DE2317183C2 - Benzylamine analgesics - Google Patents

Description

F) if desired, the free base of a compound of the general form! I with a pharmacological compatible acid converted into the corresponding pharmacologically compatible acid addition salt.

3. Pharmaceutical agent containing at least one compound of the general formula 1:

R ³ OR ¹ R ²

(D ™

essentially free of the trans isomer, wherein

R ¹ denotes hydrogen, C, -C ₃ -alkyl or Ci-C ₃ -alkylcarbonyl;

R ² Q-Cr-alkylamino, NQ-Cj-alkyl-N-methylamino, N-phen- (C, -C ₄ ) -alkvI-N-methylamino or

N-Cj-Q-Cycloalkylmethyl-N-methylamino;
R ^{3 is} hydrogen or methyl;
X is hydrogen, hydroxy, C, -C ₃ -alkOXy, C, -Qr-alkoxymethoxy. C, -Qr-alkylcarbonyloxy or halogen

means; and

has the benzyl carbon »normalew configuration as defined in claim 1, or their pharmacologically acceptable carriers.

In US Pat. No. 2,767,185 there is a process for the preparation of certain aminocyclanol compounds the formula:

Φ

R -CH-NR1 HC-CH-OH

45

in which η is an integer from 3-5, R is a phenyl radical and NR] is a secondary amino group, namely an N-methyl-N-alkyl-ammo, N-methyl-N-aralkyl-amino, piperidino, morpholino -, pyrrolidino or N'-alkylpiperazino group. These compounds, which are formed by reacting benzal cyclanones with suitable secondary amines and subsequent reduction, are obtained as a mixture of two epimeric racemic modifications, that is to say as a mixture of the racemates de. Forms which are arranged with respect to the configuration at the asymmetric carbon atoms indicated by 2 and 3 in the above formula cis and trans. Various compounds in which NR] denotes piperidino or N'-alkyloiperazho have been separated into their two racemic modifications without identifying them. The two additional epimeric racemic modifications which are theoretically possible due to the opposite configuration at the asymmetric carbon atom denoted by ® were not obtained. The special utility ascribed to the products in this patent would be the use of the N'-alkylpiperazine compounds as intermediates for the preparation of corresponding hexahydrobenzhydrylpiperazines, the quaternary salts of which are referred to as strong antispasmodics. This use is also described in US Pat. No. 2,748,126, with specific reference being made to the use of the trans-epimer.

In Baltzly et al., J. Am. Chem. Soc. 77,624-628 (1955) is the implementation of secondary amines with benzal cyclanones and subsequent reduction with the formation of Aminocycianoien 'described, with the cis- and trans-Epimer.n the piperidino- and N'-alkylpipe.-azinobenzylcyclohexanols by melting point data Marked are. In Rüssel et al., J. Am. Chem. Soc. 77,629-633 (1955) is the configuration verification method the epimeric piperidino and N-alkylpiperazino-benzylcyclohexanoIe described

Huisgen et al., Chem. Ber. 101, 2043 (1968) describe the addition of C-Phenvl-nitmn to CvHnn _P nt _P n

or cyclohexene, a corresponding isoxazolidine being obtained and the reduction with the formation of an α-methylamino-benzylcyclopentanol is also described in all of the cyclopentene. The stereochemistry at the / carbon atom has not been described.
The invention relates to 2- (i / -aminobenzyl) -cyclohexanol derivatives of the general formula I:

(I)

essentially free of the trans isomer, wherein

R is hydrogen, C _: -C -alkyl or C, -C -alkylcarbonyl;

R ^: C -CVAIkylamino. NO-CVAIkyl-N-methylamino, N-phen- (Ci-C ₄ ) -alkyl-N-methylamino or

NC. - C-Cy c loa I kv I me th> lNm represents ethylamino;
R 'VVasserstolT or methyl;
X water tunnel. Hydroxy. C -CVAIkoxy, C ₁ -C -alkoxymethoxy, C ^ Ci-alkylcarbonyloxy or halogen

means;

the benzyl carbon has the "normal" configuration, the compounds with the "normal M configuration on the carbon atom by condensation of a benzalcyclohexanone of the general formula III

(III)

with an amine of the general formula

RiI

where \ and R ^{: have} the meaning given above, and further processing of the compound obtained ocr angciTiCincn ι orrüci II

OR ²

ι il (ID

/ V

according to claim 2 are available;

and their pharmacologically acceptable acid addition salts, with the exception of 2- (a-dimethylamino-

benzyl »-cyclohexanol.

The compounds of the formula I are colorless to yellow in the form of the free base or solid substances which are essentially insoluble in water and are generally soluble in organic solvents such as ether, benzene, hexane, ace'one and pyridine. In the form of their acid addition salts, they are generally white or gray-white crystalline solid substances which are appreciably soluble in water. An investigation of the compounds prepared according to the method described below with the aid of infrared, UV and NMR spectro graphic analyzes provides spectral data which support the molecular structures given above. The above- mentioned physical properties together with the nature of the starting materials, the products obtained therefrom and the elemental analysis confirm the above-mentioned molecular structures.

The compounds of formula 1 and their pharmacologically acceptable salts exert analgesic effects on warm-blooded living beings, as shown by pharmacological investigations using standardized test methods .

The invention also relates to pharmaceutical compositions which are suitable for administration to warm-blooded organisms and which contain a compound of the formula I including 2-iff-dimethylaminobenzyl) cyclohexanol or one of its pharmacologically acceptable salts and a pharmaceutically acceptable carrier.

Particularly suitable compounds of the formula 1 for use in the agents according to the invention are:

cis-I-iff-dimethylamino-m-hydroxybenzyijcyclohexanol;

cis ^ -for-dimethylamino-m-methoxymethoxybenzyl / cyclohexanol;

cis ^ -ia-dimethylaminobenzylcyclohexanol;

l-cis-2- (u-DimethyIamino-m-hydroxybenzyl) cyclohexanoI and their pharmacologically acceptable salts.

The invention also relates to a process for the preparation of the compounds of formula I, which thereby is characterized in that a compound of the general formula II is used in a manner known per se

wherein K ^} and X have the meanings given above, either

A) to a compound of the general formula 1, in which R ¹ and R 'are hydrogen, reduced, preferably with diborane, or

B) mi! a methyl Grignard reagent to a compound of the general formula I in which R ^{1 is} hydrogen and R ^{3 is} methyl,

C) if necessary, separating the compound obtained from its trans isomer, if desired

D) one of those obtained in stage A or B either before or after the separation from the trans isomer Compounds of general formula I to a compound of general formula I in which R | C | -C -, - alkyl or Ci-QrAlkylcarbonyl, etherified or esterified, where one optionally: o

F.) the compound obtained in stage A, B or C,

a) if X is hydroxy, to a compound of the general formula I in which X is C, -Ci-alkoxy, C | -Ci -alkoxymethoxy or Q-Cr-alkylcarbonyloxy, etherified or esterified,

b) if X is Ci-Cj-alkoxymethoxy, to a compound of the general formula I in which X is Hydroxy stands, hydrolyzed,

c) if R ² stands for methylamino, to a compound of the general formula I. in which R ^{2 stands} for NC.-C ₃ -alkyl-N-methylamino, N-Cj-Qr-cycloalkylmethyl-N-methylamino or N-phen- (C _: -C ₄ ) -alkyl-N-methylamino, alkylated and

F) if desired, the free base of a compound of the general formula I with a pharmacologically acceptable one Acid converted into the corresponding pharmacologically acceptable acid addition salt.

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

The product obtained in the reduction generally comprises two isomeric forms, before and after a further treatment, such as etherification or esterification, can be separated in the usual way.

Compounds with the constitution of the formula I, which, however, have the other configuration on the BenzylkohlenstolT- 4j atom, like the compounds of formula I, are obtained using the following nitrone method, where one compound of the formula:

50

in which X has the meanings defined above, and the grouping

R ⁴
NR ³

60

together has the ^{meanings given above for R 2} , hydrogenolyzed to a compound of the formula (I) with the other configuration on the benzyl carbon, where R ^{1 represents} hydrogen or, if desired, etherifies or esterifies the product, so that a compound is formed, where R ' Means lower alkyl or lower alkylcarbonyl.

The hydrogenolysis is carried out with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel preferably in the presence of a weak base, e.g. B. anhydrous sodium acetate, and desirably in a suitable non-reactive solvent, e.g. B. in ethanol performed.

Certain compounds of the formula I can be converted into other compounds of the formula I. Such processes are the etherification or esterification of a compound of the formula I in which R ^{1 is} water to give a corresponding compound in which R ^{1 is} C | -C ₃ -AIk) ¹ I or C 1 -Cj -alkylcarbonyl; the etherification or esterification of a compound of formula I, where X is hydroxy, to a corresponding compound in which X is C ₁ -Cjalkoxy, Ci-Cralkoxymethoxy or Ci-CrAikylcarbonyloxy; the hydrolysis of a compound of the formula I, where X is Ci-Cj-alkoxymethoxy, to a corresponding compound in which X is hydroxy; and the alkylation of a compound of the formula I, where R ^{2 is} methyiamino, to a corresponding compound in which R ^{2 is} N-Ci-Cr-alkyl-N-methylamino, N-Cj-Cn-cycloalkylmethyl-N-methylamino or N- Phen- (Ci-C ₄ ) -alkyl-N-methylamino stands, for example by acylation and subsequent reduction of the carbonyl group to a CH ₂ group.

Compounds of the formula I in which R 'represents methyl are made by reacting a methyl Grignard reagent made with compounds of formula II.

For the preparation of pharmacologically acceptable acid addition salts of the compounds of the formula I, a compound of formula I in the form of its free base treated with a pharmacologically acceptable acid

15 delt.

The following are ways of performing the above-mentioned methods and preparing starting materials for the above methods.

In the further description of the present invention, reference is made to the accompanying drawings.

Fig. 1 schematically illustrates the reaction sequence for the preparation of a cis-aminobenzylcycloalkanol, especially the production of cis ^ -iff-dimethylamino-m-methoxybenzyOcyclohexanol.

The starting materials for the process of FIG. 1, i.e. the cycloalkanones (IV) and benzaldehydes (V) are known or can be prepared from known compounds by methods that are familiar to the person skilled in the art obvious, such as B. that of Edward et al. method described in J. Chem. Soc, (c) 411 (1967).

Reaction of IV with V in the presence of an aqueous base such as potassium hydroxide gives this accordingly substituted benzalcycloalkanone (III). Although the reaction temperature is not critical, the condensation will take place most conveniently at reflux temperature and, for optimal yield, under nitrogen carried out. The product can be prepared using standard methods such as extraction with an organic solvent, such as diethyl ether, subsequent washing, drying and evaporation of the solvent and distillation of the residue, the product being obtained as an oil, can be isolated from the reaction medium. That so Benzalcycloalkanone obtained is then with the required amine in a non-reactive solvent such as Diethyl ether, implemented with the formation of the corresponding benzylcycloalkanone (II). This implementation will expediently carried out at room temperature in a pressure vessel, preferably an excess used on amine. After so much time has passed that optimal formation of the benzylcycloalkanone product is guaranteed, are the reaction mixture or the isolated addition product to a Suspension of a reducing agent, e.g. B. a complex metal hydride, e.g. B. lithium aluminum hydride, Sodium or potassium borohydride, lithium aluminum trimethoxyhydride or diborane, in a non-reactive organic solvent, such as diethyl ether, and then reflux the mixture for several hours, to form the corresponding benzylcycloalkanol product (I). The product can then be known Way to be isolated. For example, the reaction mixture with dilute aqueous base, such as 3% Sodium hydroxide, the organic phase separated from solids and the aqueous phase are then extracted with dilute mineral acid, such as dilute hydrochloric acid, the aqueous acidic extract can be extracted with a basified solvent such as ether Solvent phase are washed and dried and then the solvent is evaporated.

The product so obtained, usually an oil, generally contains two epimeric forms, which then continue be separated.

The compounds of the invention have three asymmetric carbon atoms.
In theory, they should exist in eight optically active forms or four racemic modifications. However, not all of these forms are obtained in the process described above and the product of the reduction is essentially a mixture of only two racemic modifications. The aminoketones (II) of the precursor contain two asymmetric centers and can theoretically exist in two racemic modifications. However, as long as you do not use the amino ketones for a very long time, e.g. B. left in the preparation reaction system for 3 days or more, only one isomer is isolated. When the carbonyl group is reduced, a new asymmetric center is formed, which leads to two epimeric racemic modifications, H _A H _B cis and H _A H _B trans, which can be represented in the following formula:

ice trans

If in the present description the term “ice” is used in connection with the compounds according to the invention, this means the isomer which has the H _A H _B -cis arrangement.
The cis and trans isomers prepared in the above manner can be separated using known techniques

become, ζ. B. by fractional crystallization or preferably by chromatography, expediently they are separated by chromatography on aluminum oxide, e.g. B. of neutral aluminum oxide of the activity level IU, in a column made with benzene / hexane 1: 1. With systems like benzene / I lexan and then with benzene / ether or with benzene / hexane and then with benzene and then elute with benzene / ether. The trans isomer is eluted first, usually in the first mixture of solvents. then the cis form follows in the second mixture.

Another powerful system is an alumina column made with chloroform, where the trans epimers are first eluted with chloroform or chloroform containing 5-10% acetone and the cis component c is eluted with methanol after cutting the column just above the cis component. The cis component is made visible with the help of UV light. The cheapest chromatographic system for the most effective separation is of course dependent on the particular connections to be separated, one trained However, it is not difficult for chemists to choose such optimal systems. The cis and trans configuration can be distinguished with the help of the NMR spectrum, the cis configuration has a closer one NMR signal.

It was found that the above step is not always required for the separation of the cis form. Will diborane for the reduction of the intermediate aminoketone is used, the cis-epimer can be essentially free from isolate the trans form.

Although the above procedure was specifically described with reference to FIG. 1, which illustrates the preparation of a compound uci veneer (i) in which R 'is hydrogen, R "is dimethylamine, R ^{1 is} hydrogen and X is m-methoxy, it will be clear to those skilled in the art that any of the variously substituted compounds according to the invention , in which R ^{3 represents} hydrogen, can be prepared by this process and by modifications of this process which are obvious to the person skilled in the art, for example compounds in which X represents hydrogen, hydroxy, C 1 -C 4 -alkoxy, C _; -CrAlkoxymethoxy or halogen, by using the appropriately substituted benzaldehyde compound in the first stage of the process described above. Compounds in which R ^{2 are} Ci-Ci-alkyiamino, N-Ci-Ci-alkyl-N-methylamino, NC ₁ -C ₆ -Cycloalkylmethyl-N-methylamino or N-phen- (C | -C ₄ ) -alkyl-N-methylamino means, are prepared by ver the appropriately substituted primary or secondary amine in the second reaction stage turns. Compounds in which R ^{1 is} Ci-Ci-alkylcarbonyl can be prepared by reacting the corresponding products, bii where R ^{1 is} hydrogen, with a Ci-Ci-alkyl-carboxylic acid _{anhydride or a C | -C 3} -alkyl carboron . acid chloride treated and compounds where XC | -Ci-alkyl-carbonyloxy can be prepared by treating the corresponding products, in which X is hydroxyl, with such an acylation agent. Compounds in which R ^{1 is} methyl can be prepared by treating the corresponding compound in which R ^{1 is} hydrogen with a strong base such as butyl lithium and methyl iodide. In addition to their synthesis from the appropriately substituted benzaldehydes, compounds in which X is hydroxy can be prepared in a preferred way by acid hydrolysis of a corresponding product in which X is alkoxymethoxy. Compounds in which X is hydroxy can be converted into compounds in which X is methoxy by treating with diazomethane or they can be converted into compounds in which X is C ₁ -Cj -alkoxy by reaction with the appropriate alkyl halide in the presence of a base be convicted. Carrying out these and modifications of the method described in FIG.

Compounds in which R ^{3 is} methyl are conveniently prepared using an alternative process in which the benzylcycloalkanone (II) is treated with methyl Grignard reagent, e.g. . '.; with methyl magnesium bromide under the usual conditions for Grignard addition to ketones, e.g. B. in ether with refluxing for up to several hours. As in the general case of the synthesis of compounds in which R 'is hydrogen, the cis isomer is formed in admixture with the trans epimer and can be separated using the same techniques.

Although compounds in which R 1 is C 1 -C 6 alkylamino can be prepared by using the appropriate primary amine in the condensation step, it has been found that using a primary amine the reaction is less stereospecific than that using secondary Amines is described; as a result, the second possible isomer is formed in this stage in noticeable amounts, which at the same time brings about a reduction in the yield of the desired isomer in the last process stage. It is for this reason that the general procedure is preferably modified in the synthesis of these secondary amine products. In this modification, the benzalcyclohexanone compound formed in the first reaction stage is reacted with a benzyl-Ci-C ₃ -alkylamine to form the corresponding ff- (N-benzyl-NC | -C _t -alkylamino) benzyl-cycloalkanone, which is then converted into is reduced to the corresponding cycloalkanol in the manner previously described. Hydrogenolysis of this compound, e.g. With 10% palladium on charcoal, in the presence of an acid such as acetic acid, gives the desired α- (C, -Cj-alkylaminoibenzylcycloalkanol. These latter compounds can also be used as intermediates in alternative syntheses of compounds in which R-NC , -C ₃ - alkyl-N-methylamino, NC., - C ,, - cycloalkylmethyl-N-methylamino or N-phen-C, -C ^ -alkyl-N-methylamino. In this variation the a- (C <-C ₃ -alky-iAmino) benzylcycloalkanol with a carboxylic acid, for. example, with acetyl chloride, when the desired substituent R ² is N-ethyl-N-methylamino, and reacting the intermediate so formed is reduced, for example with. Lithium aluminum hydride, whereby the desired product is formed.A special method for the production of compounds in which R denotes dimethylamine) is the reaction with ethyl chloroformate or with Ν, Ν'-carbonyldiimidazole to give the corresponding N-methyl-carbethoxy-urethane or cyclic urethane, that in the reduction, e.g. B. with lithium aluminum hvririri ria «ppu / iin« rhte Pm-

As mentioned above, dLiS provides processes illustrated in FIG. 1, here as the amine condensation process referred to as. Mixtures of two isomeric racemic modifications, namely the cis and trans isomers (based on the two asymmetric centers in the Cycloa'kylring), from these mixtures it becomes desired cis isomers of the formula [isolated.

In the present specification, these compounds are referred to as "normal" configuration compounds and are mentioned without an additional prefix. The compounds made by the nitrone process are available, have exclusively the cis configuration based on the two asymmetric centers in the cycloalkane ring. It has been found, however, that these compounds have the opposite configuration have on the benzyl carbon atom.

ίο Where in the present description and in the claims the terms "C ₁ -C ₃ -Alkyl" and "Ci-QrAlk-"

are used, they refer to straight-chain and branched hydrocarbon radicals, such as methyl, ethyl, n-propyl, isopropyl. Examples of C ₅ -Cf, -cycloalkyl are cyclopropyl and cyclobutyl. The term "Phen niedalkyi" stands for a phenyl group that is bonded via an alkyl radical with 1-4 carbon atoms.

The agents for producing analgia in warm-blooded creatures can be in a variety of dosage forms.

! 5 men can be administered either orally or parenterally. The required dosage varies depending on the person on the particular composition used, the severity and nature of the pain and depending on the living being to be treated. For large living beings (about 70 kg body weight), the dose for oral Administration about 2 to about 40 mg. preferably about 10 to about 25 mg every 4 hours or as needed. When administered intramuscularly, the dose is from about 1 to about 20 mg, as required. At the

; o It is best to start therapy with lower doses and then increase the doses until the desired analgia is achieved.

For dosage units, the active ingredient can be processed in the usual oral dosage forms, e.g. B. to tablets, capsules and liquid preparations, such as elixirs and suspensions, which contain various colorants, flavorings, stabilizing and taste masking substances. For compounding oral dosage forms, the active ingredient can be mixed with various tablet materials, such as starches of various types, calcium carbonate, lactose. Sucrose and dicalcium phosphate can be diluted to simplify the tablet and capsule manufacturing process. A smaller amount of magnesium stearate is suitable as a lubricant. The compounds according to the invention can be used in the form of the free bast or in the form of a pharmacologically acceptable acid addition salt. These salts can be formed simply by reacting the free base with an equivalent amount of an acid of which the acid addition salt formed is essentially non-toxic under the conditions of use. Examples of such salts are the hydrochloride, hydrobromide, fumarate, maleate and succinate. Sulphate, phosphate, tartrate, acetate, citrate, etc. For parenteral administration it is expedient to use the compounds according to the invention 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.

The following examples serve to further illustrate the invention. The temperature specifications are in ⁰ C.

example 1

m-methoxymethoxybenzalcyclohexanone

m-Methoxymethoxybenzaldehyde (167 g, 1.0 mol) and cyclohexanone (318 ml, 3.0 mol) are mixed with a solution of potassium hydroxide (50 g, 0.89 mol) in water (1 l) for 4 hours under nitrogen Refluxed. After cooling, the oily layer is extracted with ether (twice). The ethereal solution is washed with water (three times). Saline solution, dries (NajSO *) and evaporates. The residue is distilled and the product is obtained as a yellow oil 1132 g), bp = 173-176 ° 4.0 mbar (0.3 mm Hg), X _max , 95% EtOH, 287 μm (c = 13 100); ν (KBr) 1685, 1600, 1580 cm ^"; NMR (CDCI _3): (5 5.2 (singlet 2H, -OCH ₂ O), 3.48 (3H, singlet, -QCH _1).

Example 2

cis ^ -fff-Dimethylamino-m-methoxybenzyl / cyclohexanol

A solution of m-methoxybenzalcyclohexanone (50 g, 2.31 x 10 "mol) in ether (50 ml) is cooled to -5 ° in a pressure vessel and treated with 20 ml of dimethylamine (3 x 10" mol). The vessel is closed with a stopper and left to stand at room temperature for 60 hours. The above reaction is carried out twice (monitoring by IR spectroscopy shows that the mixture assumes an equilibrium concentration at which the S-dimethylaminoketone addition product is favored by a ratio of about 2: 1 over the m-methoxybenzalcyclohexanone). The combined total reaction mixtures are added dropwise under nitrogen to a stirred suspension of LiAlH ₄ (20 g) in ether (1.21) and the mixture is refluxed for 4 hours. The reaction mixture, cooled with ice, is treated with 3 ° strength aqueous NaOH solution (100 ml) and filtered. The precipitated solid is washed with boiling ether and the combined filtrates are evaporated to about 1 liter. The ether layer is extracted twice with excess dilute HCl, then extracted with water. The combined aqueous extracts are back-extracted with ether, made basic with 50% NaOH and extracted with ether (twice). The ethereal layers are washed with salt solution and evaporated to an oil (50 g), gas chromatography (they) shows that it consists predominantly (96%) of two components. 32 g of the residue are chromatographed on an aluminum oxide column (Woelm 900 g, neutral, activity level HI), prepared with benzene /

Hexane (1: 1). Benzene / hexane fractions (1: 1 and 2: 1) elute the main component, namely trans-2- (ff-dimethylamine) -m-methoxybenzyl) -cyclohexanol (20 g), NMR (CDCl ₃ ): δ 2.28 (6 H singlet N (CHj) ₂ ), 3.0 (1 H doublet, J = 3 HzCH N (Me) ₂ ), 3.3-3.7 (1 H wide multiple «, CH (OH)), 3.8 (3 H singlet, OCH ₃ ) ppm.

Benzene / ether (4: 1 and 2: 1) fractions elute cis ^ -ia-dimethylamino-m-methoxybenzyD-cyclohexanol s (10 g). NMR (CDCl ₃ ): δ 2.12 (6 H singlet, N (CH ₃ ),), 3.44-3.66 (2 H multiple «, CH (OH) and CH N (CH ₃ ),), 3.8 (3 H singlet, - OCH ₃ ) ppm.

The hydrochloride, mp = 203-206 °, of the trans-epimer (19.5 g) is recrystallized from hexane / dichloromethane

Analysis (air-dried sample):
for C ₁₆ H ₂₆ O ₂ NCl · H ₂ O: C 60.46, H 8.88, N 4.41%; found: C 60.68, H 9.07, N 4.53%.

The hydrochloride of the cis-epimer (8.6 g), mp = 205-208 °, is recrystallized from methanol / ether. is

Analysis:

for C ₁₆ H ₂₆ O ₂ NCl (299.84): C 64.14, H 8.98. N 4.40%; found: C 64.09, H 8.74, N 4.67%.

B e i s ρ i e 1 3

cis ^ -ia-dimethylamino-m-methoxybenzyD-cyclohexanol, acetate, hydrochloride

Cis ^ -iff-dimethylamino-m-methoxybenzyO-cyclohexanoI (3.0 g), acetic anhydride (5 ml) and pyridine (15 ml) are warmed briefly to achieve dissolution and the mixture is left to stand overnight at room temperature. The mixture is poured into dilute NaOH solution and extracted with ether (twice). The ether layers are washed twice with water and dried (K ₂ CO ₃ ) and then evaporated. Traces of pyridine are removed by azeotropic distillation with toluene, a crystalline residue being obtained. IR: 1738, 1615, 1590 cm ^"1 NMR _(CDCl3):. Ö 1.96 (3H singlet, O · CH ₃ CO), 2.06 (6H singlet, N (CH ₃ J _2), 3.38 (2H doublet, J = 10.5 Hz, CHNMe ₂ ), 3.77 (3H singlet, CH ₃ O-), 4.5! (IH multiplet, W1 / 2 H 8 Hz) ppm. _

The crystalline acetate thus formed is converted directly into the hydride, l-p = 235-237 ° with foaming. The analysis sample is crystallized from acetone / dichloromethane.

Analysis:

for C ₇ H ₂₆ O ₁ N (327.845): C 63.24, H 8.25, N 4.10, Cl 10.37%;

Found: C 63.46, H 8.46, N 4.07, Cl 10.29%.

B e i s ρ i e 1 4

cis -2- [a-Dimethylamino-m- (methoxymethoxy) benzyl] cyclohexanol

A solution of m- (methoxymethoxy) benzal cyc! Ohexanone (100 g, 4 x 10 "'mol) in ether (100 ml) is cooled to -5 ° in a pressure bottle and mixed with 50 ml of dimethylamine, ^ x 10"' mol ) and allowed to stand for 60 hours at room temperature. The reaction mixture is then added dropwise under nitrogen to a stirred suspension of LiAlH ₄ (20 g) in ether (1.4 L) over the course of one hour. The reaction mixture is stirred for an additional hour and then refluxed for 2 hours. The reaction mixture, cooled with ice, is treated with 3% strength aqueous NaOH solution (100 ml) and filtered. The precipitated solids are washed with boiling ether and the combined filtrates are evaporated to a volume of about 1 l. The ether layer is extracted (twice) with excess dilute HCl and then with water. The combined aqueous extracts are back-extracted with ether, made basic with ice and 50% NaOH and extracted with ether (twice). The ether layers are washed with brine, dried (K ₂ COj) and evaporated to an oil (46 g) which, according to gas chromatography (glc), consists of two main components. The oil is chromatographed on an aluminum oxide column (Woelm, 1.5 kg neutral, activity level III), prepared with benzene / hexane 1: 1, benzene / hexane, benzene and the first benzene / 10% ether fractions elute 25.8 g trans -2- [a-Dimethylamino-m- (methoxymethoxy) benzyl | -cycloxanol. NMR (CDCI _3): ö 2.28 (6H singlet, N (CH,),). 3.0 (1 H doublet, J = 3 I Iz, CHN (CH.,),), 3.3-3.8 (1 II broad multiplet, CHOH), 3.48 (3 H singlet, OCH ₁ ) . 5.17 (211 singlet, -OCH ₂ -O-) ppm. bi

Later benzene / ether fractions (9: 1 to I: 2) elute cis-2- [i? -Dimethylamino-ni- (methoxymethoxy) bcn- ^ yl | -cyclohcxanol. NMR _(CDCl3): ö 2.1 (6II singlet, N (CH,),.), 3.47 (3H singlet, - OCH _3), 3.37 to 3.7 (overlapping multiplets, CHOH and CHN (CH ₃ ) ₂ ), 5.21 (2 H singlet, -OCHjO-) ppm.

Example 5

cis ^ -iiz-Dimethylamino-rn-hydroxybenzyOcycIohexanoI, hydrochloride

Treat cis-2- (ff-dimethylamino-m- (methoxyrnethoxy) benzyl] cyclohexanol (10 g) in ether with a slight excess of isopropanolic hydrogen chloride recrystallized from ethanol / ether and finally from methanol / acetone to give the compound named in the title, mp = 263-265 °, NMR fD ₆ MSO): δ 2.47 (6 H singlet, N (CHj) ₂ ) ppm.

Analysis:

calculated for C ₁₅ H ₁₄ NC ^ Cl (285.805): C 63.03, H 8.46, N 4.68, Cl 12.41%;
Found: C 63.02, H 8.65, N 4.9, CI 12.77%.

15th

Example 6
cis ^ -tc-DimethylaminobenzylJcyclohexanoI

A solution of benzalcyclohexanone (100 g, 5.39 x 10 "'mol) in ether (100 ml) is in a pressure bottle cooled to -5 ° and treated with 50 ml of dimethylamine (7.5 X 10 "'mol) and for 60 hours at room temperature calmly. The reaction mixture is then added dropwise to a stirred tank under nitrogen

Suspension of LiAlH ₄ (20 g) in ether (1.3 l), over the course of one hour. The reaction mixture is stirred for an additional hour and then refluxed for 2 hours. The reaction mixture, cooled with ice, is treated with 3% strength aqueous NaOH solution (100 ml) and filtered. The precipitated solid is washed with boiling ether, the combined filtrates are evaporated to a volume of about 1 liter, the ether layer is extracted twice with excess dilute HCl and then with water. The United

Aqueous extracts are back-extracted with ether, made basic with ice and 50% NaOH and extracted with ether (zv? imal). The ethereal layers are washed with salt solution, dried (K ₂ CO ₃ ) and evaporated to an oil (70 g) which, according to gas chromatography, consists of two main components. The oil (60 g) is chromatographed on an aluminum ex! D column (vVoelm, 1.8 kg, neutral, activity level III), prepared in benzene / hexane 1: 1. Benzene / hexane, benzene and earlier benzene / 10% ether fractions elute 34.2 g of trans product (free base), mp = 73-75 °. NMR (CLCI ₃ ): «52.27 (6H singlet, N (CH) ₃ ) ₂ ), 3.05 (IH doublet, J = 3.5-4 Hz, CHN (CH ₃ ),). 3.47 (1 H wide multiple. 3.27-3.74, CHOH), 4.04 (1 H singlet., Exchangeable, -OH), 7.35 (5 H singlet, aromatic protons) ppm. Later benzene / ether fractions (4: ί to 3: 2) elute 14 g of cis product (free base), mp = 88-89.5 °. NMR (CDCl ₃ ): J 2.07 (6H singlet, N (CH ₃ ) J), 3.5! (close multiple, W 1/2 H 5 Hz, CHOH), 3.6 (1 H doublet, J = 10.5 Hz, peak at high field overlaps with CH; 'OH) multiple)

The hydrochloride salt of the cis compound is made from the free base in ether with isopropanolic hydrogen chloride produced, analytical sample: mp = 227-228 ° (from acetone / dichloromethane).

Analysis:

calculated for C ₁₅ H ₁₄ NOCl: C 66.77, H 8.97, N 5.19, Cl 13.4%;
Found: C 66.83, H 9.11, N 5.49, CI 12.9%.

NMR (DMSO-DjO exchange): 2.65 (6 H singlet, NH (CH ₃ ) ₂ ), 3.27 (1 H multiple, W 1/2 H 5 Hz, CHOH).

50

Example 7
cis-2- [ö ^f -dimethylamino-m-methoxybenzyl] cyclohexanol, propionate, hydrochloride

A mixture of cis -2- (a-dimethylamino-m-methoxybenzyl) -cyclohexanol hydrochloride (3 g) in pyridine (15 ml) and propionic anhydride (5 ml) is heated briefly to achieve dissolution and then at for 20 hours Room temperature stirred. The mixture is poured into dilute NaOH solution and extracted twice with ether. The ether layers are washed twice with water, dried (K ₂ CO ₃ ) and then evaporated. Traces of pyridine are removed by azeotropic distillation with toluene. The residue is on an aluminum oxide column (90 g, Woelm, activity level III, neutral), prepared in hexane, chromatography; Hexane / benzene and benzene fractions elute the product in the form of the free base (1.0 g) as a colorless oil. The hydrochloride, prepared with isopropanolic hydrogen chloride and an ether / hexane solution of the free base, has a melting point of 226-228 ° with foaming (from acetone / hexane). IR: 1730, 1595 cm '.

Analysis:

Calcd. Door C ₁₉ H ₃₀ O ₅ NCI: C 64.12, H 8.50, N 3.94, Cl 9.96%;
found: C 64.18, HS, 54, N 3.82, Cl 9.68%.

Example 8
cis ^ -tff-iDimethylaminoi-rn-hydroxybenzylj-cyclohexanol, diacetate, maleate

cis-2- [ff- (Dimethylam! no) -m-hydroxybenzyl] -cyclohexanol hydrochloride (1.5 g), acetic anhydride (5 ml) and pyridine (15 ml) are heated briefly to achieve dissolution and then at Left to stand at room temperature overnight. The mixture is poured into dilute NaOH solution and extracted twice with ether. The ether layers are washed twice with water, dried (K ₂ CO ₃ ) and then evaporated. Traces of pyridine are removed by azeotropic distillation with toluene, an oil residue being obtained which is converted directly into the crystalline maleate salt in acetone after two recrystallizations from acetone / hexane a melting point of 152-155 °. IR: 1765.1725 cm "" ^1. NMR (CDCl ₃ ): δ 2.05 (3 H singlet, CH ₃ CO), 2.33 (3H Singlet, CH ₃ CO), 2.7 (6H singlet, N (CH ₃ ) ^ H ⁺ ), 4.3 (IH doublet, J = 12 Hz, CH - N (CH ₃ ) ₂ ), 4.45 ( 1 H multiplet, CH (OAc)), 6.3 (2 H singlet, vinyl protons, maleate anion) ppm.

Example 9
cis ^ -iff-dimethylamino-rn-hydroxybenzyO-cyclohexanol, acetate, maleate

Cis ^ -iar-dimethylamino-m-imethoxynrethoxy-benzyl-cyclohexanol maleate (1.8 g) is converted into its free base and acetylated with acetic anhydride (5 ml) and pyridine (15 ml) for 48 hours at room temperature. The mixture is poured into dilute NaOH solution and extracted with ether. The ether layers are washed with water (twice). Brine, dried (Na ₂ SO ₄ ) and evaporated. The residue is azeotropically distilled with toluene in order to remove traces of pyridine and then treated in acetone solution with a small excess of isopropanolic hydrogen chloride (pH <2). After 15 hours the acetone is removed by evaporation and the residue is _{partitioned between ether and dilute NH 3} - NaHCO ₃ solution. The ether extract is washed with salt solution, dried over Na ₂ SO ₄ and evaporated. The residue is treated with an excess of maleic acid in ethyl acetate, the solvent is removed, the residue crystallizes (from acetone / hexane), the product has a melting point of 158-160 °. NMR (CDCl ₃ ): δ 2.04 (3 H singlet, CH ₃ CO), 2.7 (6H singlet, N (CHj) ₂ ), 4.14 (2H doublet, J = 10.5 Hz, CHN ( CH,) ₂ ), 4.5 (1 H multiplet, W 1/2 H 6 Hz, CHOAc), 6.25 (2 H singlet, vinyl protons, maleate anion) ppm.

Analysis:

calculated for C ₂ -H ₂₅ NO ₇ ; C 61.90, H 7.17, N 3.44%;
found: C 61.77, H 7.44, N 3.52%.

B e i s ρ i e 1 9A

d-cis ^ -far-dimethylaminobenzy-cyclohexanol and l-cis-2-iu - dimethylaminobenzyl) cyclohexanol

A warm solution of cis ^ -ia-dimethylaminobenzyocyclohexanol (38.16 g, 0.167 mol) and 1-malic acid (22.8 g, 0.17 m) in methanol (200 ml) is diluted with 600 ml of ether and the crystalline precipitate is recrystallized up to a constant optical rotation value (five times from methanol / ether), this gives the d-cis ^ -ia-Dimethylarr.inobenzyOcyclohexanol-I-maläuresalzOS g), mp = 195-196 °, [a) i ^s = +15.2 (c = 1.006 MeOH).

Calculated for C) ₉ H ₂₉ NO ₆ : C 62.11, H 7.96, N 3.82%:
Found: C 62.44, H 8.43, N 3.98%.

Part of it is converted back into the free base, which has a rotation value [a] " of +53.2 (c = 1.057 MeOH). The filtrates from the recrystallizations of the 1-malic acid salt are stirred in water and ether, made basic with NaOH, extracted, washed, dried and evaporated to give 28.0 g of residue, which can be dissolved with d-malic acid (17 g) in hot methanol (200 ml ) is dissolved and diluted with ether (600 ml). The crystalline precipitate is recrystallized three times from methanol / ether and added 1-cis-Ma-dimethylaminobenzyl) cyclohexanol-d-malate, mp = 195.5-196.5 °, [a] j; = -15.8 (c = 0.9095 MeOH).

Part of it is converted back into the free base, which has a rotation value of [er] ;; = -53.6 (c = 1.049 MeOH).

Example 10

If the methods of Examples 2 and 4 are used and the required Benzalcyclohexanon- and the amine component, the following compounds (the crystallization solvent is in brackets):

Compound melting point

cis-2- (m-chloro-i / -dimethylaminobenzyl) cyclohexanol hydrochloride salt: 140-145 °

(Mixture of isomers)
(Ether)

ei s-2- (ff- (ethyl methylamino) -m- (methoxymethoxy) benzyl] cyclohexanol fumarate salt: 155-157 °
ίο (methanol ether)

cis-2- [tf- (Bcw \ lmethylamino) -m- (methoxymethoxy) benzyl] cyclohexanol

Example 11
cis ^ -fa-l-dimethylamino-m-hydroxybenzyD-cyclohexanol, hydrochloride

Treat cis ^ -lff-Dimethylarnino-m-methoxymethoxyibenzyl-cyclohexanol (260 g) as a suspension in tetrahydrofuran (1.5 L) with isopropanolic hydrogen chloride (300 ml, 4.65 N). You immediately get a klan Solution from which the compound named in the title separates out in crystalline form (23Og).

Example 12

If the methods of Example 5 are used and the appropriate methoxymethyl ethers are used, see (

one obtains the following connections:

Compound melting point

cis-Z-iff-lÄthylmethylaminoj-m-hydroxybenzyljcycIohexanol hydrochloride salt (hemihydrate)

85 ° with foaming (ether;

L-is-2- [cr- (Benzylmethylaminol-m-hydroxybenzyllcyclohexanol hydrochloride (· H ₂ O): 239-240 '

rv Ui 3Vi laun ιιίι

(Tetrahydrofuran)

in cis-2- [m-Hydroxy-ff- (methylam! no) benzyl] cyclohexanol hydrochloride salt: 263-265 °,

Lather up
(Methanol-acetone)

Examples

ice - 2 - [m - methoxymethoxy - a - (methylaminoibenzyllcyclohexanol

d A mixture of cis ^ -Iff-iBenzylmethylaminoJ-m-imethoxymethoxyJ-benzylJcyclohexanol (2 ^ Og, 6.68 χ 10 ^: mol), methanol (300 ml), 10% Pd on C (4 g) and acetic acid (5 ml Glacial acetic acid, 8.75 × 10 ² mol) is hydrogenated at room temperature using a hydrogen pressure of 1.41-3.16 kg / cm ² (20-45 psi). After the catalyst has been filtered off, the reaction mixture is concentrated in vacuo and the residue distributed between ether and excess NaOH solution. The ether extract is washed with saline.

eet dried (Na-SO ₄ ) and evaporated. Crystallization of the residue from ether / tetrahydrofuran gives the product Π 2 g). M.p. 87-89 °. NMR (CDCl-.): Ö 2.27 (3H singlet, NHCH _3). 3.45 (3 H singlet, OCHj), 3.72 (1 H apparent singlet. Wl / 2 H 3 Hz), 4.15 (1 H multiple, Wl / 2 H 6 Hz), 5.12 (2H Singlet, - OCH ₂ O -; ppm.

Analysis:

calcd for CH4 NO-: C 68.78, Fl 9.02, N 5.01%;
found: C 68.98, H 9.21, N 4.88%.

Maleate salt, m.p. 152-154 ° (acetone / hexane).

Analysis:

for C, ₆ H, -NO-, • C ₄ H ₄ O ₄ : C 60.74, H 7.39, N 3.54%;
found: 'C 60.98, H 7.41, N 3.48%.

Example 14

Use the procedure of Example 13, but replace acetic acid with hydrochloric acid (since none acid-labile methoxymethoxy group is present) cis-2- [m-Hydroxy-a- (methylamino) ben7.yl] cyclohexanol hydrochloride is obtained, Mp = 263-265 ° (methanol / ether).

Example 15
cis-2- [mM? thoxy-ff- (methylamino) benzyl] cyclohexanol

Treating cis-2- [m-Hydroxy-a- (methylamino) benzyl] cyclohexunol hydrochloride (1 g) in methanol with an excess of ethereal diazomethane for 2 days at room temperature. The solution is evaporated and the residue is partitioned between ether and dilute NaOH solution. The ether extract is washed with salt solution, dried (NaSO ₄ ) and treated with isopropanolic HCI, the product being obtained as the hydrochloride, mp = 222-223 ° (methanol-ether).

Analysis:

for C ₅ H ₂₃ NO ₂ • HCl: C 63.03, H 8.46, N 4.9, Cl 12.41%; Found: C 63.05, H 8.45, N 5.01, Cl 12.57%.

Trans-2- [m-methoxy-ff- (methylamino) benzyl] -cyclohe \ anol fumarate is obtained in the same way, Mp = 142-155 ° (hemihydrate from acetone).

Example 16

d-cis-2- (u'-dimethylamino-m-hydroxybenzyl) cyclohexanol and l-cis-2- (a-dimethylamino-m-hydroxybenzyl (cyclohexanol

A warm solution of 2 R: 3 R tartaric acid (7.5 g, 5 x 10 ² mol) and cis-2- (ff-DimethyIamino-m-hydroxybenzyl) cyclohexanol (12 g, 4.82 x 10 " ² mol) in ethanol (100 ml) is diluted with boiling acetone to a final volume of 900 ml, filtered to clarify the solution, inoculated with positively rotating isomer and kept at about 25 ° for 20 hours ) is recrystallized twice from ethanol-acetone and gives d-cis ^ -ia-dimethylamino-m-hydroxybenzyOcyclohexanol, 2 R: 3 R-Tarirai (mono) acetone derivative (4.9 g), mp = ϊ98-2ΰϋ °, [α ] ^: _η ' = +45.53 (c = 1.05 MeöH) The NMR spectrum shows that the product is a partial acetone solvate even after intensive drying.

A solution (3.7 g) of the above salt in water is _{made basic with a 1: 1 mixture of saturated NaHCOi solution and concentrated NH 4} OH and the base is extracted twice with ether. The ether extracts are washed with salt solution, dried (Na ₂ SO ₄ ), the solvent is removed and a crystalline solid substance is obtained (1.89 g). Recrystallization of a part from acetone / hexane gives the analysis sample, mp = 191-193 °, [a] i ^! = +45.21 (c = 1.074 MeOH) of d-cis ^ -fa-dimethylamino-m-hydroxybenzydcyclohexanol.

Analysis:

calculated door CcH ₂₃ NO ₂ : C 72.25, H 9.30, N 5.62%;
found: C 72.28, H 9.40, N 5.58%.

The hydrochloride, mp = 255-257 °, foaming, [«£ = +14.70 (c = 1.045 MeOH) is obtained by Treatment of the base in ether with isopropanolic hydrogen chloride and trituration of the precipitate with boiling acetone until the product is crystalline.

Analysis:

calcd for C ₅ H ₂₃ NO ₂ · HCl: C 63.03, H 8.46, N 4.9. Cl 12.41%;

Found: C 62.66, H 8.46, N 4.92, Cl 12.52%.

A part that has been converted back into the free base has a rotation value Ia] J; of +43.3, which shows that no racemization has taken place.

The acetone / ethanol filtrates remaining after the separation of the 2 R: 3 R tartrate are combined, freed from the solvent and the residue is partitioned between ether and a mixture of saturated NaHCO ₃ solution and concentrated NH ₄ OH. The aqueous extract is washed twice with ether and the combined ether extracts are washed with salt solution, dried (Na ₂ SO ₄ ) and the solvent is removed. A solution of the residue (6.0 g, 2.4 x 10 ^"2 mole) in warm ethanol (100 ml) with 2 S: treated 3S-tartaric acid (3.75 g, 2.49 x 10 ^-2 mole) and diluted with boiling acetone (900 ml), filtered and left to stand for 60 hours at 25 ° The separating crystalline solid (6.8 g) is crystallized twice from ethanol / acetone and gives l-cis-2- (a-dimethylaminechm -hydroxybenzyi) cyclohexanoI, 2 S: 3 S-tartrate (mono) acetone solvate, 4.5 g, m.p. 198-200 °, [a] ~ = -45.70 (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 NaHCO, solution and concentrated NH ₄ OH and dit. Base is extracted twice with ether. The ether extracts are washed with salt solution, dried (NaSO ₄ ), the solvent is removed and a crystalline residue is obtained (1.75 g). A portion is recrystallized from acetone / hexane and gives the analytical sample, mp = 191-193 °, [«], '/ = -46.92 ° (c = 1.061 MeOH) of l-cis-2- (a-dimethylamino- m-hydroxybenzyl) -cyclohexano!

Analysis:

for C ₁₅ H ₂₅ NO ₂ : C 72.25, H 9.30, N 5.62%;

Found: C 72.54, H 9.37, N 5.68%.

The hydrochloride, mp = 255-257 °, foaming, [a] y! = -15.31 (c = 1.067 MeOH) is obtained by treating the base in ether with isopropanolic HCI and triturating the precipitate with boiling acetone.
I?

Analysis:

for C ,, H ,, NO ₂ -HCl: C 63.03, H 8.46, N 4.90, Cl 12.41%;

Found: C 62.90, H 8.57, N 4.93, CI 12.00%.

A portion that has been converted back into the free base has a rotation value [α]; / of -45.86 °, which shows that none Racemization has taken place.

Example 17

cis ^ -fff-Dimethylamino-rn-ethoxybenzyOcycIohexanol-rnaleate

A mixture of cis ^ -ia-dimethylamino-m-hydroxybenzyOcyclohexanol (6.6 g, 2.5 x 10 ~ ^: mol) and pulsed

Vertem K ₂ COj (10 g, 7.2 x 10 "mol) in warm ethanol (30 ml) is treated with a solution of ethyl iodide (2.2 ml, 4.3 g, 2.75 x 10" ² mol) ) in ethanol (15 ml) added dropwise over 20 minutes. The reaction mixture is refluxed for 90 minutes, evaporated and the

The residue is distributed between ether and water (pH of the aqueous phase = 11-12), and the ethereal layer is washed

one with water and brine and dry it over Na ₂ SO ₄ . Evaporation of the ether gives an oily one

Residue, which is characterized in the form of its maleate salt, mp = 166-167 ° (from ethanol / ether).

Analysis:

calcd Oir CiH ₃ , NO ,,: C 64.10, H 7.94, N 3.56%;
found: C 64.19, H 7.94, N 3.63%.

Example 18

cis ^ -Methoxy-ü-im-methoxymethoxyphenyD-NN-dimethylcyclohexanmethylamine-maleate and
ff-Dimethylamino-a- (cis-2-methoxycyclohexyl) -rn-cresol, hydrochloride

Treating cis ^ -tß-Dimethylaminoi-m-imethoxymethoxyibenzyl-cyclohexanol (5.9 g, 0.02 mol) in Tetrahydrofuran (100 ml) at room temperature and in a nitrogen atmosphere with 1.6 molar butyl lithium

so (12.5 ml, 0.02 mol) for one hour. The mixture is cooled to -70 °, treated for 30 minutes with a solution of methyl iodide (1.25 ml, 0.02 mol) in tetrahydrofuran, stirred at room temperature for 48 hours, mixed with 5 ml of methanol and evaporated. The residue is washed in ether with water and brine and dried (Na ₂ SO ₄ ). The product (4.0 g) is purified by descending column chromatography on alumina using CH ₂ Cl ₂ to develop the column. 1.0 g of product are converted into the maleate, namely the cis ^ -methoxy-a-im-methoxymethoxyphenyD-NN-dimethylcyclohexanemethylamine maleate, mp = 112-115 °, NMR (CDCl ₃ ): δ 3.0 (3 H Singlet, OCH ₃ ), 4.45 (1H doublet, J = 10.5 Hz, CHN (CHj) ₂ ) ppm.

Analysis:

for C ₂ H ₁₁ NO ₇ : C 62.39, H 7.85, N 3.30%;
Found: C 62.47, H 7.92, N 3.29%.

Treatment of the free base in tetrahydrofuran with dilute HCl gives cr-dimethylamino-ff- (cis-2-methoxycyclohexyl) -m-cresol hydrochloride, Mp = 227-228 ° (from ethanol / ether).

Analysis:

for C ₁₆ H ₂₆ NO ₁ Cl · 1/4 H ₂ O: C 63.15, H 8.83, N 4.60, Cl 11.65%;
Found: C 63.25, H 9.17, N 4.25, Cl 11.53%.

Example 19
cis-2- [a- (Cyclopropylmethyl) methylamino-m-hydroxybenzyl] cyclohexanol, Hydrochloric!

cis ^ -Im-Methoxymethoxy-a-imethvlamhioibenzylJcyclohexanol (2.5 g, 8.95 x 10 " ³ mol) and cyclopropanecarboxylic acid chloride (2.0 g, 1.91 X 10" * mol) are in a two-phase system consisting of Stirred 10% K ₂ CO ₃ solution (100 ml) and CH ₂ Cl ₂ (60 ml). After 6 hours the organic layer is separated and evaporated to give a colorless oil which is refluxed in THF / ether (120 ml, 1: 1) with LiAlH ₄ (1.0 g) overnight. The ice-cold reaction mixture is treated with 5 ml of 3% NaOH solution, filtered, the organic layer is evaporated and the residue is treated in THF (15 ml) with ethanolic hydrogen chloride (5 ml), the product (1.7 g) crystallizes overnight, Mp = 228 °, foaming (from methanol / ether).

Analysis:

Calculated for Ci ₈ H ₂₇ NO ₂ · HCl: C 66.34, H 8 66, N 4.30%;

Found: C 66.69, H 8.71, N 4.11%.

cis - ^ - ia-Dimethylamino-m-hydroxybenzs'Dcyclohexanol

Treat m-methoxymethoxybenzalcyclohexanone (30 g, 1.21 x 10 ^M mol) in ether (40 ml) with dimethylamine (25 ml, 4 X 10 "mol) in a pressure bomb for 2 days at room temperature. The solvents are removed in vacuo removed, the residue is diluted with ether (100 ml!) and the solvents are again removed in vacuo to remove the last traces of dimethylamine.The residue is added to an 1 molar solution of tetrahydrofuran in THF (60 ml) over 40 minutes with stirring / borane (150 ml, 1.5 x 10 ^-2 mol) come under a nitrogen atmosphere. During the addition, the reaction mixture is maintained in the range of 0-10 °. in Vei course of 2 hours, allowed to the reaction mixture to room temperature, then cooled to -10 ° before treating with 10% aqueous tetrahydrofuran (8.1 ml H ₂ O (4.5 x 10 " ² Mo!), 81 ml THF) and then with 35 ml 4.3 η isopropanolic hydrogen chloride. The decomposition of intermediate amine boranes is characterized by the slow evolution of hydrogen as part of a mild exothermic reaction. After inoculation with cis-2- (a-dimethylamino-m-hydroxybenzyl) cyclohexanol hydrochloride, the product slowly crystallizes (19.5 g). The hydrochloride is dissolved in water and _{treated with an excess of NH 4} OH and NaHCO 3 solution, the free base produced is extracted into ether. The ether extracts are evaporated and triturated with hexane, which contains small amounts of THF, cis-2- (ff-dimethylamino-m-hydroxybenzy!) Cyclohexano! obtained (15 g), mp = 142 °.

Example 21
cis ^ -te-dimethylamino-m-hydroxybenzylH-methylcyclohexanol fumarate

A solution of m- (methoxymethoxy) benzylcyclohexanone (100 g, 4 × 10 " ¹ mol) in ether (100 ml) is cooled to -5 ° in a pressure vessel, treated with 100 ml of dimethylamine and left to stand at room temperature overnight. The reaction mixture is evaporated and the residue dissolved in ether, washed with water (twice, discarded) and extracted with dilute HCl (twice) and water. The combined acidic extracts are washed with ether and then made basic with ice-cold NaOH. Extraction with ether gives 96.5 g of the dimethylamine oadduct (IR SAT only C = O peak). The adduct (96 g) in ether (400 ml) is added to a 3 molar solution of methyl magnesium bromide in ether (250 ml) in the course of 30 minutes. refluxed for 90 minutes and finally left to stand overnight at room temperature.After treatment with 75 ml of ice-cold saturated NH ₄ Cl solution, basic material (50 ml) is isolated, exactly as described for the dimethylamino adduct, and on aluminum oxide (1.7 kg , Woelm, activity level III, neutral) chromatographed. Benzene / hexane (1: 2) and benzene fractions elute trans ^^ c-Dimethylamino-m-methoxymethoxybenzyD-l-methylcyclohexanol as an oil, NMR (CDCl ₃ ): 82.05 (6 H singlet, N (CH ₃ J ₂ ), 1.12 (3 H singlet, CHj-C (OH) =) ppm. Benzene with increasing proportions of ether elutes cis-2- (ff-DimethyIaminom-methoxymethoxybenzyl) -l-methylcyclohexanol as an oil, NMR (CDCl ₃ ) : 82.26 (6 H singlet, N (CH ₃ ),), 1.15 (3 H singlet, CH ₃ - C (OH) =) ppm. The stereochemical assignments of the above compounds are based on their NMR spectrum POCl ₃ pyridine dehydration products showing that the trans compound ^{gives exclusively a Λ 2} -Ο1βΠη, while the cis compound gives a Λ olefin as the main product along with a small amount of Λ 'compound on acid hydrolysis the trans-2- {ar-dimethylamino-m-hydroxybenzyl) -l-methylcyclohexanol, mp = 151-153 °, fumarate salt, mp = 177-179 °. The cis compound (10.0 g) is treated with HCl (12.5 ml, 4.7N) in tetraydrofuran (50 ml) and left to stand overnight. After the solvent has evaporated, the residue is triturated with ammonia and ether. The ether extract is washed with water, salt solution and dried over Na ₂ SO ₄ . On evaporation of the solvent, highly crystalline cis ^ -iff-dimethylamino-m-hydroxybenzyO-l-methylcyclohexanol, mp = 175-177 °, the fumarate salt melts at 199-203 ° (decomposition).

Analysis:

calcd for C _{16 H 4} -NO, ■ C 4 H ₄ O ₄ : C 63.30, H 7.70, N 3.69%; found: C 62.92. H 7.69, N 3.88%.

(NMR DMSC ^: 82.2 (6H singlet, N (CHj) ₂ ), 0.65 _{(3H singlet, CH 3} -C (OH) =) ppm.

Example 22

ίο One prepares an injectable preparation in the form of dose units by adding 1 g of cis-2- (a-dimethylamino-m-hydroxybenzyD-cyelohexanol hydrochloride in 50 ml of a 0.1m phosphate buffer, pH 7.4, dissolves and with distilled water made up to 100 ml. This drug solution, which contains 10 mg / ml of active ingredient, is made by a 0.45 μm filter is sterile filtered and 1 ml portions are aseptically filled into sterile ampoules. The ampoules are melted shut with the flame and the contents are frozen and stored at -20 ° C until needed

Become 15.

Example 23
Tablets for oral use are made from the following formulation:

20th

Eviiüigramm

cis-2- (ff-Dimethylamino-m-hydroxybenzyl) -cyclohexanoI hydrochloride 10 If

Lactose 287 282

Magnesium stearate 3 3

^2y 3ÖÖ IOC

The following cis isomers with "normal" configuration (compounds according to the invention) and trans-Epi mers were examined:

30th

1 a - cis ^ -ia-dirnethylamino-rn-methoxybenzyOcyclohexanol;

1 b - trans ^ -iff-dirnethylamino-m-methoxybenzyocyclohexanol;

2 a - cis ^ -ia-dimethylamino-rn-hydroxybenzyOcyciohexanol; 2b-trans ^ -fff-dimethylamino-m-methoxybenzyocyclohexanol;

35 3 a - cis ^ -iff-Iethylmethylaminol-m-hydroxybenzyOcyclohexanol;

3b-t. ^r ar: S-2- (ir- [ethy! methy! arr! no] -m-hydroxybenzyl) cyclohexanol; 4a - cis ^ -ia-dimethylaminobenzy-dcyciohexanol; 4b - trans -2- (ar-dimethylaminobenzyl) cyclohexanol;

The following procedure was used to determine analgesic efficacy in rats:

Rats weighing approximately 150 to 200 g are placed in individual holders, and each shark it is arranged so that a high intensity beam of light is incident on the tip of the tail. The intensity de; The light beam is regulated so that normal rats react within 3 to 8 seconds by making their Move the tail out of the light beam. The mean of two readings 20 minutes apart serves as a controlled for behavior prior to drug administration. There are those Rats selected for the experiment whose control values agree for one second. Man administer the compounds orally or intraperitoneally and measure the reaction times every 20 minutes for 2 hours.

Analgesics cause a significant increase in reaction time. One speaks of analgesic efficacy when the reaction time of rats for two successive measurements is 50 ° / so greater than that of the rats used as controls.
The following results were achieved:

Connection b trans

⁵ ' ~ "· ·""' Dose Ad- A / T *)

delivery type

^w la and Ib 25th IP 3/5 25th LP. 0/5

25. I. P. 0/5

65

16

connection a
ice cream Appointment
reaching
art AT") link dose LP. 3/5 1 a and Ib 25th I. P. 1/5 12.5. 1. P. 4/5 2 a and 2 b 25th 1. P. 4/5 12.5 LP. 9/15 3.12 I. P. 5/15 1.56

(Continuation)

Connection a ds

Compound dose

Mode of administration

AT*)

Connection b trans

dose

Mode of administration

AT*)

a and 3 b
4a and 4b

0.78
10.
5.
2.5
5.
2.5
1.25

25th

25th

12.5
6.25
3.12
3.12
6.25
5.
2.5

LP.

P.O.

P.O.

P.O.

LM.

LM.

LM.

LP.

LP.

LP.

LP.

LP.

LM.

LM.

P.O.

P.O.

2/10 7/10 5/10 1/10 8/10 18/32 3/10

25. 25.

LP. LP.

0/5 0/5

*) Number of rats that showed allergies / number of those examined. Rats, dose in rp.g / kg.

In addition, the following compounds were tested using the above procedure: Resulting connection

cis-2- (ff-Dimethylamino-m-methoxybenzyl) cyclohexanol propionate hydrochloride

cis-2- (ff-Dimethylamino-m-methoxymethoxybenzyl) -cyclohexanol maleate

cis-2- (e-dimethylaminobenzyl) cyclohexanol hydrochloride

l-cis-2- (ur-dimethylamino-m-hydroxybenzyl) cyclohexanol hydrochloride

for morphine in this procedure:

Appointment dose Number of rats the reaching Show analgia / number of path mg / kg tested rats LP. 12.5 3/5 LM. 15.0 3/10 LP. 25.0 5/5 LP. 6.25 2/5 LM. 5.0 5/10 LM. 2.5 3/10 LP. 12.5 8/10 LP. 6.25 9/10 LM. 6.25 8/10 P.O. 5.0 6/10 LP. 6.25 6/10 LP. 3.12 8/10 IN THE. 0.62 7/10 LM. 0.41 4/10 P.O. 6.25 7/10 P.O. 3.12 5/10 LP. 3.5 mg / kg LM. 2.0 mg / kg P.O. 10.0 mg / kg

10

15th

20th

25th

30th

35

40

AS

50

55

65

The abovementioned compounds according to the invention were also examined to what extent they do affect the central nervous system. These compounds were administered orally in doses of 400, 127, 40 and 12.7 mg / kg administered to three mice each. The animals were then examined to see if they had any Signs of general stimulation (increased spontaneous motor activity, hyperactivity with tactile stimulation, General depression (decreased spontaneous motor activity, decreased Respiration) or an autonomic activity (miosis, mydriasis / diarrhea). The animals were also then examined to what extent their reflexes (e.g. flexor, extensor) changed. Sedating the tests Effects were carried out with the help of the "stick" test and the "inclined plane" test.

These studies showed that the cis and trans epimers of the compounds according to the invention affect the central nervous system in the same way, that is, it is irrelevant whether an cis or trans epimer a particular compound is administered.

However, such an influence on the central nervous system could only be determined at a dose of the compounds according to the invention, be it cis- or trans-epimers, of generally 127 mg / kg.
In summary, this results in the following:

The investigated trans-epimers show no analgesic whatsoever even at the highest administered dose Effectiveness, while the cis-epimers have a strong analgesic effect.

Regarding the other generally undesirable side effects on the central nervous system the cis and trans epimers are about equally ineffective.

Thus, the cis compounds of the invention are powerful analgesics while the corresponding trans compounds have no such effectiveness.

The investigations also found that the LD ₅₀ (mouse) must be greater than 127 mg / kg, since this dose did not lead to death in any of the animals examined.

The compounds according to the invention also have a large therapeutic index, since the distance between the ED ₅₀ (the ED ₅₀ (rat) po for compound 2a is, for example, 5 mg) from the LD _{50 is} large.

1 sheet of drawings

Claims (2)

Patent claims:
1. 2- {ff-Aminobenzyl) -cycIohexanolderivate of the general formula I: R ³ OR ¹ R ² essentially free of the trans isomer, wherein R ^ is hydrogen, C, -C ₃ -alkyl or C, -C ₃ -alkylcarbonyl; R ^: Ci-Cj-alkylamino, NC ₁ -C ₃ -alkyl-N-methylamino, N-phen-id-O-alkyl-N-methylamino or N-Cj-Q-Cycloalkylmethyl-N-methylamino;
R ^{3 is} hydrogen or methyl; ^X denotes hydrogen, hydroxy, C ₁ -C ₃ -alkOXy, C ₁ -Cj -alkoxymethoxy, QQ-alkylcarbonyloxy or halogen; the Benzyikohienstoff has "normaie" configuration, the compounds with "normalerw configuration on the benzyl carbon atom by condensation of a benzalcyclohexanone of the general formula III with an amine of the general formula
R ² H where X and R have the meanings given above, and further processing of the compound obtained of the general formula II OR ² according to claim 2, are available; and their pharmacologically acceptable acid addition salts, with the exception of 2- (a-dimethylamino- benzyO-cyclohexanol. 2. Process for the preparation of the compounds of general formula I according to claim 1, characterized so characterized that in a known manner a compound of the general formula II wherein R ² and X have the meanings given above, either A) to a compound of the general formula I in which R ¹ and R ^{3 are} hydrogen, reduced, preferably with diborane, or B) with a methyl Grignard reagent to form a compound of the general formula I, in which R ^{1 is} hydrogen and R ″ is methyl, C) if necessary, separating the compound obtained from its trans isomer, if desired D) one of those obtained in stage A or B either before or after the separation from the trans isomer Compounds of general formula I to a compound of general formula I in which R, C | -C, -Alkyl or Ci-Cr-alkylcarbonyl, etherified or esterified, whereby one optionally E) the compound obtained in stage A, B or C, a) if X is hydroxy, to a compound of the general formula I in which X is C ₁ -C ₃ -alkoxy, C, -C ₃ -alkoxymethoxy or C, -C ₃ -alkylcarbonyloxy, etherified or esterified, b) if X is C, -Q-alkoxymethoxy, to a compound of the general formula I in the X door Hydroxy stands, hydrolyzed, c) if R ^{2 represents} methylamino, to a compound of the general formula I in which R ^{2 represents} NQ-Cj-alkyl-N-methylamino, N-Cj-Q-cycloalkylmethyl-N-methylamino or N-phen- (C | -C ₄ ) -alkyl-N-methylamino, alkylated and