46 H 8.46 N 4.07 Cl 10.29 Calculated for C17H2603N (327.845): C 63.24 H 8.25 N 4.10 Cl 10.37
Example 3 trans-2 - (α-dimethylamino-m-methoxybenzyl) cyclohexanol acetate
Following the procedure of Example 2, trans-2 - (α-dimethylamino-m-methoxybenyl) cyclohexanol was converted to the title compound, which was obtained as a clear oil: IR 1738,
1615, 1590 cm-1 NMR (CDCl3): b 1.58 (3 H singlet, CH3CO-O).       2.06 (6H singlet. 

  N (CH3) 2).  3.35 (1 H doublet J = 9. 5 cps CH N (CH3) 2).     3rd 82 (3 H singlet CH3O-), 4.65 (1 H broad multiplet W l / 2 H 16 cps ppm. 



   Example 4 cis-2- [a -Dimethylamino-m- (methoxymethoxy) benzyl cyclohexanol and trans-2- [a -dimethylamino-m- (methoxymethoxy) benzyl] cyclohexanol maleate
A solution of 100 g (4 10-1 mol) of m- (methoxymethoxy) benzene cyclohexanone (preparation A) in 100 ml of ether was cooled in a pressure bottle to -5 C and with 50 ml of dimethylamine (7.5 10-1 Mol), then left to stand at room temperature for 60 hours.  The reaction mixture was then added dropwise in a nitrogen atmosphere with stirring to a suspension of 20 g of lithium aluminum hydride in 1.4 l of ether over the course of 1 hour.  Then the mixture was stirred for a further hour and refluxed for 2 hours. 



  The reaction mixture cooled with ice was treated with 100 ml of 3% aqueous sodium hydroxide solution and filtered.  The precipitated solids were washed with boiling ether and the combined filtrates were concentrated to about 11.  The ether phase was extracted twice with excess dilute hydrochloric acid and then with water.  The combined aqueous extracts were washed back with ether, then basified with ice-cold 50% sodium hydroxide solution and extracted twice with ether.  The ether layers were washed with saturated sodium chloride solution, dried over potassium carbonate and concentrated to an oil (46 g), which according to the gas chromatogram consists of two main components. 

  The oil was chromatographed on Woelm alumina (1.5 kg neutral, grade III) with the column packed with benzene / hexane (1: 1).  Benzene / hexane, benzene and the first benzene / 10% ether fractions eluted 25.8 g of trans-2 - [a -dimethylamino -m- (methoxymethoxy) benzyl] cyclohexanol, NMR (CDCI3): 6 2.28 (6 H singlet, N (CH3) 2), 3.0 (1 H doublet J = 3 cps, CH N (CH3) 2), 3.3-3.8 (1 H broad multiplet CH OH), 3.48 ( 3 H singlet, OCH3), 517 (2 H singlet, -OCH2O) ppm. 



   The later benzene / ether fractions (9: 1 to 1: 2) eluted the -NMR (CDCl3): 6 2.1 (6 H singlet, N (CH3) 2), 3.47 (3 H singlet, -OCH3) ), 3.37-3.7 (overlapping multiplet CH OH and CH N (CH3) 2), 5.21 (2 H singlet-OCH2O-) ppm. 



   The maleate of the trans connection from F.  147-148 C was crystallized from acetone / methylene chloride, NMR (CDCl3): 6 2.97 (6 H singlet, N (CH3) 2), 3.48 (3 H singlet, -OCH3), 3.73 (1 H broad multiplet, CH OH), 4.0 (1 H singlet, J = 3 cps CH N (CH3) 2), 5.2 (2 H singlet, -OCH2O-), 6.3 (2 H singlet, vinylic proton , Maleatanion), 10.75 (3 H wide signal W l / 2 H 24 cps - exchangeable protons). 



  Analysis: Found: C 61.74 H 7.77 N 3.19 Calculated for C2, H3lNO7 (409.47): C 61.59 H 7.63 N 3.42
Example 5 trans-2 - (CL -dimethylamino-m -hydroxybenzyl) cyclohexanol maleate
Concentrated -cis-2 - [a -Dimethylamino-m- (methoxymethoxy) -benzyl] - was added to 6 g of trans-2- [cr -dimethylamino-m- (methoxymethoxy) benzyl] cyclohexanol maleate in 150 ml of methanol. Cyclohexanol hydrochloric acid added dropwise to pH 2.  After refluxing for one hour, the solution was poured onto ice containing excess sodium bicarbonate and ammonium hydroxide.  The crystalline precipitate (4 g) was recrystallized, giving an analytically pure sample of the title compound in the form of the free base of F.  220-225 C.  NMR (D6MSO): 6 2.2 (6 H singlet N (CH3) 2). 

 

  Analysis: Found: C 72.10 H 9.43 N 5.47 Calculated for C15H23NO2 (249.338): C 72.25 H 9.30 N 5.62 maleate from F.  182-183 C, NMR: (D6MSO): 6 H singlet N (CH3) 2). 



  Analysis: Found: C 62.45 H 7.42 N 3.82 Calculated for C19H27NO6 (365.41): C 62.45 H 7. 45 N 3.83
Example 6 cis-2- (a -Dimethylamino-m-hydroxybenzyl) cyclohexanol
Hydrochloride
10 g of cis-2 - [α-dimethylamino-m- (methoxymethoxy) benzylj-cyclohexanol in ether were treated with a slight excess of hydrogen chloride in isopropanol.  The resulting gummy solid crystallized on trituration with boiling ether / acetone.     It was first recrystallized from ethanol / ether and then from methanol / acetone.  the title compound from F.    263-265 C was obtained.  NMR (D6MSO): a 2.47 (6 H singlet, N (CH3) 2) ppm. 



  Analysis: Found: C 63.02 H 8.65 N 4.9 Cl 12.77 Calculated for Cl5H24NO2Cl (285.805): C 63.03 H 8.46 N 4.68 Cl 12.41
Example 7 cis-2- (a -Dimethylamino-m-hydroxylbenzyl) cyclohexanol
N-oxide
To 2.59 g of cis-2- (a -dimethylamino-m-hydroxybenzyl) cyclohexanol (1.04 10-2 mol) in 40 ml of tetrahydrofuran was added a solution of 2.14 g of m- at 0-5> C Chloroperbenzoic acid (85% purity) (1.06 10-2 mol) in tetrahydrofuran was added dropwise over the course of 30 minutes.  Then the ice bath was removed and after a further 30 minutes the solution was adsorbed on basic alumina (grade I, 100 g) and eluted with chloroform / methanol (3: 1). 

  The eluate residue was made from ethanol / hexane as hemiethanol solvate of F.    125-129 C (with foaming) crystallized. 



  Analysis: Found: C 66.43 H 9.34 N 5.21 Calculated for C15H23NO3 - / 2 C2HsOH: C 66.63 H 9.09 N 4.86
Example 8 cis-2 - [α-dimethylaminobenzyl] cyclohexanol and trans-2- [α-dimethylaminobenzyl] cyclohexanol
A solution of 100 g (5.39 10 mol) of benzalcyclohexanone in 100 ml of ether was cooled to -5 C in a pressure bottle and treated with 50 ml of dimethylamine 7.5 10-1 mol and left to stand at room temperature for 60 hours.  The reaction mixture was then added dropwise in a nitrogen atmosphere with stirring to a suspension of 20 g of lithium aluminum hydride in 1.3 l of ether over the course of one hour.  Then the mixture was stirred for another hour and refluxed for 2 hours. 

  The ice-cooled reaction mixture was treated with 10 () ml of 3% aqueous sodium hydroxide solution and filtered.  The precipitated solids were washed with boiling ether and the combined filtrates were concentrated to a volume of about 11.  The ether phase was extracted twice with excess dilute hydrochloric acid and then with water.  The combined aqueous extracts were extracted with ether, made basic with ice-cold 50% sodium hydroxide solution and extracted twice with ether. 

  The ether layers were washed with saturated sodium chloride solution, dried over potassium carbonate and concentrated to an oil (70 g) which, according to the gas chromatogram, consisted of 2 main components.  60 g of the oil were chromatographed on Woelm alumina (1.8 g neutral, grade I) in a column packed with benzene / hexane (1: 1).  Benzene / hexane, benzene and the first benzene / 10% ether fractions eluted 34.2 g of the trans compound in the form of the free base of F.    73-75 C, NMR (CDCl3): b 2.27 (6 H singlet N (CH3) 2), 3.05 (1 H doublet J = 3.5-4 cps CHN (CH3) 2), 3.47 (1 H broad multiplet 3.27-3.74, CHOH), 4.04 (1 H singlet interchangeable-4H), 7.35 (5 H singlet aromatic protons) ppm. 

  Later benzene / ether fractions (4: 1 to 3: 2) eluted 14 g of the cis compound in the form of the free base of F.    88-89.5 C, NMR (CDCl3): 6 2.07 (6 H singlet N (CH3) 2), 3.51 (narrow multiplet W 1/2 H 5 cps CHOH), 3.6 (1 H doublet J = 10.5 cps, peak at high field superimposed on CH (OH) multiplet) ppm.  The fumarate of the trans compound was prepared from the free base with fumaric acid in acetone solution, melting point of analysis sample 171-172> C (from acetone / ethanol). 



  Analysis: Found: C 65.40 H 8.07 N 4.37 Calculated for ClgH27NO5 C 65.31 H 7.79 N 4.01 NMR (DMSO): # 2.53 (6 H singlet N (CH3) 2) , 3.27 (1 H broad multiplet CHOH), 3.77 (1 H doublet J = 4 cps CHN (CH3) 2), 6.69 (2 H singlet, vinylic proton fumarate anion), 7.45 (5 H singlet , aromatic protons) ppm. 



   The hydrochloride of the cis-compound was formed from the free base in ether with hydrogen chloride in isopropanol, melting point of the analysis sample 227-228 C (from acetone / ethylene chloride).    



  Analysis: Found: C 66.83 H 9.11 N 5.49 Cl 12.9 Calculated for C 5H 4NOCl: C 66.77 H 8.97 N 5.19 Cl 13.4 NMR (DMSO-D2O exchange) 2.65 (6 H singlet NH (CH3) 2), 3.27 (1 H multiplet W 1/2 H 5 cps CHOH). 



   Example 9 cis-2- [α-dimethylamino-m-methoxybenzyl] cyclohexanol propionate hydrochloride
A mixture of 3 g of cis-2- (α-dimethylamino-m-methoxybenzyl) cyclohexanol hydrochloride in 15 ml of pyridine and 5 ml of propionic anhydride was warmed briefly to effect solution, then stirred for 20 hours at room temperature.  The mixture was poured into dilute sodium hydroxide solution and extracted twice with ether.  The ether phases were washed twice with water, dried over potassium carbonate and then evaporated.  The last traces of pyridine were removed by azeotropic distillation with toluene.  The residue was chromatographed on Woelm alumina (90 g, grade III neutral) in hexane.  Hexane / benzene and benzene fractions eluted 1.0 g of the product in the form of the free base, which consists of a colorless oil.  

  The hydrochloride of F. is obtained from a solution of the free base in ether / hexane and a solution of hydrogen chloride in isopropanol.    226-228 C (with foaming, from acetone / hexane), IR 1730, 1595 cm.    



  Analysis: Found: C 64.18 H 8.54 N 3.82 Cl 9.68 Calculated for C19H30O3NCl: C 64.12 H 8.50 N 3.94 Cl 9.96
Example 10 cis-2- [a - (Dimethylamino) -m-hydroxybenzyl] cyclohexanol diacetate maleate
1.5 g of cis-2 - [α- (dimethylamino) -m-hydroxybenzyl] cyclohexanol hydrochloride in 5 ml of acetic anhydride and 15 ml of pyridine were briefly warmed to effect solution and then left overnight at room temperature.  The mixture was then poured into dilute sodium hydroxide solution and extracted twice in ether.  The ether phases were washed twice with water, dried over potassium carbonate and evaporated.  Traces of pyridine were removed by azeotropic distillation with toluene, giving an oily residue which was converted directly into the crystalline maleate in acetone. 

  After recrystallization twice from acetone / hexane, the analytical sample had a melting point of 152-155 C, IR 1765, 1725 cm-1.    



   NMR (CDCl3): Ï 2.05 (3 H singlet CH3CO) 2.33 (3 H singlet CH3CO), 2.7 (6 H singlet N (CH3) 2H +), 4.3 (1 H doublet, J = 12 cps CH-NQCH3) 2), 4.45 (1 H multiplet CH (OAc)), 6.3 (2 H singlet vinylic protons maleate-an ion) ppm.    



   Example 11 cis-2- (α-Dimethylamino-m-hydroxybenzyl) cyclohexanol acetate maleate
1.8 g of cis-2 - [α-dimethylamino-m- (methoxymethoxy) benzyl cyclohexanol maleate were converted into the free base and acetylated with 5 ml of acetic anhydride and 15 ml of pyridine for 48 hours at room temperature.  The mixture was then poured into dilute sodium hydroxide solution and extracted with ether.  The ether phases were washed twice with water, then with saturated sodium chloride solution, dried over sodium sulfate and concentrated.  The residue was azeotroped with toluene to remove traces of pyridine, then in acetone solution with a slight excess of isopropanolic hydrogen chloride (pH <2) treated.



  After 15 hours the acetone was distilled off and the residue was partitioned between ether and dilute ammonia / sodium bicarbonate solution. The ether extract was washed with saturated sodium chloride solution, dried over sodium sulfate and freed from the ether. The residue was treated with excess maleic acid in ethyl acetate, then the solvent was removed. The residue thus obtained, after recrystallization from acetone / hexane, gave the product of mp 158-160 C.



   NMR (CDCl3): 6 2.04 (3 H singlet CH3CO), 2.7 (6 H singlet N (CH3) 2), 4.14 (2 H doublet J = 10.5 cps CHN (CH3) 2), 4.5 (1 H multiplet W 1 / i H 6 cps CH OAc), 6.25 (2 H singlet vinylic maleate anion) ppm.



  Analysis: Found: C 61.77 H 7.44 N 3.52 Calculated for C2lH29NO7: C 61.90 H 7.17 N 3.44
Example 12
The following products were prepared using the methods of Examples 1 and 4, starting from the corresponding benzalcyclohexanones and amines: Compound F. (> C) cis-2- (a-dimethylamino-free base: 88-89.5 benzyl) - cyclohexanol HCI salt: 227-228 (dichloromethane-acetone) trans-2- (-dimethylamino-free base: 73-75 benzyl) -cyclohexanol fumarate: 171-172 (ethanol-acetone) cis-2- [a-dimethylamino- p-fumarate: 167-168 (methoxymethoxy) benzyl] - (hemiacetonate) cyclohexanol (acetone-hexane) trans-2- [u -dimethylamino-p-maleate:

   125-127 (methoxymethoxy) benzylj- (ethyl acetate-hexane) cyclohexanol cis-2- (m-chlorine <t -dimethyl-hydrochloride: 140-145 aminobenzyl) -cyclohexanol (mixture of isomers) (ether) compound F. ("C) trans-2- (m-chloro-dimethyl-hydrochloride: 207-208 aminobenzyl) -cyclohexanol (mixture of isomers) (CH Cl2 ether) cis-2- [a - (ethylmethylamino) - fumarate: 155-157 m- (methoxymethoxy) - (methanol ether) benzyl] cyclohexanol trans-2- [a- (ethylmethyl maleate: 138 -140 amino) -m- (methoxymethoxy) - (methanol ether) benzyl] cyclohexanol cis-2- [m-methoxymethoxy fumarate: 149-150 CL- (1-pyrrolidinyl) benzyl] - cyclohexanol trans-2- [m-methoxymethoxy maleate:

   117-118 a- (l-pyrrolidinyi) benzyl] - cyclohexanol cis-2- [m-methoxymethoxy fumarate: 170-172 a -morpholinobenzyl] cyclohexanol trans-2- [m-methoxymethoxy maleate: 126-127 CL -morpholinobenzyl] -cyclohexanol cis-2- (a-dimethylamino-o- maleate: 125-126 methoxymethoxybenzyl) - (methanol ether) cyclohexanol trans-2- (a-dimethylamino-o- maleate: 134-135 methoxymethoxybenzyl) - ( Methanol ether) cyclohexanol cis-2- [a-benzylmethylamino) m- (methoxymethoxy) benzyl] cyclohexanol trans-2- [a - (benzylmethylamino) -m- (methoxymethoxy) benzyl] -cyclohexanol cis-2- (p- Chlora-dimethyl hydrochloride: 230-232 aminobenzyl) cyclohexanol (ethanol) (isomer mixture) (ethanol-ether) trans-2- (p-chloro-dimethyl hydrochloride:

   120-125 aminobenzyl) cyclohexanol (methanol) (mixed isomer gehexanol) (methanol ether)
Example 13 cis-2- (a -Dimethylamino-m-hydroxybenzyl) cyclohexanol hydrochloride
260 g of cis-2- [a-dimethylamino-m- (methoxymethoxy) benzyl] cyclohexanol were treated in the form of a suspension in 1.5 l of tetrahydrofuran with 300 ml of 4.65 n-isopropanolic hydrogen chloride. A clear solution was immediately obtained, from which the crystalline title compound separated out in an amount of 230 g on standing overnight.



   Example 14
The following compounds were prepared from the corresponding methoxymethyl ethers according to the instructions of Examples 5 and 6: Compound F. (C) cis-2- (a -dimethylamino-p-hydrochloride (1/3 H2O: hydroxybenzyl) cyclohexanol 159-163 ( Ether) trans-2- (a-dimethylamino-p-hydrochloride (1/3 H2O): hydroxybenzyl) cyclohexanol 130-135 (ether) cis-2- [cc- (ethylmethylamino) hydrochloride (hemihydrate): m-hydroxybenzyl ] -cyclohexanol 85 (with foaming) (ether) compound F. ("C) trans-2 - [α-( ethylmethyl hydrochloride (hemihydrate):

  : amino) -m-hydroxybenzylj- 85-90 (with foaming) cyclohexanol (ether) cis- [m-hydroxy-a - (l-pyrrole-hydrochloride: 238 dinyl) -benzyl] -cyclohexanol (with foaming) (methanol- Ether) trans- [m-hydroxy-α- (1-fumarate: 227 pyrrolidinyl) -benzyl- (with foaming) cyclohexanol (methanol-ether) cis-2- (m-hydroxy-α-morpho-hydrochloride: 247 (with linobenzyl) -cyclohexanol foaming) (ethanol) trans-2- (m-hydroxy-α-fumarate:

   230 (with morpholinobenzyl) -cyclo-foaming) (methanol) hexanol cis-2 - [α-dimethylamino-o-maleate: 145-146 hydroxybenzyl] -cyclohexanol (ethyl acetate) trans-2 - [α-dimethylamino-o- maleate: 150-151 hydroxybenzyl] -cyclohexanol (ethyl acetate ether) cis-2- [a- (benzylmethylamino) - hydrochloride (H2O): m-hydroxybenzyl] -cyclohexanol 239-240 (with foaming) (tetrahydro furan) trans- 2- [a-benzylmethyl-free base: 207-209 amino) -m-hydroxybenzyl] - (acetone-tetrahydrofuran) cyclohexanol cis-2- [m-hydroxyu - (methyl hydrochloride: 263-265 amino) -benzyl] - cyclohexanol (with foaming) (methanol-acetone) trans-2- [m-hydroxy-α - - hydrochloride:

   232-232.5 (methylamino) benzyl] - (methanol ether) cyclohexanol
Example 15 cis-2- [m-methoxymethoxy <t - (methylamino) -benzylj- cyclohexanol
A mixture of 24.6 g of cis-2- [a - (benzylmethylamino) -m- (methoxymethoxy) benzyl] cyclohexanol (6.68 10-2 mol), 300 ml of methanol, 4 g of 10% palladium / carbon and 5 ml Glacial acetic acid (8.75 10-2 mol) was hydrogenated at room temperature and a hydrogen pressure of 1.4 to 3.2 at. After filtering off the catalyst, the reaction mixture was concentrated in vacuo and the residue was partitioned between ether and excess sodium hydroxide solution. The ether extract was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated.

  Crystallization of the residue from ether / tetrahydrofuran gave 12.0 g of product of F. 87-89 C, NMR (CDCl3): 6 2.27 (3 H singlet NHCH3), 3.45 (3 H singlet, OCH3), 3.72 (1 H apparent



  Singlet W 1/2 H cps), 4.15 (1 H multiplet W t / 2 H 6 cps), 5.12 (2 H singlet, -OCH2O-) ppm.



  Analysis: Found: C 68.98 H 9.21 N 4.88 Calculated for Cs6H2sNO3: C 68.78 H 9.02 N 5.01
Maleate F. 152-154> C (acetone-hexane).



  Analysis: Found: C 60.98 H 7.41 N 3.48 Calculated for C16H25NO3. C4H4O4: C 60.74 H 7.39 N 3.54
The trans-2- [m-methoxymethoxy-α- (methylamino) benzylcyclohexanol fumarate (1.5 moles fumaric acid per mole), F.



     147-148> C (methanol ether) was produced analogously according to the above method.



   Example 16
If the procedure of Example 15 is repeated, but with the acetic acid replaced by hydrochloric acid (since there is no acid-labile methoxymethoxy group), the compound trans-2 - [m-hydroxy-cr - (methylamino) benzyl] -cy- clohexanol- hydrochloride, F.232-232.5 C (acetone), and cis 2 -lm-hydroxy-a - (methylamino) benzyl] cyclohexanol hydrochloride, F. 263-265> C (methanol ether).



   Example 17 cis-2- [m-methoxy-α- (methylamino) benzyl] cyclohexanol
1 g of cis-2- [m-hydroxy-α- (methylamino) benzyl] cyclohexanol hydrochloride in methanol was treated with excess ethereal diazomethane at room temperature for 2 days.



  The solution was then concentrated and the residue was partitioned between ether and dilute sodium hydroxide solution. The ether extract was washed with saturated sodium chloride solution, dried over sodium sulfate and treated with isopropanolic hydrogen chloride, whereby the title compound in the form of the hydrochloride of F.



  222-223 C (methanol / ether) was obtained.



  Analysis: Found: C 63.05 H 8.45 N 5.01 Cl 12.57 Calculated for C, sH23NO2 HCl: C 63.03 H 8.46 N 4.9 Cl 12.41
The trans-2- [m-methoxy-a- (methylamino) benzyl] cyclohexanol fumarate, mp 142-155> C (hemihydrate, from acetone) is obtained in an analogous manner.



   Example 18 d-cis-2- (a -dimethylamino-m-hydroxybenzyl) cyclohexanol and l-cis-2- (a -dimethylamino-m hydroxybenzyl) cyclohexanol
A warm solution of 7.5 g of 2R: 3R-tartaric acid (5.10-2 moles) and 12 g of cis-2- (a-dimethylamino-m-hydroxybenzyl) cyclohexanol (4.82 10-2 moles) in 100 ml of ethanol was diluted with boiling acetone to a final volume of -900 ml, filtered to clarify the solution and inoculated with the clockwise isomer and then kept at about 25 ° C. for 20 hours. The crystalline solid which separated out (7 g) was recrystallized twice from ethanol / acetone, 4.9 g of d-cis-2- (a -dimethylamino-m-hydroxybenzyl) cyclohexanol 2R: 3R-tartrate-monoacetone solvate from F .



  198-200 C, [α] D25 + 45.53 (c = 1.05, MeOH) were obtained. The NMR spectrum shows that the product consists of an acetone partial solvate even after intensive drying.



   A solution of 3.7 g of the above salt in water is made basic with a 1: 1 mixture of saturated sodium bicarbonate solution and concentrated ammonia and extracted twice with ether. The ether extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. Removal of the solvent gives 1.89 g of crystalline residue. By recrystallization from acetone / hexane, the analytically pure d-cis-2 - (α.-dimethylamino-m-hydroxybenzyl) cyclohexanol of F. 191-193 C, [Cr] D25 + 45.21 (c = 1.074 MeOH) receive.

 

  Analysis: Found: C 72.28 H 9.40 N 5.58 Calculated for C15H23NO2: C 72.25 H 9.30 N 5.62
The hydrochloride melts at 255-257 C with foaming, [α] D25 + 14.70 (c = 1.045 MeOH). It is obtained by treating the base in ether solution with isopropanolic hydrogen chloride and triturating the precipitate with boiling acetone.



  Analysis: Found: C 62.66 H 8.46 N 4.92 Cl 12.52 Calculated for C, sH23NO2 HCl: C 63.03 H 8.46 N 4.9 Cl 12.41
Part of the salt was converted to the free base, the rotation of [alD25 + 43.3 indicating that no racemization had occurred.



   The acetone / ethanol filtrates remaining after the separation of the 2R: 3R tartrates are combined and freed from the solvent, the residue is partitioned between ether and a mixture of saturated sodium bicarbonate solution and concentrated ammonia. The aqueous extract is washed twice with ether and the combined ether extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and freed from the solvent. A solution of 6.0 g of the residue (2.4 10-2 mol) in 100 ml warm ethanol is treated with 3.75 g 2S: 35-tartaric acid (2.49.10-2 mol) and boiling with 900 ml Diluted acetone, filtered and left at 25 "C for 60 hours.

  The crystalline solid which separates (6.8 g) is crystallized twice from ethanol / acetone, giving 4.5 gl -cis-2 - (a -dimethylamino-m-hydroxybenzyl) cyclohexanol 2S: 35-tartrate, ( Mono) acetone solvate, mp 198-200 C, [? ] D25 - 45.70> C (c = 0.965 MeOH).



   A solution of 3.7 g of the above salt in water is made basic with a 1: 1 mixture of saturated sodium bicarbonate solution and concentrated ammonia and the base is extracted twice with ether. The ether extracts are washed with saturated sodium chloride solution and dried with sodium sulfate. Removal of the solvent gives 1.75 g of crystalline residue. By recrystallization from acetone / hexane, an analytical sample of l-cis2- (a -dimethylamino-m-hydroxybenzyl) cyclohexanol of F.



     191-193 C [α] D25-46.92 C (c = 1.061 MeOH) was obtained.



  Analysis: Found: C 72.54 H 9.37 N 5.68 Calculated for C15H23NO2: C 72.25 H 9.30 N 5.62
The hydrochloride melts at 255-257 C with foaming, [CL] D 5 - 15.31 (c = 1.067 MeOH). It is obtained by treating the base in ether with isopropanolic hydrogen chloride and triturating the precipitate with the acetone.



  Analysis: Found C 62.90 H 8.57 N 4.93 Cl 12.00 Calculated for C, sH23NO2 @ HCl: C 63.03 H 8.46 N 4.90 Cl 12.41
Part of the salt is converted back to the free base, the optical rotation of [a] D25 - 45.86> C indicating that no racemization has occurred.



   Example 19 Epi-cis-2- (a -dimethylamino-m-hydroxybenzyl) cyclohexanol
5 g of epi-cis-2 - [α-dimethylamino-m- (methoxymethoxy) benzyl] cyclohexanol fumarate in 120 ml of tetrahydrofuran were treated with 2 ml of concentrated hydrochloric acid (pH of the solution = 2) and left overnight at room temperature . The mixture was concentrated in vacuo at temperatures below 30 ° C. and diluted with a mixture of sodium bicarbonate and ammonium hydroxide. The product obtained by extraction with chloroform was recrystallized from ether / hexane, giving an analytically pure sample (2.7 g) of F 172-173.5 C.

  NMR (CDCl3): 6 2.17 (6 H singlet N (CH3) 2). 4.05 (2 H overlaps 1 H duet J = 12 cps CHN (Me2) and 1 H multiplet CH OH), 8.4 (2 H exchangeable protons of phenolic and alicyclic hydroxyl groups) ppm.



  Analysis: Found: C 72.19 H 9.68 N 5.54 Calculated for C15H 3NO: C 72.25 H 9.30 N 5.62
The hydrochloride melts at 241-242 C with foaming (from acetone / ethanol / hexane).



  Analysis: Found: C 63.02 H 8.65 N 4.68 Cl 12.77 Calculated for C, 5H24NO2CI: C 63.03 H 8.46 N 4.9 Cl 12.41
Example 20
According to the procedure of Example 19, the epi cis-2- (a-dimethylamino-m-hydroxybenzyl) cyclopentanol, of F. 172-173> C (acetone / hexane) is also obtained. The hydrochloride of this compound melts at 201-202 C (ethanol / hexane).



   Example 21 Epi-cis-2- (a -dimethylamino-m-hydroxybenzyl) cyclohexanol N-oxide
2.06 g of epi-cis-2 - (α-dimethylamino-m-hydroxybenzyl) cyclohexanol (8.3 1 10-3 mol) in 25 ml of tetrahydrofuran are cooled to 0 ° C., then in the course of 45 1.74 g of m-chloroperbenzoic acid (8.4 10-3 mol) in 18 ml of tetrahydrofuran was added dropwise, and the reaction mixture was allowed to warm to room temperature over the course of one hour, then passed through a column with 100 g of Woelm clay (grade l, basic) filtered and eluted with chloroform / methanol (3: 1).



  The eluate residue is crystallized from ethanol / hexane, giving 1.2 g of product with a melting point of 147-148> C.



  Analysis: Found: C 68.21 H 9.38 N 4.78, 4.99 Calculated for C15H23NO3: C 67.89 H 8.74 N 5.08
Example 22 Epi-cis-2 - (α-dimethylamino-m-methoxybenzyl) cyclohexanol acetate
1.5 g of epi-cis-2 - (α-dimethylamino-m-methoxybenzyl) cyclohexanol, 3 ml of acetic anhydride and 10 ml of pyridine are briefly warmed to effect solution. The mixture is then poured into dilute sodium hydroxide solution and extracted with ether. The ether phase is washed twice with water, dried over potassium carbonate and evaporated.

  The last traces of pyridine are removed by azeotropic distillation with toluene, the product being obtained in the form of a colorless oil; IR 1730 cm; NMR (CDCl3): 6 2.04, 2.06 (2 singlets (9 H) -N (CH3) 2 and OCOCH3), 3.32 (1 H doublet J = 10.5 cps CHN (CH3) 2), 3.8 (3 H singlet-OCH3), 5.43 (1 H multiplet, W t / 2 H 7 cps, -CH-OCOCH3) ppm.

 

      Instructions for use:
An injectable formulation is prepared by dissolving 1 g of cis-2- (α-dimethylamino-m-hydroxybenzyl) cyclohexanol hydrochloride in 50 ml of 0.1 M phosphate buffer, pH 7.4, and making up to 100 ml with distilled water.



  This formulation with 10 mg active ingredient per ml is subjected to sterile filtration through a 0.45 micron filter, then 1 ml fractions are aseptically filled into sterile ampoules. The ampoules are sealed with a flame, the contents are frozen and stored at -20 C until use.



  Oral tablets are formulated as follows:
Milligrams of cis-2 - (a -dimethylamino-m-hydroxybenzyl) cyclohexanol hydrochloride 10 15 lactose 287 282 magnesium stearate 3 3
300 300
Example 23 cis-2 - (a -Dimethylamino-m-ethoxybenzyl) cyclohexanol maleate
To a mixture of 6.6 g of cis-2- (a -dimethylamino-mhydroxybenzyl) cyclohexanol (2.5. 10-2 mol) and 10 g of powdered potassium carbonate (7.2 10-2 mol) in 30 ml of warm ethanol a solution of 2.2 ml of ethyl iodide (4.3 g, 2.75 10-2 mol) in 15 ml of ethanol is added dropwise over the course of 20 minutes.

  The reaction mixture is refluxed for 90 minutes and concentrated, the residue is partitioned between ether and water (pH of the aqueous phase 11-12), the ether phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate.



   When the ether is evaporated off, an oily residue is obtained from the product, which is in the form of its maleate
Melting point 166-167 C (from ethanol / ether) is characterized.



  Analysis: Found: C 64.19 H 7.94 N 3.63
Calculated for C2lH3, NO6: C 64.10 II H 7.94 N 3.56
Example 24 cis-2-methoxy-cyclohexyl- (m-methoxymethoxyphenyl) N, N-dimethylamino-methane-maleate and a -dimethylamino a - (cis-2-methoxycyclohexyl) -m-cresol hydrochloride
To 5.9 g (0.02 mol) of cis-2- [a - (dimethylamino) -m- (methoxymethoxy) benzyl] cyclohexanol in 100 ml of tetrahydrofuran are added 12.5 ml (0, 02 mol) of 1.6 molar butyllithium solution were added over the course of an hour. The mixture is cooled to -70> C and a solution of 1.25 ml (0.02 mol) of methyl iodide in tetrahydrofuran is added in the course of 30 minutes.



  The mixture is then stirred at room temperature for 48 hours, then 5 ml of methanol are added and the reaction mixture is concentrated. The residue is taken up in ether, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The product (4.0 g) is purified on a descending chromatography column on alumina using methylene chloride as the eluent. 1.0 g of product is converted into the cis-2-methoxy-cyclohexyl- (m-methoxymethoxy-phenyl) -N, N-dimethyl-aminomethane maleate of F. 112-115 "C, NMR ( CDCl3): d 3.0 (3 H singlet OCH3), 4.45 (1 H doublet J = 10.5 cps CHN (CH3) 2) ppm.



  Analysis: Found: C 62.47 H 7.92 N 3.29 Calculated for C22H33NO, C 62.39 H 7.85 N 3.30
Treating the free base in tetrahydrofuran with dilute hydrochloric acid gives the a-dimethylamino-a- (cis-2-methoxy-cyclohexyl) -m-cresol hydrochloride of F.



     227-228 C (ethanol / ether).



  Analysis: Found: C 63.25 H 9.17 N 4.25 Cl 11.53 Calculated for Ci6H26NO2CI l / 4H20: C 63.15 H 8.83 N 4.60 Cl 11.65
Example 25 d-cis-2- (a -dimethylaminobenzyl) cyclohexanol and I-cis-2- (a -dimethylaminobenzyl) cyclohexanol
A warm solution of 38.16 g (0.167 mol) of cis-2 - (α-dimethylaminobenzyl) cyclohexanol and 22.8 g (0.17 mol) of 1-malic acid in 200 ml of methanol is diluted with 600 ml of ether, the crystalline Precipitation is recrystallized until constant optical rotation (5 times from methanol / ether). This gives the d-cis-2 - (α-dimethylaminobenzyl) cyclohexanol-l-maleate of F. 195-196 C, [a-ID25 + 15.2 (c = 1.006 MeOH) in an amount of 15 g.



  Analysis: Found: C 62.44 H 8.43 N 3.98 Calculated for C1gH29NO6: C 62.11 H 7.96 N 3.82
Part of the salt is returned to the free base, which has an optical rotation [alD25 + 53.2 (c = 1.057 MeOH).



   The filtrates from the recrystallization of the l-maleate are stirred with water and ether and made basic with sodium hydroxide solution, extracted, dried and concentrated to give a residue of 28.0, which is dissolved in 200 ml of hot methanol with 17 g of d-malic acid. Then it is diluted with 600 ml of ether. The crystalline precipitate is recrystallized 3 times from ethanol / ether, giving the l-cis-2 (a -dimethylaminobenzyl) cyclohexanol-d-maleate of F.



     195.5-196.5 C, [α] D25-15.8 (c = 0.9095 MeOH).



   Part of the salt is returned to the free base, [α] D25-53.6 (c = 1.049 MeOH).



   Example 26 cis-2- [m-Hydroxy (methyl- (3-methyl-2-butenyl) aminobenzyl] cyclohexanol hydrochloride
2.5 g of cis-2- [m-methoxymethoxy-α- (methylamino) benzyl] cyclohexanol (8.95 10-3 mol), 1.2 g sodium bicarbonate (1.43 10-2 mol) and 1, 05 g of 1-chloro-3-methyl-2-butene (1 10-2 mol) are refluxed with stirring in dimethylformamide for 4 hours. The solvent was chased away and the organic residue was treated with 2.5 ml of isopropanolic hydrogen chloride in 30 ml of tetrahydrofuran overnight. The crystalline precipitate was recrystallized from acetone, giving the product of melting point 202-203 C (with foaming).



  Analysis: Found: C 66.72 H 9.15 N 3.97 Calculated for CsgH29NO2 HCl: C 67.14 H 8.90 N 4.12
Example 27 cis-2 - (α-dimethylaminobenzyl) cyclohexanol, epi-cis-2- (a-dimethylaminobenzyl) cyclohexanol, trans-2- (a-dimethylaminobenzyl) cyclohexanol and epi-trans-2- (a-dimethylaminobenzyl) cyclohexanol
A solution of 68 g benzalcyclohexanone in 80 ml ether containing 36 ml dimethylamine was stored in a Parr bomb for one month, then the entire reaction mixture was reduced with excess lithium aluminum hydride and the product worked up as described in Example 8, 47 g product that was in the form of oil,

   were absorbed into 200 g of alumina and applied to a column with 1.8 kg of alumina (Woelm grade III neutral) and eluted first with hexane, then with hexane with increasing amounts of benzene. The later fractions consisted of benzene and benzene containing increasing amounts of ether. The compounds were eluted in the following order: trans (hexane-benzene fractions), epi-trans (benzene fractions), epi-cis and cis 2- [a l-dimethylaminobenzyl-cyclohexanol (benzene ether fractions) . The cis and trans forms were identical to the products of Example 8. The epi-trans fraction, which was obtained in an amount of 12.8 g, was heated with a slight excess of fumaric acid in acetone, the fumarate being obtained as a crystalline precipitate of F.

 

     177-180 C (from ethanol), NMR (DMSO): 6 2.48 (6 H singlet, NH (CH3) 2+) 3.35 (1 H broad multiplet, CH (OH)) 4.23 (1 H Doublet J = 8 cps, CH N (CH3) 2) ppm.



  Analysis: Found: C 65.75 H 8.08 N 3.93 Calculated for C 9H 7NO5: C 65.31 H 7.79 N 4.01
Example 28 cis-2- [a - (Cyclopropylmethyl) methylamino-m-hydroxybenzyl Jcydohexanol hydrochloride
2.5 g of cis-2- [m-methoxymethoxy-α- (methylamino) benzyl] cyclohexanol (8.95 10-3 mol) and 2.0 g of cyclopropanecarboxylic acid chloride (1.91 10-2 mol) were combined in one 2-phase system stirred from 100 ml of 10% potassium carbonate solution and 60 ml of methylene chloride. After 6 hours the organic phase was separated and concentrated to a colorless oil which was refluxed in 120 ml of a 1: 1 mixture of tetrahydrofuran and ether overnight with 1.0 g of lithium aluminum hydride.

  The ice-cooled reaction mixture was then treated with 5 ml of 3% sodium hydroxide solution and filtered. The organic phase was concentrated and the residue was treated in 15 ml of tetrahydrofuran with 5 ml of ethanolic hydrogen chloride. The product (1.7 g) crystallized overnight, melting point 228 C with foaming (from methanol / ether).



  Analysis: Found: C 66.69 H 8.71 N 4.11 Calculated for C18H27NO2 HCl: C 66.34 H 8.66 N 4.30
Example 29 cis-2- (a -Dimethylamino-m-hydroxybenzyl) cyclohexanol
30 g of m-methoxymethoxybenzalcyclohexanone (1.21 1 (t 'mol) in 40 ml ether were heated with 25 ml dimethylamine (4 1 Cr 1 mol) in a pressure bomb for two days at room temperature. Then the solvents were removed in vacuo, the residue was removed with Dilute 100 ml ether, after which the solvent was removed again in vacuo to remove the last traces of dimethylamine.



  The residue thus obtained was then added in 60 ml of tetrahydrofuran over the course of 40 minutes with stirring to a molar solution of tetrahydrofuran-borane (150 ml, 1.5 10-1 mol) in a nitrogen atmosphere. During the addition, the reaction mixture was kept at 0-10> C. The mixture was then allowed to reach room temperature in the course of 2 hours, then the mixture was cooled to -10> C and with 10% aqueous tetrahydrofuran solution (8.1 ml of H2O (4.5 10-1 mol), 81 ml of THF) and then treated with 35 ml of 4.3 n-isopropanolic hydrogen chloride. A slow evolution of hydrogen with a mildly exothermic reaction characterizes the decomposition of the amine boranes which have appeared as intermediates.

  After inoculation with cis-2- (α-dimethylamino-m-hydroxybenzyl) cyclohexanol hydrochloride, the product crystallizes slowly (19.5 g). The hydrochloride is dissolved in water and treated with excess ammonia and sodium bicarbonate solution, the base released is extracted into ether. The ether extracts are concentrated and triturated with hexane which contains little tetrahydrofuran, 15 g of cis-2 (α-dimethylamino-m-hydroxybenzyl) cyclohexanol of F.



     142> C receives.



   Preparation B
According to the specification of preparation A, cycloheptanone and the corresponding aldehyde are converted to the following compounds: (1) m-methoxymethoxybenzalcycloheptanone, Kpo.8 = 175> C (2) benzalcycloheptanone, Kpo, 8¯0.9 = 137-143> C.



   Example 30
According to the procedure of Example 4, the following compounds are prepared from the corresponding benzylidene compound and dimethylamine: (1) cis-2- [a -Dimethylamino-m- (methoxymethoxy) benzylj cycloheptanol maleate, F. 123-125 C (from ethyl acetate Ether).



  (2) cis-2 - [α-dimethylaminobenzyl] cycloheptanol hydrochloride, mp 159-160> C (from isopropanol ether)
ATTEMPT
The analgesic effect of the compounds obtained according to the invention was determined by the method described below, which is a modification of the method by D'Amour and Smith, J. Pharmacol. 72: 1941.



   Rats of approximately 150-200 g body weight are placed in individual holders, each holder being attached so that a high-intensity light beam shines on the tip of the tail.



  The intensity of the light beam is adjusted so that normal rats react in such a way that they remove their tail from the light beam within 3-8 seconds. The average of two measurements taken 20 minutes apart is used as a comparative value prior to drug administration. Those rats whose values do not differ from one another by more than 1 second are used for the experiment. The active ingredients are then administered and the reaction times are determined at 20 minute intervals for 2 hours. The response time is noticeably increased by the analgesics.



  Compound Ver Dose Number of animals that show analgesic effects / number of tested
Animals cis-2- (CL -dimethylamino-m-methoxybenzyl) -cyclo-hexanol-hydrochloride I.P. 25.0 3/5 cis-2- (a-dimethylamino-I.P. 12.5 4/5 m-hydrobenzyl) -cyclo- I.P. 3.12 3/5 hexanol hydrochloride I.M. 2.5 5/10
P.O. 5.0 5/10 cis-2- (a-dimethylamino-I.P. 12.5 3/5 m-methoxybenzyl) -cyclo- I.M. 15.0 3/10 hexanol-propionate hydrochloride cis-2- (a-dimethylamino-I.P. 25.0 5/5 m-methoxymethoxybenzyl) - I.P. 6.25 2/5 cyclohexanol maleate I.M. 5.0 5/10
IN THE. 2.5 3/10 cis-2- (CL-dimethylamino- I.P. 12.5 8/10 benzyl) -cyclohexanol- I.P. 6.25 9/10 hydrochloride I.M. 6.25 8/10
P.O. 5.0 6/10
1-cis-2- (a-dimethyl-I.P. 6.25 6/10 amino-m-hydroxybenzyl) - I.P. 3.12 8/10 cyclohexanol hydro I.M.

   0.62 7/10 chloride I.M. 0.41 4/10
P.O. 6.25 7/10
P.O. 3.12 5/10
ED50 for morphine in this procedure:
I.P. 3.5 mg / kg
IN THE. 2.0 mg / kg
P.O. 10.0 mg / kg


    

Claims (11)

    PATENT ADDRESS 1. Process for the preparation of compounds of the formula EMI1.1  in the specified, essentially free of trans-epimer cis form, in which 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-cycloalkyl-methyl-N-methylamino radical, X is hydrogen, the hydroxyl group, an alkoxy, alkoxymethoxy or alkylcarbonyloxy radical or a halogen atom and n is an integer from 3 to 6, where the specified alkyl, alkenyl and alkoxy radicals have up to 8 carbon atoms and the cycloalkyl ring shown can carry further substituents, and their pharmacologically acceptable acid addition salts, characterized in that a corresponding compound of the formula EMI1.2  reduced,  separates any trans-epimer formed and, if desired, converts a free base (A) obtained with an acid into a pharmacologically acceptable acid addition salt.  2. The method according to claim 1, characterized in that reducing the compound of formula (C) with diborane.  3. The method according to claim 1, characterized in that a compound of the formula (A) obtained, in which X represents an alkoxymethoxy radical, is hydrolyzed to a corresponding compound with X = hydroxy.  4. The method according to claim 1, characterized in that a compound of the formula A in which X = ZH is etherified to a corresponding compound in which X = alkoxymethoxy.  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.  6. The method according to claim 1, characterized in that a compound of the formula (A) obtained, wherein X = -OH, is converted by esterification into a corresponding compound with X = alkylcarbonyloxy.  7. The method according to claim 1 or 2, characterized in that reducing a compound of formula C, wherein X = alkoxymethoxy, R2 = dimethylamino and n = 4.  8. The method according to claims 3 and 7, characterized in that a compound of formula C, wherein x = alkoxymethoxy, R2 = dimethylamino and n = 4, is reduced and then hydrolyzed to form a compound of formula A, wherein X = hydroxy, R2 = dimethylamino and n = 4.  9. A process for the preparation of a compound of the formula A, as shown in claim 1, in which R1 represents an alkyl radical having up to 8 carbon atoms, characterized in that the compound of the formula A is prepared by the process according to claim 1 and the OH group etherified.  10. A process for the preparation of a compound of the formula A 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 the formula A is prepared by the process according to claim 1 and the OH group is esterified accordingly.  11. A process for the preparation of a compound of formula A 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 A with R2 = N-alkyl-N- methylamino by the process according to claim 1 and then reacting this compound with a peracid.  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 aminocycloalkanols of the formula EMI1.3  in which n is an integer from 3 to 5, R is a phenyl radical and -NR21 is one of the following secondary amino groups: N-methyl-N-alkylamino, N-methyl-N-aralkylamino, pipe ridino, morpholino, pyrrolidino and N'-alkylpiperazino. These compounds, which were prepared by reacting benzalcycloalkanones with corresponding amines and subsequent reduction, were obtained as mixtures of two epimeric racemic modifications, i. H. 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 cis and trans. Numerous compounds in which NR21 represents a piperidino or N'-alkylpiperazine radical 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. The usability in the above patent specification of the usefulness of the N'-alkylpiperazine compounds as intermediates in the preparation of corresponding hexahydro-benzhydryl-piperazines was specified, the quaternary ammonium salts of which are said to be effective spasmolytics. 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 aminocyclanones in the subsequent reduction. The cited reference also contains the ** WARNING ** End of CLMS field could overlap beginning of DESC **.