AU2518100A

AU2518100A - 3-amino-3-arypropan-1-ol derivatives, and their preparation and use

Info

Publication number: AU2518100A
Application number: AU25181/00A
Authority: AU
Inventors: Helmut Buschmann; Hagen-Heinrich Hennies; Babette-Yvonne Kogel; Bernd Sundermann
Original assignee: Gruenenthal GmbH; Chemie Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 1999-04-07
Filing date: 1999-04-07
Publication date: 2000-10-19

Description

S&F Ref: 496951

AUSTRALIA

i PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

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Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Grunenthal GmbH Zieglerstrasse 6 D-52078 Aachen Germany Bernd Sundermann, Hagen-Heinrich Hennies, Babette- Yvonne Kogel and Helmut Buschmann Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 3-amino-3-arylpropan-1 -ol Derivatives, and their Preparation and Use The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c PaetApiainfie yGu nnhlGr4,D508Ace (ompay re erene: G2811 R I.

i R 1 R wherein R R

R

denote, in each case independently of one another, Ci- alkyl or R' and R- together denote a ring that may also be substituted by phenyl, denotes alkyl, C.-6 cycloalkyl, aryl with optionally heteroatoms in the ring system and the substituents to RP on the aryl ring, or a substituted Ci- 1 alkylphenyl of the formula XII,

R'

to R" .n 1, 2 or 3

XII,

denote, in each case independently of one another, Ci,- alkyl, cycloalkyl, phenyl, benzyl, phenethyl or R' and together form a (CHII) ring or CH:CH.OCH-CH, ring, denote, in each case independently of one another, F, Cl, Br, CHF.:, CF-, OH, OCFl, OR", NR SR", phenyl, SO.:CIIH, SO.:CF,, alkyl, CN, COOR', CONR R' or R" and R together form a OCH.:O, OCH CH:O, CH=CHO, CH=C(CH 3 )O or (CH2) ring, wherein denotes Ci-s alkyl, phenyl, benzyl, phenethyl and denote, in each case independently of one another, H, Cl-6 alkyl., phenyl, benzyl, phenethyl, and denotes an aryl radical that may optionally contain heteroatoms in the ring system and/or that may optionally be substituted,

R

15

R'"

A

and their diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids, whereas 1benzyl-2-(dimethylaminophenylmethyl) cyclohexanol, its diastereomers and its enantiomers in the form of their bases and its reaction product with methyliodide are disclaimed, as well as their preparation and use as medicinal drugs.

The treatment of chronic and non-chronic painful states is extremely important in medicine since pain is one of the basic symptoms encountered in clinical practice. At the present time there is a worldwide demand for additional, not exclusively opioid, but highly effective pain treatments. The urgent need for a patient-friendly and targeted treatment of chronic and non-chronic painful states, by which is meant the successful and satisfactory management of pain for the •patient, is documented in the large number of scientific :articles that have recently appeared in the field of applied analgesics and fundamental research in nociception.

20 Conventional opioids such as for example morphine are extremely effective in treating severe to extremely severe pain. Their use is limited however by the known side effects, for example respiratory depression, vomiting, sedation, constipation, addiction, dependence and development of 25 tolerance. Accordingly they can be administered over a prolonged period or in relatively high doses only if particular safety precautions, for example special regulatory provisions, are observed (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York, 1990).

Furthermore, they are less effective in some painful states, in particular in the case of neuropathic pain.

The object forming the basis of the present invention is to provide a new structural class of analgesically effective substances that are suitable for treating pain. Further objects of the invention are to provide active agents that are also suitable for use as a local anaesthetic and/or antiarrythmic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence and/or inflammation. As a rule the substances are also suitable for treating depression and/or for improving alertness and attentiveness, and/or improving libido.

It has now been found that the class of compounds of the general formula I is characterised by a pronounced analgesic action. Furthermore the compounds of the general formula I exhibit a marked affinity for the binding site 2 of the sodium channel (BTX binding) for the benzothiazepine and the 15 phenylalkylamine binding site of the L-type calcium channel (diltiazem and verapamil binding) and inhibit synaptosomal noradrenaline uptake (NA uptake inhibition). Accordingly the class of compounds of the general formula I is also suitable for use as a local anaesthetic and/or anti-arrythmic and/or 20 anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence, and/or inflammuation.

As a rule the class of compounds of the general formula I is 25 also suitable for improving alertness and attentiveness and/or S* improving libido and/or for treating depression.

The invention thus relates to substituted 3-amino-3arylpropan-l-ols of the general formula I, 3 OH A R

R

4 R N RI

R

wherein the radicals R' to R' and A have the meanings given above, and the corresponding diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids, whereas l-benzyl-2-(dimethylaminophenylmethyl)cyclohexanol, its diastereomers and its enantiomers in the form of their bases and its reaction product with methyliodide are disclaimed.

Preferred are compounds of the general formula I in which R' and R' together form a ring, in particular a (CH:) ring, which is optionally substituted by phenyl, R to R and A have the meanings according to the definition of the 15 general formula I, or compounds of the general formula I in which R' denotes a substituted CI-3 alkylphenyl of the formula XII, R' and R and A have the meanings according to the definition of the 20 general formula I, or compounds of the general formula I in which R' denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R' to R" on the aryl ring, R R R and R' and A have the meanings according to the definition of the general formula I, or compounds of the general formula I in which A denotes a radical from the group of substituted phenyl of the formula XI

R

1 1

R

1 2 9 'N 13 R R wherein R? to R 13 denote, in each case independently of one another, H, F, Cl, Br, I, CF,, OH, OCF 3 SR", SO.CIH,

SOCF

3 Ci-, alkyl, phenyl, CN, COOR 14 NO:, or R and

R'

i or R 1 and R 11 together form a OCH:0 or OCHCH-O ring,

R

14 denotes C 1 alkyl, phenyl, benzyl, phenethyl or A denotes an unsubstituted or substituted thiophene or an unsubstituted or substituted furan, and the radicals R' to R have the meanings according to the definition of the general 15 formula I.

Also preferred are compounds of the general formula I in which

R

1 and R 2 together form a ring, in particular a ring, which is optionally substituted by phenyl, R 1 denotes a 20 substituted C 1 alkylphenyl of the formula XII, R to R and A have the meanings according to the definition of the general formula I, or compounds of the general formula I in which R i and R together 25 form a ring, in particular a ring, which is optionally substituted by phenyl, R'denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R to R" on the aryl ring, and R' to Rn and A have the meanings according to the definition of the general formula I, or compounds of the general formula I in which R' and R' together form a ring, which is optionally substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstituted or substituted furan, R 3 denotes a substituted Ci-3 alkylphenyl of the formula XII, and R- to R' have the meanings according to the definition of the general formula I, or compounds of the general formula I in which R' and R- together form a (CH)4 ring, which is optionally substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstituted or substituted furan, R denotes an aryl radical with optionally heteroatoms in the ring system and the substituents

R

6 to RP on the aryl ring, and R' to R' have the meanings according to the definition of the general formula I.

Also preferred are compounds of the general formula I in which 15 R' and R 2 together form a (CHI) ring, A denotes unsubstituted or substituted thiophene, R 'denotes a substituted Ci-, alkylphenyl of the formula XII, and R' to R have the meanings according to the definition of the general formula I, or 20 compounds of the general formula I in which R 1 and R together form a (CH-)4 ring, A denotes unsubstituted or substituted thiophene, R 3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R to R" on the aryl ring, and R' to R have the meanings according to 25 the definition of the general formula I, or compounds of the general formula I in which Rl and R2 together form a(CH.) ring, A denotes unsubstituted or substituted furan, R 3 denotes a substituted alkylphenyl of the formula XII, and R4 to R5 have the meanings according to the definition of the general formula I.

Compounds of the general formula I in which R' and R together form a (CH 2 ring A denotes unsubstituted or substituted furan, R 3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R to R" on the aryl ring, and R' to R 5 have the meaninigs according to Llie definition of the general formula I.

Further preferred compounds include: 2- (diinethylaminopheniylmiethaYl) 1- (3-methoxypheniyl) cyclohexanol. and the corresponding hydrochloride 2- (dirnethylaminophenylflethYl) -l-(3-fluoroplhen-yl-) cyclohexanol and the corresponding hydrochloride 2- (diliuethylamiriophenyl-lneth-yl) -phenylcycioh-exanlol and the corresponding hydrochloride 3 2- (d ii e th yl1am inop h en yllinet hy1) 1- hyd ro xy cy clo h ex yl] phenol and the corresponding hydrochloride 2- (dimethyl aminophen ylmie thyl) (4-methoxyphenyl) cyclohexanol and the corresponding hydrochloride 1- (4-chiorophenyl) (dime thyiamiinophenylitie thyl) cyclohexanol. and the corresponding hydrochloride 2- (dime thyl aminophenylutetliyl) (4-f luorophenyl) cyclohexanol and the corresponding hydrochloride 2- (dime thyl aminophen ylme th-yl) tolylcycl-ohexanlol- and the corresponding hydrochloride 1- (3-chloroplienyi) [diinethylamino- (3-methoxyphetnyl) methyllIcyclohexanol and the corresponding hydrochloride 1- (4 -dime thyl.aminophenyl) (dimnethylaminophenylllethYlI cyclohexanol and the corresponding hydrochloride 1 -ben zo 3] dioxol-4-yi-2- (dime thylami nophenllnfe thyl1) cyci-ohexanol and the corresponding hydrochloride 1- 4 -dimethoxyphenyl) (dime thyl aminoPhenlinlfe th yl) cyciohexanol. and the corresponding hydrochloride 2- (dimethylaininophiefylrnethyl) (3-methoxybenizyl) cyciohexanol and the corresponding hydrochloride 1-benzyl-2- (dirnethylanin-ophel-methYl) cyclohexanol, hydrochloride 2- (dime thylalninophely lutiethyl) (4-f luoro-3-trif luoromethyiphenyl) cyclohexanol and the corresponding hydrochloride 2- (dime thylarninopheflylliethyl) (4-trif luoromethoxybenzyl) cyclohexanol and the corresponding hydrochloride 2- (dime thyl aminophely linlethyl) -i-furai-3-ycycloiexanl and the corresponding hydrochloride 1 -butyl-2- (dimiethylaninophelyl1fethyl) cycloh-exanio 1 and] the corresponding hydrochloride 1- 4-dichiorophenyl) (dimiethylaminoph-erly-ltllethiyi) cyclohexanol and the corresponding hydrochloride 4-dichiorophenyl) (dlimethylaminophenl methyl) cyclohexanol and the corresponding hydrochloride H- 4-diciorophenyl) (dlime thylaninophellyli methyl) cyclohexanol and the corresponding hydrochloride 4- (dimethylaminophenylmethyllI-hydroxycyclohexyllV phenol and the corresponding hydrochloride 2- (dime thyl arinophenylintethyl) 1-naphthalene-2ylcyclohexanol] anid the corresponding hydrochloride 2- [dimietlhylamiino- (4-tnLfIlorornethyiphen-yl)imethiyl] methoxybenzyl) cyciohexanol and the corresponding hydrochloride 1- (4-chlorobenzyl) (dime thyl aminophenylmte thyl) -1cyclohexanol and the corresponding hydrochloride 2- (dime thylaiinoi(-pherlyliuetlhyl) (2-f luorobenzyl) cyclohexanol and the corresponding hydrochloride 2- (dimethiylaminopheniyimethyl)-l- (4-fluorobenzyl) cyclohexanol and the corresponding hydrochloride 1I- 5-dimethoxyphenyl) (dimethylaminopheniylmeth-yl) cyclohexanol and the corre sponding hydrochloride 1- (2-chJloro-4-fluorobenzyi (climiietlhylim:i.nophen-ylmethyl) cyclohexanol anid the corresponding hydrochloride 1- (4-tent. -butylbenzyl) (imi~ethiylaininioph-eniylmethyl) cyclohexanol anid the corresponding hydrochloride (dimiethylainrophienyliriethyl) (3-f luorobenzyi) cyclohexanol and the corresponding hydrochloride 1- (2-chlorobenzyl) (climie thylaminophaenylmrethiyl) cyclohexanol and the corresponding hydrochloride l-benzo 3] dioxol-S-yl-2- [dimethylamino (3methaoxyphienyl) methyl] cyclohexanol and the corresponding hydrochloride 1- (3-chlorobenzyl) (diimethyliarnopheflylifleth-Yl) cyciohexanol anid the corresponding hydrochloride 1- 4-dichlorobenzyl) (diniethylairinoph-enyitlethyl) cyclohexaniol and the corresponding hydrochloride l-benzyl-2- [dime thyl arinopheflyl (3-phenoxyphenyl) methylicyclohexanol and the corresponding hydrochloride 1-benzyl-2- [dirnethylaminopheflyl- (3-miethoxypheniyl) -methiyl] cyclohexanol and the corresponding hydrochloride see**: 2- (dime thyl1aininopheiy lnethy) (3-trif luoromethylbenzyl) cyclohexanol anid the corresponding hydrochloride 2- (dimethylamino- (3-methoxyphenyl)Ifethyll (3methoxybenzyl) cyclohexanol and the corresponding h ydr o c hl0ride 2- [i (2-chlorophenyl) dime thyl aminome thyl- I l-riaphtIhalene-2 ylcyclohexanol and the corresponding hydrochloride l-benzyl-2- L(3, 4-dichlorophenyl) diniethylaininoinethyl]I cyclohexanol and the corresponding hydrochloride 4-dichlorophenyl) (dimethylainifiomfethyl I -1-phene Llylcyclohexanol and the corresponding hydrochloride l-benzyl-2- [dimnethylainino- (4-f Iluorophenyl) methyl] cyclohexanol anid the corresponding hydrochloride 2- (3-chlorophenyl) (dimiethylaminoinethyl] -1-phenylcyclohexanol and the corresponding hydrochloride 1- 4-dichlorophenyl) (3-'-dimethylaminomethyl) -1cyclohexanol anid the corresponding hydrochloride 1-ben zyl-2- (3-chiorophenyl-) diniechylarninornethyl] cyclohexanol and the corresponding hydrochloride 1-benzyi-2- (2-chiorophenyl) dirnethylaminornethyl] cyclohexanol and the corresponding hydrochloride 1-(4-tert.-butylbenzyl)-2-[ (3,4-dichiorophenyl) dimethylaininaornethyl) cyci ohexano 1 anid the co rresponding hydrochloride 2- [dimethylamino- (4-fluorophenyi)mieth-yl (3trifluoromethyibenizy-) cyclohexano~l and the corresponding h ydr o c hl0ride (diinethylaininophenylme thy1) bi cyclohexy 1 olI and the 0 t corresponding hydrochloride 2- (dime thyl arinophen ylne thyl1) -1 (4-methoxybenzyl) cyclohexanol and the corresponding hydrochloride 1- (2,4-difl -urobenzy) (ci nehlaiuopenyl iruethyl)aminomethyl Icyclohexanol and the corresponding hydrochloride 2- [dimnethiylamnino- (3-phienoxyphien-yl) methyl] -1-ph-enethiylcyclohexanol anid. the corresponding hydrochloride 2- [diliuetliylar-nino- (3-phien-oxypheniyl) methiyl-] (3-triLfluoromethylbenzyl) cyclohiexanoc)l and the corresponding hydrochloride 1- 5-dif luorobenzyl) (diniethylaminophenylmethyl) cyciohexanol and the corresponding hydrochloride 1- 4-difiluorobenzyi) (dirnieth-ylamuinophienylmteL-h-yi) cyclohexanol and the corresponding hydrochloride 1- (2-chioro--6-f luorobenzyl) (diinethyl amino phenylmnethyl) cyclohexanol and the corresponding hydrochloride 1- 3-di fluorobenzyl) -2 (diinethylaminophenylme thyl) cyclohexanol and the corresponding hydrochloride l-benzyl-2- (4-chiorophenyl) dime thylaminomethyl] cyclohexanol and the corresponding hydrochloride S. -dime thylamino- 3-ethyl-2-me thyl- 1, 5-diphenylpentane-3-ol and the corresponding hydrochloride too* 000 20 1- (2-chlorobenzyl) -2-[((2-chiorophienyl) -dimethiylaminomethyl] cyciohexanol, and the corresponding V,06 hydrochloride 1-ben zyl-2- (4-bromophenyl) dime thylaminornethyl] 25 cyclohlexanol and the corresponding hydrochloride 2- (4-cioroph-enyl) dimie Lliylaintinomuetiyi]-1- trifluoroinethyiphenyl) cyclohexanol and the corresponding hydrochloride 2- (4-chiorophenyl) dimethylaminomethyl] (3-trif luoroiuethylbenzyl) cyclohexanol and the corresponding hydrochloride 1- (4-tert. -butYlbelzyl) [dimethylamino- (3-phienoxyphenyl) methyl I cyclohexanol and the correspondinci hydrochloride 4- {diinethylarnino- [2-hydroxy-2- (4-trif luorometl-Iylphenyl) cyclohexyl I methyl I ben zoni tryl and thle corresponding hydrochloride 2- (diiethiyiatnin-o-o- Lolylmethyl) -phien-ylcycinchexaniol and the corresponding hydrochloride l-benzyl-2- (dimethylaimino-o-tolYlmethYl) cyclohiexanol and the corresponding hydrochloride 2- (dime th yl alnirophenylmfethyl) (3-phenyipropyl) :cyclohexanol and the correspondinrg hydrochloride 2* 2-1[ (2 -c hlo ro ph e nylI) d ilethIiyam inone t h y l 1- [12- fl1uo ro ,*S.phenyl) ethyl]I cyclohexanol and the corresponding hydrochloride 2 d ime t hyla i n o th ioph eniie -2 -yIllle tIiy1]- (3 tr ifl1uo r o methylbenzyl) cyclohexanol and the corresponding h ydr o c hl0ride MeLhyl-4- (diimeL--ylaniflopienyil-iethlyl) i-hiydroxycyclohiexyl] benzoate arid the corresponding hydrochloride 1-benzyl-2- (diinethylarninophienyllflethyl) -4-phenylcyclohexanol and the corresponding hydrochloride 1- (4-broinophenyl) (dimethyl1ani nophefly llfethyl1) cyclohexanol and the correspondlingi hydrochloride 2- (dime thyl ami nophenyllle thyl1) -l-na-phthalene-l-ylcyclohexanol and the corresponding hydrochloride 2- (dimethylaminophenehyethyl)-1- (2-methylsulf anylphenyl) cyclohexanol and the corresponding hydrochloride 1-benzyl-2- (dimethylaminonaphthalene-2-ylmethyl) cyclohexanol and the corresponding hydrochloride l-benzyl-2-(dimethylaminronapentafluorophenylmethyl) cyclohexanol and the corresponding hydrochloride l-benzyl-2- (phenylpiperidin-1-ylmethyl)cyclohexanol and the corresponding hydrochloride 2- (dimethylaminophenylmethyl) (4-trifluoromethyl- 15 phenyl)cyclohexanol and the corresponding hydrochloride 3- (4-tert.-butylbenzyl)-l-dimethylamino-2-methyl-lphenylpentan-3-ol and the corresponding hydrochloride 20 2- (dimethylamino-o-tolylmethyl)- -phenethylcyclohexanol *and the corresponding hydrochloride 1-(4-tert.-butylbenzyl)-2- [dimethylaminothiophen- 2 ylmethyl]cyclohexanol and the corresponding hydrochloride o* Compounds according to the invention are also compounds of the general formula I as diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids.

In a special embodiment of the invention the compounds according to the invention including the disclaimed compounds are used as a mixture of the enantiomers in non-equimolar amounts as active agent in a medicinal drug, optionally together with further active agents. In this case the proportion of one enantiomer is preferably between 5 and wt. 16 The expression alkyl" denotes within the scope of the present invention straight-chain or branched hydrocarbons with 1 to 6 carbon atoms. Methyl, ethyl, propyl, isopropyl, nbutyl, sec.-butyl, tert.-butyl, n-pentyl, neopentyl and nhexyl may be mentioned by way of example.

The expression cycloalkyl" denotes within the scope of the present invention saturated cyclic hydrocarbons or straight-chain or branched alkyl radicals that contain saturated cyclic hydrocarbons, with a total of 3 to 7 carbon atoms. Cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclobutyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl or cycloheptyl may 15 be mentioned by way of example.

The expression "aryl" denotes within the scope of the present invention preferably aromatic ring systems, optionally singly or multiply substituted, which may optionally contain 20 heteroatoms in the ring system. The aryl radicals are preferably singly or multiply substituted by the radicals

R

to R' 3 The preferably 5-membered or 6-membered unsaturated :'heterocyclic compounds, optionally condensed with further rings, optionally singly or multiply substituted may contain one or two heteroatoms such as nitrogen, oxygen and/or sulfur in the ring system.

There may be mentioned by way of example from the group of heteroaryl compounds: furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline.

Furthermore, processes for preparing the compound of the general formula I are also an object of the invention.

17 These processes for producing the compounds of the general formula I with the exception of l-benzyl-2- (dimethylaminophenylmethyl)-cyclohexanol, its diastereomers and its enantiomers are characterised in that Mannich bases of the formula II are reacted with suitable nucleophilic compounds, preferably organometallic compounds R:Y in which Y denotes MgCl, MgBr, MgI or Li, at temperatures between and +110 0

C

0 A 0 4

R

1 R R

II

The conversion of a Mannich base of the formula II with a Grignard compound R'Y in which Y denotes MgCl, MgBr or McfI, or with an organolithium compound R'Li, may be carried out in an aliphatic ether, for example diethyl ether and/or tetrahydrofuran, a hydrocarbon, for example hexane or toluene, or mixtures of hydrocarbons and aliphatic ethers, at temperatures between -70 0 C and +110°C. The preparation of a Grignard compound R'Y may be carried out with or without the addition of an entrainment reagent, preferably 1,2-dibromomethane. Alternatively, aromatic Grignard compounds R:Y may be obtained by reacting an aromatic iodide R"I with an organomagnesium compound, for example isopropylmagnesium chloride or diisopropylmagnesium, by iodine-magnesium exchange. Organolithium compounds R'Li can be obtained from organohalogen compounds R'Z, in which Z denotes Cl, Br or I, by reaction with for example a n-butyllithium/hexane solution by halogen-lithium exchange.

In the reaction of a Mannich base of the formula II with an organometallic compound R'Y, depending on the reaction 18 conditions preferably tertiary alcohols having the relative configuration of the formula Ia are obtained, in which the aminoarylmethyl group is arranged in the cis position relative to the hydroxl group when R' and R" form a ring system. In open-chain systems the analogous relative stereochemistry is obtained, which is specified as anti. The compounds of the general formula I, as well as their salts, for example the hydrochlorides, can be obtained in a diastereomer pure form by column chromatographic separation or by crystallisation.

H

3 O0 A R 4 R1 15 la The Mannich bases of the formula II can be obtained by reacting enamines of the formula III with an inuninium salt of the formula IV, in which Y denotes for example Cl-, AlCl.-, Br 20 or I-.

RN.R

A

1 R 4 Y

N

R Y R

R

III I V The enamines are prepared by processes known in the literature from ketones of the formula V and secondary amines, for example dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53). The imminium salts are prepared by processes known in the literature by reacting aminals of the formula VI with acid chlorides, for example 19 acetyl chloride or thionyl chloride (Houbeni-Weyl iHethodenl der Organii.schen. Chemie, E2lb (1995) 19125-19,29) o AN

R

R N NR RR R The imtmin-iumi salts of the formula IV need niot be separated, but can be produced in- sitLu and reactedt with enaiines oF the formula III to form Maninich bases of the formnula IIL (Agnew.

Cheim. 106 (1994) 2531-2533) On- account of the enamine-imi-re .tautomerism, which is similar to the keto-eriol tautonerisw, imines of the formula VII may also be used instead of the enamiiies of the formlafl~ Ill. Al ternati.velv, ketones cof thEu formula V can also be reac:[ted dlirectly vwith iiimiiliLIJ salts. of the formula IV.

Mlan-nich bases of the formula 11 may however. al]so 1be p.,repared directly be reacting enauines of thie formula 111 with all aromatic aldehyde of the formtula VIII and a second-ary amine HNR*'R", which may also be in the forit of the corresponiding hydrochloride HNRV HCl, in the presence of triethiylamline, chlorotrimethylsilaiie and sodium iodide (8')ynil( tt (1 997) 974-976)

A

0z VI iI Depending on the reaction conditions, the Mannich bases of the formula II prepared by the aforeclescribed processes are preferably obtained having the relative configuration of the formula IIa, in which the amino group is arranged anti to iR'.

The compounds of the formula IIa, as well as their salts, for example the hydrochlorides, can be obtained in a diastereomer pure form by crystallisation or by chromatographic separation.

0 A R

R

1 IIa The formation of Mannich bases of the formula II by 1, 4addition of secondary amines of the formula X to enones of the formula IX, which are obtained by the aldol condensation of ketones of the formula V with aromatic aldehydes of the 20 formula VIII, proceeds in a less stereo-selective manner however (US 4,017, 631) This procedure is accordingly suitable for preparing the other possible stereoisomers.

O A O A A HNR 4

R

5 2 R 4 I 1 R N R R R P V VIII IX X II If cliiral amines are used to prepare enamines of the formula III or imines of the formula VII, then enantiomerenriched to enantiomer-pure Mannich bases of the formula II may be obtained in the following Mannich reaction (Houben-Weyl Methoden der Organischen Chemie, E21b (1995) 1925-1929).

3-amino-3-arylpropan-l-ol compounds of the general formula I in which R' contains a phenolic substituent can be prepared for example from the corresponding methyl ether derivatives with diisobutylaluminium hydride in an aromatic hydrocarbon, for example toluene, at a temperature between 60 0 C and 130°C (Synthesis (1975) 617-630) The compounds of the formula I can be converted in a manner known per se into their salts with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salt formation is preferably carried out 15 in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solution is suitable for preparing the hydrochlorides.

20 The substances corresponding to formula I are toxicologically safe, which means that they can be used as a pharmaceutical active agent in medicinal drugs. A further object of the invention are accordingly medicinal drugs containing as active agent at least one compound of the general formula I. The medicinal drugs according to the invention are preferably used •as analgesics.

a Biochemical investigation has shown that the substances according to the general formula I, in addition to their analgesic action, a pronounced affinity for the binding site 2 of the sodium channel (BTX binding), or the benzothiazepine and phenylalkylamine binding site of the L-type calcium channel (diltiazem and verapamil binding) and inhibit synaptosomal noradrenaline uptake (NA uptake inhibition). In addition to their particularly preferred use in the treatment of pain, the substances according to the general formula I are therefore also suitable for use as a local anaesthetic and/or anti-arrythmic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence and/or inflanmmation. As a rule the substances according to the invention are also suitable for treating depression and/or for improving alertness and attentiveness, and/or improving libido.

The analgesics according to the invention contain, in addition to at least one 3-amino-3-arylpropan-l-ol derivative of the formula I, excipients, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances as well as 15 the amounts thereof to be used depends on whether the medicinal drug is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example to treat skin infections, eye infections or infections of the mucous 20 membranes. For oral application suitable preparations are in the form of tablets, sugar-coated pills, capsules, granular powders, drops, juices and syrups, while for parenteral, topical and inhalative application suitable forms are solutions, suspensions, easily reconstitutable dry preparations as well as sprays. Compounds according to the invention of the formula I in a sustained-release substance, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, are suitable percutaneous application preparations. Forms of preparations that can be used orally or percutaneously may produce a delayed release of the compounds according to the invention of formula I.

The amount of active agent to be administered to the patient depends on the patient's weight, on the type of application, symptoms and the severity of the illness. Normally 0.5 to 500 O mg/kg of at least one 3-amino-3-arylpropan-l-ol derivative of the formula I are administered.

Pharmacological Investigations Analgesic Effect in the Writhing Test in Mice The analgesic effect was investigated in the phenylquinoneinduced writhing test in mice (as modified by I.C. Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240) Male NMRI mice weighing 25 to 30 g were used for the test.

Groups of 10 animals each received by intraperitoneal application, for each substance dose, 0.3 ml/mouse of a 0.02% 15 aqueous solution of phenylquinone (phenylbenzoquinone, Sigma Company, Deisenhofen; solution prepared with addition of 5% of ethanol and kept in a water bath at 45 0 C) 10 minutes after intravenous administration of the test substances. The animals were placed individually in observation cages. The 20 number of pain-induced stretching movements (so-called writhing reactions straightening of the body together with stretching of the rear extremities) was measured by means of a push-button counter 5 to 20 minutes after administration of the phenylquinone. Animals that had received only 25 physiological saline solution served as controls. All substances were tested in the standard dose of 10 mg/kg. The percentage inhibition inhibition) of the writhing reaction produced by a substance was calculated according to the following formula: writhing reactions inhibition 100 of the treated animals x 100 writhing reactions C of the control animals 24 For some substances the values were calculated with confidence range of the writhing reaction by means of regression analysis (evaluation program from Martens EDV Service, Eckental) from the dose-dependent reduction in the writhing reactions compared to phenylquinone control groups investigated in parallel.

All the compounds according to the invention that were investigated exhibited a pronounced analgesic effect. The results are summarised in Table 1.

a.

a a a a o a Table 1 (Part Analgesia Examination in the Writhing Test in Mice 1 85 29 9 2 88 30 85 3 83 31 76 4 75 32 100 100 33 84 *6 83 34 99 7 85 35 81 81 36 100 On9 73 37 93 97 38 11 99 39 94 12 95 40 7 F, 1310.1-8 0*1 147*27 3438 1 6 **4410 17 10*58 Table 1 (Part 2/2) :Analgesia Examination in the Writhing Test iii Mice Inhibition of the Ex a anmple Fwrithing r ea ction a t mug/kVg intravenously 62*.96 63 86 64 88 76 66 91 *67 84 *68 69 71 727 SBiochemical Investigations Investigations on the Noradrenaline Uptake Inhibition (NA Uptake Inhibition) In order to carry out these in vitro studies, synaptosomes are isolated fresh from rat brains. In each case a so-called

"P.

fraction is used, which is prepared according to the protocol of Gray and Whittaker Gray and V.P. Whittaker (1962)

J.

Anat. 76, 79-88). For the NA uptake these vesicular particles are isolated from the hypothalamus of male rat brains.

The following characteristic data were determined for the NA transporter: NA uptake: Km 0.32 0.11 tM (in each case N 4, i.e. mean values SEM from 4 independent series of experiments that were carried out in the form of 20 triple parallel experiments) A detailed description of the methodology can be found in the literature (M.Ch. Frink, Hennies, W. Englberger,

M.

Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036) Binding Investigations in the L Calcium Channel Benzothiazepine Binding Site (Diltiazem Binding) The biological membrane material was isolated from the rat cerebral cortex. [H]-cis-(+-)-diltiazem (5 nM in the assay) was used as ligand. The material was incubated for 20 minutes at 25 0 C. The radioactivity that is measured in the presence of (+)-diltiazem (10- M in the assay) is defined as nonspecific binding. After completion of incubation the nonbound fraction of the radioactive ligand is separated by means of a filtration process using Whatman Glasfiber

GF/B

membranes. The membranes are washed and the radioactivity is then measured using a p-counter. The method is based on the details published by Schoemaker and Langer Schoemaker and S.Z. Langer (1985) Eur. J. Pharmacol. 111, 273-277). The KI, value for this high-affinity binding site was 4.10 0.75 IM (N 3, i.e. mean values SEM from 3 independent series of experiments that had been carried out in triple parallel experiments).

Phenylalkylamine Binding Site (Verapamil Binding) S" The biological material (ion channel particles) was prepared on the basis of the publication of Reynolds, Gould and Snyder Reynolds, R.J. Gould and S.H. Snyder (1983)

J.

Pharmacol. 95, 319-321).

N-methyl-[ H]-verapamil (2 nM in the assay) was used as radioligand. The radioactivity that is measured in the presence of non-radioactive verapamil (10- M in the assay) is defined as non-specific binding. The material was incubated at 25 0 C for 45 minutes. The material was then filtered using a Whatman GF/B filter, followed by washing. The radioactivity remaining on the filter (ion channel binding) was measured using a P-counter.

The K, value for this binding site was found to be 138.6 inM (N S2, i.e. mean values from 2 independent series of experiments that had been carried out in the form of triple parallel experiments).

Binding Investigations in the Sodium Channel Binding Site 2 (BTX Binding) The binding site 2 of the sodium channel is the so-called batrachotoxin (BTX) binding site. -batrachotoxin a-benzoate (10 nM in the assay) was used as ligand. These ion channel particles (synaptosomes) were concentrated from rat cerebral cortex according to the procedure of Gray and Whittaker Gray and V.P. Whittaker (1962) J. Anat. 76, 79-88). The radioactivity that is measured in the presence of veratridine (0.3 mM in the assay) is defined as non-specific binding. The material was incubated at 37oC for 120 minutes.

The assay conditions are carried out according to the protocol 15 published by Pauwels, Leysen and Laduron Pauwels,

J.E.

Leysen and P.M. Laduron (1986) Eur. J. Pharmacol. 124, 291-298).

The Kp value for this binding site is 24.63 1.56 nM.

20 (N 3, i.e. mean values SEM from 3 independent series of experiments that were carried out in the form of triple parallel experiments).

Evaluation In addition to the percentage inhibition of the test systems at fixed test substance concentrations (NA uptake: lrLM in the assay; ion channel assays: 10 M in the assay), the dose dependencies were investigated. For this purpose values are obtained, which can be converted to inhibitor constants (Ki) according to the "Cheng-Prusoff equation" Cheng and W.H. Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108). The ICso values were obtained by means of the computer program "Figure P" (version 6.0, Biosoft, Cambridge, England). Km values were calculated according to Lineweaver and Burk Lineweaver and D. Burk (1934) J Ant. Chem. Soc. 56, 658- 666) The "Ligand" computer program (version 4, Biosoft, England) was used to obtain KL. values.

The results of the biochemical inivesticiations are summnarised in Table 2.

0 9Table 2 (Part 1/3) :BiochemistrY NA uptake Verapaflil Diltiaze Example Inhibitionl Bindingc at Binding a t 1 PiM 10 ,ilm 10 ptm 14 7 6 2 52' 3 41 685 6. 51 48 1 5461 9 62 144 1018 1691 1 17 57 7295 *18 8457 81 8. 1 100_ Table 2 (Part BiochelilS try Example inhibition binding at binding 2996V 98 98 31 43 32 100 33 83 86 34 96 100 100 8'7 36 91 **37 100 9 :38 1-7 67 39 61 76 58 86 41 100 87 42 82 s0 43 14-/ A A q q Table 2 (Part Biochemistry NA Uptake Verapail Diltiaze Example Inhibitionl Binding at Bindingj a t 1 [LM 10 [IM4 10 [iIM 64 36 8 *65 0 -72 66 15 67 83 0.68 49 88 *e.69 76 93 74 91 0 71 88 74 72 64 97 o 7 3 61. 89 00074 24 83 0 89 0 0 76 80 7 o ?7 0 Examples The following examples serve to illustrate the process according to the invention in more detail.

The yields of the prepared compounds are not optimised.

All temperatures are uncorrected.

The term "ether" denotes diethyl ether.

Silica gel 60 (0.040 0.063 umm) from E. Merck, Darmstadt, was used as stationary phase for the column chromatography.

15 The thin-layer chromatography investigations were carried out with IIPTLC ready prepared plates, silica gel 60 F 254, from E. Merck, Darmstadt.

The racemate separations were carried out on a Chiracel OD S 20 column 250 x 4.6 mm with a precolumn from Daicel.

The mixing ratios of the solvents for all chromatography investigations are in each case expressed in volume/volume.

RT denotes room temperature, vol. denotes volume per cent, m% denotes wt. per cent and %ee denotes enantiomeric excess in per cent.

0 Example 1 2- (dimethylaminophenylmethyl) (3-methoxyphenyl) cyclohexanol, hydrochloride 1st Stage Benzylidene dimethyl amunonium chloride g (56 munole) of -tetramethyl-C-phenylmethanediamine Am. Chem. Soc. 77 (1955) 1114-1116) were dissolved in 100 ml of ether and cooled to 0°C in an ice bath. 4.0 ml (56 mmole) of acetyl chloride were added under nitrogen.

After the first few drops a white salt precipitated out and the temperature rose slightly. After 15 hours at RT the 15 liquid was decanted off and the solids were washed three *times, each time with 100 ml of ether, filtered under nitrogen through a protective gas frit, and dried to constant weight in an oil pump vacuum. 7.7 g of benzylidene dimethyl ammonium chloride (80.9% of theory) were obtained in this way.

2nd Stage 2- (dimethylaminophenyliuethyl) cyclohexanone 7.1 ml (44 mmole) of 1-(pyrrolidino)-l-cyclohexene were dissolved in 45 ml of dichloromethane and cooled under nitrogen to -70 0 C in a dry ice/isopropanol bath. 7.5 g (44 mmole) of benzylidene dimethyl ammonium chloride from Stage 1 were added while stirring, the mixture was heated to within two to three hours, and then kept for 15 hours at this temperature. The mixture was worked up by adding 60 ml of semi-concentrated hydrochloric acid and stirring for minutes. The mixture was washed at RT with 50 ml of ether, 440 ml of ammonia solution (25 vol. was added to the aqueous phase, and the latter was quickly extracted three times, each time with 150 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar) 10.1 g of crude base (99.5w of theory) were obtained in this way. 9.81 g (42.4 ummole) of the crude base were dissolved in 83 ml of 2-butanone, and 0.76 ml (42.2 mmole) of water and 5.36 ml (42.4 mmole) of chlorotrimethylsilane were added in succession. The solution was kept for 15 hours at RT, and the precipitated solids were suction filtered, washed with small amounts of ether, and dried to constant weight in an oil pump vacuum. 8.92 g of the hydrochloride of 2-(dimethylaminophernylimethyl) cyclohexanone (78.6% of theory) were obtained in this way.

15 3rd Stage 2- (dimethylaminophenylmethyl) -1-(3-methoxyphenyl) cyclohexanol, hydrochloride 20 1.08 g (44.5 mmole) of magnesium turnings were stirred in 10 ml of tetrahydrofuran of analysis purity. 5.57 ml (44.5 mmole) of 3-bromoanisole dissolved in 40 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the mixture was stirred for a further hour at RT. From 11 g (41.1 mmole) of the hydrochloride of 2- (dimethylaminophenylmethyl) cyclohexanone obtained after Stage 2, the base was released by adding 100 ml of water and 10 ml of caustic soda (32 mA), extracted three times, each time with 100 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 8.57 g (37 mmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise to the Grignard reagent, and stirred for 15 hours at RT. The reaction mixture was worked up by adding dropwise 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 12.4 g of crude base (99.0% of theory) were obtained. The crude base was dissolved in 125 ml of 2-butanone, and 0.33 ml (18.3 mmole) of water and 4.63 ml (36.5 mmole) of chlorotrimethylsilane were added in succession. The solution was kept for 15 hours at RT, and the Sprecipitated solids were suction filtered, washed with small portions of ether and dried to constant weight in an oil pump vacuum. 8.27 g of 2-(dimethylaminophenylmethyl)-1-(3- 15 methoxyphenyl) cyclohexanol, hydrochloride (59.4% of theory) with a melting point of 227 0 -229 0 C were obtained in this way.

Example 2 2- (dimethylaminophenylmethyl) (3-fluorophenyl) cyclohexanol, hydrochloride 25 0.87 g (36.0 nuuole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 4.02 ml (36.0 mmole) of 3-bromofluorobenzene dissolved in 30 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the mixture was stirred for a further hour at RT. 7.0 g (30 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 iml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated anunonium chloride solution while cooling in an ice bath, and was extracted three times at RT 38 with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 9.27 g of crude base (93.6% of theory) were obtained. 6.04 g of 2-(dimethylaminophenyl-methyl)-1-( 3 fluorophenyl)cyclohexanol, hydrochloride (54.8% of theory) were obtained from the crude base according to Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes when heated above 140 0

C.

Example 3 15 2- (dimethylaminophenylmethyl) -1-phenylcyclohexanol, hydrochloride 0.87 g (36.0 immole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.8 ml (36.0 nunole) of bromobenzene dissolved in 30 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 7.0 g (30 mmole) of the 2-(dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were 25 dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 8.99 g of crude base (96.0% of theory) were obtained. 6.85 g of 2- (dimethylaminophenylmethyl) -1-phenyl- cyclo-hexanol, hydrochloride (65.4% of theory) were obtained from the crude base according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes when heated above 140 0

C.

Example 4 3-[2-(dimethylaminophenylmethyl)-l-hydroxycyclohexyl]phenol, hydrochloride 1 Stage (3-bromophenoxy)trimethylsilane 23.4 g (0.145 mole) of hexamethylsilazane were added dropwise under nitrogen to 49.3 g (0.285 mole) of 3-bromophenol, and the solution was heated slowly to 150°C and stirred for one hour until no more gas was produced. The solution was purified by distillation at 6 mbar, the main fraction boiling at 79°C. 66.7 g of (3-bromophenoxy) trimethylsilane of theory) were obtained in this way.

2 n Stage 25 3- (dimethylaminophenylmethyl)- l-lhydroxycyclohexyl] phenol, hydrochloride 1.25 g (51.6 mmuole) of magnesium turnings were stirred in ml of ether of analysis purity. 12.7 g (51.6 mmole)of (3-bromophenoxy)trimethylsilane from stage 1, dissolved in ml of ether, were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 10.0 g (43.0 mmole) of 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 150 ml of hydrochloric acid (1 two phases being formed, one of which was an acetonesoluble oil. The aqueous phase and the acetone-soluble oil were adjusted with sodium bicarbonate to be slightly alkaline (pH ca. 8) and extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 7.51 g of crude base were obtained, which were added to a 5.5 x 50 cm column filled with silica gel. Elution with ethyl acetate/methanol (24:1) yielded 0.85 g of base, from which a 15 hydrochloride was precipitated according to the procedure described in Example 1 (3 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The base was released from the hydrochloride with 10 ml of water and sodium bicarbonate (pH ca. extracted three times with in each case 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). The 670 mg of base that were obtained were added to a 3 x 17 cm column filled with silica gel. Elution with ethyl acetate/n-hexane yielded 25 580 mg of base, from which 0.53 g of the 3-[2-(di-methylaminophenylmethyl)-l-hydroxycyclohexyl]phenol, hydrochloride (3.4% of theory) were obtained with 0.16 ml of hydrochloric acid (32 and 5 ml of acetone. The hydrochloride decomposes on heating above 140 0

C.

41 Example 2- (dime thylaminophenylme thyl) (4-methoxyphenyl) cyclohexanol, hydrochloride 0.88 g (36.3 mmole) of magnesium turnings was stirred in 10 ml of tetrahydrofuran of analysis purity. 4.55 ml (36.3 mmole) of 4-bromoanisole dissolved in 30 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was stirred for a further hour at RT. 7.0 g (30.3 mmole) of 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 10 ml of 15 tetrahydrofuran, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 10.5 g of crude base (102% of theory) were obtained. 4.24 g of 2-(dimethylaminophenylmethyl)-1-(4-methoxyphenyl) cyclohexanol, hydrochloride 25 (37.2% of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimetlhylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 150 0

C.

Example 6 1- (4-chlorophenyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.63 g (25.9 unole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 4.97 g (25.9 inmole) of 4-bromochlorobenzene dissolved in 30 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was boiled for a further hour at RT. 5.0 g (21.6 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise 15 to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 7.24 g of crude base (97.4% of theory) were obtained. 5.43 g of l-(4-chlorophenyl)-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride (66.0% 25 of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 175 0

C.

Example 7 2- (dimethylaminophenylmethyl) fluorophenyl) cyclohexanol, hydrochloride 0.50 g (20.7 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.28 ml (20.7 mmole) of 4bromofluorobenzene dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 4.0 g (17.3 mmole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise 15 to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 5.50 g of crude base (97.2 of theory) were obtained. 3.61 g of 2- (dimethylaminophenylmethyl)-1- (4- *fluorophenyl)cyclohexanol, hydrochloride (57.4 of theory) 25 were obtained from the crude base according to the procedure described in Example 1 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The hydrochloride decomposes on heating above 150 0

C.

W Example 8 2-(dimethylaminophenylmethyl)-l-p-tolylcyclohexanol, hydrochloride 0.50 g (20.7 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.55 ml (20.7 mmole) of 4bromotoluene dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 4.0 g (17.3 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise 15 to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 80 ml of ethyl acetate. The combined 20 organic extracts were dried over sodium sulfate, filtered, and *concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 5.35 g of crude base (95.7% of theory) were eeee obtained. 1.73 g of 2-(dimethylaminophenylmethyl)-l-ptolylcyclohexanol, hydrochloride (27.8% of theory) with a 25 melting point of 168-169 0 C were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 9 1-(3-chlorophenyl)-2-[dimethylamino-(3-methoxyphenyl)methyl] cyclohexanol, hydrochloride Stage C- (3-methoxyphenyl) -tetramethylmethanediamine 18.3 ml (0.15 mole) of 3-anisaldehyde were heated for five hours at 50 0 C with 38 ml (0.30 mole) of dimethylamine solution m% in water) while stirring, and then stirred for a further 15 hours at RT. The reaction solution was worked up by adding 20 ml of saturated potassium carbonate solution and solid potassium carbonate until a pH of ca. 9 was reached.

The reaction solution was extracted three times, each time with 200 ml of ethyl acetate. The combined organic extracts were dried over potassium carbonate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 27.0 g of C-(3-methoxyphenyl)-N,N,N',N'tetramethylmethanediamine (86.3% of theory) were obtained in this way.

15 2 nd Stage (3-methoxybenzylidene)dimethyl ammonium chloride 30 g (144 mmole) of C-(3-methoxyphenyl)-N,N,N',N'-tetramethylmethanediamine from stage 1 were dissolved in 200 ml of ether and cooled in an ice bath (methanol/ice 1:1) to -10 0

C.

10.3 ml (144 mmole) of acetyl chloride were added dropwise under nitrogen. A white salt precipitated out, and the temperature rose slightly. After 15 hours at RT the solution was decanted off, and the solids were washed three times, each 25 time with 100 ml of ether, filtered through a protective gas frit under nitrogen, and dried to constant weight in an oil pump vacuum. 19.8 g of (3-methoxybenzylidene)dimethyl ammonium chloride (68.8% of theory) were obtained in this way.

Stage 2- [dimethylamino- (3-methoxyphenyl)methyl] cyclohexanone 15.3 ml (95 mmole) of 1-(pyrrolidino)-1-cyclohexene were dissolved in 100 ml of dichloromethane and cooled under nitrogen in a dry ice/isopropanol bath to -70°C. 19 g mmole) of (3-methoxybenzylidene)dimethyl ammonium chloride from stage 2 were added while stirring, and the mixture was heated to -30 0 C within two to three hours and kept for hours at this temperature. The reaction mixture was worked up by adding 60 ml of semi-concentrated hydrochloric acid and stirred for a further 5 minutes. The mixture was extracted at RT with 50 ml of ether, 100 ml of ammonia solution (25 vol. was added to the aqueous phase, and the latter was extracted quickly three times, each time with 200 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 19.1 g of crude base (76.6% of theory) were obtained in this way. 18.0 g of the hydrochloride of 2-[dimethylamino-(3-methoxyphenyl)methyl]cyclohexanone (63.7% of theory) having a melting point 15 of 142 0 C were obtained from the crude base according to the procedure described in Example 1 (2"1 stage) with chlorotrimethylsilane/water in 2-butanone.

4 t h Stage 1- (3-chlorophenyl) [dimethylamino- (3-methoxyphenyl) methyl] r cyclohexanol, hydrochloride 0 0.55 g (22.4 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.6 ml (22.4 mmole) of 3- 25 bromochlorobenzene dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. The base was freed from 6 g (20.1 mmole) of the hydrochloride of 2-[dimethylamino-(3methoxyphenyl)methyl]-cyclohexanone obtained according to stage 3, with 60 ml of water and 5 ml of caustic soda (32 was extracted three times, each time with 60 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 4.9 g (18.7 mmole) of this base were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath and was extracted three times at RT, each time with 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 ibar). 6.51 g of crude base (100% of theory) were obtained. 5.0 g of 1-(3-chlorophenyl)- 2 [dimethylamino-(3-methoxyphenyl)methyl]cyclohexanol, hydrochloride (70.1% of theory) having a melting point of 131 0 C 133 0 C were obtained from the crude base according to the procedure described in Example 1 (311 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 4-dimethylaminophenyl) [dimethylaminophenylmetlhyl cyclohexanol, hydrochloride 0.50 g (20.7 mnole) of magnesium turnings was stirred in 5 ml of tetrahydrofuran of analysis purity. 4.14 g (20.7 nunole) of "4-bromo-N,N-dimethylaniline dissolved in 10 ml of 25 tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at 55 0

C.

g (17.3 nunole) of the 2 -(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 10 ml of tetrahydrofuran, added to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT.

The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by 48 evaporation on a rotary evaporator (500 to 10 mbar). 6.24 g of crude base (102% of theory) were obtained, from which a hydrochloride was precipitated according to the procedure described in Example 1 (3L" stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 4 ml of caustic soda (32 extracted three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.90 g of crude base (26.99 of theory) were obtained. 0.88 g of 1-(4-dimethyl-aminophenyl)- 2-(dimethylaminophenylmethyl] cyclohexanol, hydrochloride (10.9% of theory) having a melting point of 124°C 125°C were obtained from the crude base according to the procedure 15 described in Example 1 (3'1 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 11 l-benzo 3] dioxol-4-yl-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 2.61 g (13 rmmole) of 4-bromo-l, 2-methylenedioxybenzene were 25 dissolved in 10 ml of tetrahydrofuran and cooled under nitrogen to -70 0 C in a dry ice/isopropanol bath. 9.35 ml munole) of n-butyllithiuml (1.6 M in hexane) were added dropwise while stirring so that the temperature did not rise above 0 C) The reaction mixture was stirred for 30 minutes, following which 3.0 g (13 munole) of the 2- (dimethylaminophenyl-methyl) cyclohexanone prepared according to Example land dissolved in 10 ml of tetrahydrofuran were added dropwise while cooling in an ice bath, and the whole was then heated to RT over two hours. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath and was extracted three 49 times at RT, each time with 70 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 4.67 g of crude base (102% of theory) were obtained. 3.05 g of l-benzo[l, 3 dioxol-4-yl-2- (dimethylaminophenyl-methyl)cyclohexanol, hydrochloride (60.3% of theory) having a melting point of 209 0 C were obtained from the crude base according to the procedure described in Example 1 3

L

u stage) with chlorotrimethylsilane/water in 2butanone.

Example 12 15 4-dimethoxyphenyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 2.82 g (13 mmole) of 3-bromoveratrole were dissolved in 20 ml of tetrahydrofuran and cooled under nitrogen to -70 0 C in a dry ice/isopropanol bath. 9.35 ml (15 munole) of n-butyllithiumi (1.6 M in hexane) were added dropwise while stirring so that the temperature did not rise above -60 0 C. The reaction solution was stirred for a further 30 minutes, following which 3.0 g (13 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 and dissolved in ml of tetrahydrofuran were added dropwise while cooling in an ice bath and then heated to RT within two hours. The reaction solution was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 70 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 5.09 g of crude base (106% of theory) were obtained. 3.73 g of (3,4-dimethoxyphenyl)-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride (70.8% of theory) having a melting point of 205-207 0 C were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 13 2- (dimethylaminophenylmethyl) (3-methoxybenzyl) cyclohexanol, hydrochloride 0.63 g (25.9 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 5.21 g (25.9 mmole) of 3-methoxybenzyl bromide dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 5.0 g (21.6 mmole) of the S2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and 25 concentrated by evaporation on a rotary evaporator (500 to mbar). 7.53 g of crude base (98.6 of theory) were obtained. 4.45 g of 2- (dimethylaminophenylmethyl) methoxybenzyl)cyclohexanol, hydrochloride of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes when heated above 160 0

C.

Example 14 l-benzyl-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.63 g (25.9 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 4.43 g (25.9 mmole) of benzyl bromide dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 5.0 g (21.6 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred *I 15 for 15 hours at RT. The reaction mixture was worked up by adding 40 ml of saturated aummonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 6.84 g of crude base (97.9% of theory) were obtained. 1.61 g of l-benzyl-2-(dimethylaminophenylmethyl) cyclohexanol, hydrochloride (20.7% of theory) having a melting point of 223-225°C were obtained from the crude base 25 according to the procedure described in Example 1 (3 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 2-(dimethylaminophenylmethyl)-1- (4-fluoro-3-trifluoromethylphenyl)cyclohexanol, hydrochloride 0.25 g (10.3 mmole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 2.2 g (10.3 mmole) of 5-bromo-2-fluorobenzotrifluoride dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 1.80 g (8.57 mnuole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated amunonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 40 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary I: evaporator (500 to 10 mbar) 3.9 g of crude base (126% of 15 theory) were obtained. 2.14 g of 2- (dimethylaminophenylmethyl) -1-(4-fluoro-3trifluorometylph enylpheny)cyclohexanol, hydrochloride (63.7% of theory) having a melting point of 234- 237 0 C were obtained from the crude base according to the procedure described in Example 1 (3 1 stage) with chlorotrimethylsilane/ water in 2butanone.

Example 16 2-(dimethylaminophenylmethyl) (4-trifluoromethoxybenzyl) cyclohexanol, hydrochloride 0.10 g (4.2 imnole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 1.0 g (4.2 mmole) of 4-(trifluoromethoxy)benzyl bromide dissolved in 10 iml of ether was added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was stirred for a further hour at RT. 0.8 g (3.5 mniole) of the 2- (dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 was dissolved in 10 ml of ether, added dropwise to 53 the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 30 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 1.65 g of crude base (121% of theory) were obtained. 0.64 g of 2-(dimethylaminophenylmethyl)-1-(4trifluoromethoxybenzyl)cyclohexanol, hydrochloride (41.7% of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 178 0

C.

Example 17 2- (dimethylaminophenylmethyl) -1-furan-3-ylcyclohexanol, hydrochloride 1.0 g (6.8 mmole) of 3-bromofuran was dissolved in 10 ml of tetrahydrofuran and cooled under nitrogen to -70 0 C in a dry ice/isopropanol bath. 5.1 ml (8.1 mmole) of n-butyllithium 25 (1.6 M in hexane) were added dropwise while stirring so that the temperature did not rise above -60 0 The reaction mixture was stirred for a further 30 minutes and then 1.5'7 g (6.8 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 dissolved in 10 ml of tetrahydrofuran were added dropwise while cooling in an ice bath, and heated to RT within two hours. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 50 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary 54 O evaporator (500 to 10 mbar). 2.15 g of crude base (106% of theory) were obtained, from which a hydrochloride was precipitated according to the procedure described in Example 1 (3 r stage) with chlorotrimethylsilane/water in 2-butanone.

The base was freed from the hydrochloride with 20 ml of water and 3 ml of caustic soda (32 was extracted three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.29 g of crude base (63.4% of theory) were obtained, which were added to a 4 x 30 cm column filled with silica gel. Elution with diisopropyl ether/ methanol yielded 0.33 g of base, from which 0.28 g of 2- (dimethylaminophenylmethyl) furan-3-ylcyclohexanol, 15 hydrochloride (12.4% of theory) was obtained according to the procedure described in Example 1 3 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 130 0

C.

Example 18 l-butyl-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 2.43 g (7.2 mmole) of (1-bromonaphthalene-2-yloxy)-tert.butyldimethylsilane were dissolved in 10 ml of tetrahydrofuran and cooled to -70°C in a dry ice/isopropanol bath.

5.4 ml (8.6 mmole) of n-butyllithium (1.6 M in hexane) were added dropwise under nitrogen while stirring, and then stirred for a further 30 minutes. 2.7 a (7.2 mnmole) of the 2- (dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 and dissolved in 10 ml of tetrahydrofuran were added dropwise and the reaction mixture was heated to RT within two hours. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.65 g of crude base were obtained (223% of theory), to which were added 10 ml of n-hexane, 9 ml of methanol and 4.7 ml of hydrochloric acid (2 The aqueous phase was separated, the methanol was distilled off on a rotary evaporator (500 to mbar), the solution was adjusted alkaline (pH ca. 9) with sodium carbonate solution (1 and was extracted three times at RT, each time with 50 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.34 g of crude base (53.4% of theory) were obtained, 15 which were added to a 3.5 x 15 cm column filled with silica gel. Elution with ethyl acetate/n-hexane yielded 0.23 g of base, from which 0.13 g of 1-butyl- 2 (dimethylaminophenylmethyl) cyclohexanol, hydrochloride of theory) was obtained according to the procedure described in Example 1 3 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 1100C.

25 Example 19 4-dichlorophenyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride, and 4-dichlorophenyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.78 g (32.1 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 7.13 g (31.0 mmole) of l-bromo-3,4-dichlorobenzene dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was 0 stirred for a further hour at RT. 6.0 g (26.0 mumole) of the 2-(dimethylaminophenlylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 10.4 g of crude base (106% of theory) were obtained.

1.96 g (5.2 imnole) of this base were dissolved in 20 ml of 15 2-butanone, 0.78 g of tartaric acid (5.2 mmuole) was added and dissolved by heating, and the reaction mixture was kept for one week at 4 0 C, a white precipitate being formed. The precipitate was filtered off, washed several times with a small amount of 2-butanone and ether, dissolved in 20 ml of water, following which the base was freed with 2 ml of caustic Ssoda (32 and extracted three times, each time with 30 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.69 g (1.8 mmole) 25 of crude base was obtained. The optical purity was determined by HPLC. The crude base was dissolved in hexane/isopropanol/ diethylamine( 9 9 0 10 1) (0.1 vol. and 20 tl of the solution were injected into a Chiracel OD 250 x 4.6 mm column with a precolumn (Daicel) and eluted with the solvent system hexane/isopropanol/diethylamine (990 10 1) at a flow rate of 1 ml/min through the column. The base was detected at a wavelength of 254 nm. The degree of purity was 98.8 %ee.

0.32 g (0.77 mmole) of (3,4-dichlorophenyl)-2- (dimethylaminophenylmethyl)cyclohexanol, hydrochloride (29.7% of theory) having an angle of rotation of 7 9 (c 1.097 in methanol) was obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

The mother liquor of the filtered-off base/tartaric acid mixture was concentrated by evaporation and the base was freed with caustic soda as described in the case of the previously obtained precipitate, following which a hydrochloride was precipitated with chlorotrimethylsilane/ water in 2-butanone.

The base was once more freed from the hydrochloride with caustic soda, 0.62 g (1.6 mmole) of crude base being obtained.

This crude base was dissolved in 6 ml of 2-butanone, 0.25 g (1.6 mmole) of tartaric acid was added, the resultant precipitate was filtered off, washed several times with a small amount of 2-butanone and ether, dissolved in 20 ml of 1 water, and the base was then freed with 2 ml of caustic soda (32 and extracted three times, each time with 30 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.33 g (0.87 mmole) of crude base was obtained. The optical purity was determined as above by HPLC. The purity was 98.5 -ee. 0.12 g (0.29 mmole) of 4-dichlorophenyl)-2- (dimethylaminophenylmethyl)cyclohexanol, hydrochloride (11.1 of theory) having an angle of rotation of 7 .3 (c=1.081 in methanol) was obtained from the crude base 25 according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 4-[2-(dimethylaminophenylmethyl) hydroxycyclohexyl] phenol, hydrochloride 0.38 g (15.5 mmole) of magnesium turnings was stirred in 5 ml of tetrahydrofuran of analysis purity. 3.81 g (15.5 mmole) of 1-(4-bromophenoxy)-l-ethoxyethane dissolved in 5 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at 55 0

C.

g (13.0 nmmole) of the 2- (dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in ml of tetrahydrofuran, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator (500 to 10 mbar). 5.25 g of crude base were obtained, which were dissolved in 20 ml of ether followed by 15 the addition of 10 ml of hydrochloric acid (1 The aqueous phase was separated and sufficient sodium bicarbonate was added to adjust the p-I to ca. 8. The base was extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.96 g of crude base (46.3% of theory) were obtained, from which 1.8 g of 4- [2-(dimethylaminophenylmethyl)-1-hydroxycyclohexyl] phenol, hydrochloride were obtained (38.6% of theory) with 0.49 ml of hydrochloric acid 25 (32 and 20 ml of acetone. The hydrochloride decomposes on heating above 140°C.

Example 21 2- (dimethylaminophenylmethyl) -1-naphthalene-2-ylcyclohexanol, hydrochloride 1.01 g (25.9 mmole) of potassium were added under nitrogen to 1.37 g (14.2 mmole) of dry magnesium chloride dissolved in ml of tetrahydrofuran, and heated to 65 0 C while stirring.

The suspension was heated under reflux for three hours, 2.99 g (14.0 mmole) of 2-bromonaphthalene dissolved in 10 ml of tetrahydrofuran were added dropwise, the reaction mixture was stirred for a further 1.5 hours, cooled to RT, 2.65 g (13.0 mnuole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 and dissolved in ml of tetrahydrofuran were then added dropwise, and the reaction mixture was stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 80 ml of ethyl acetate. The combined organic extracts were dried over sodium *sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.2 g of crude base (1024 of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 3 ml of caustic soda (32 and was extracted three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.42 g of 2-(dimethylaminophenylmethyl)-1-napththalene-2-ylcyclohexanol, hydrochloride of theory) was obtained from the crude base according to the procedure described in Example 1 (3 r stage) with chlorotrimethylsilane/water in 2-butanone.

The hydrochloride decomposes on heating above 240 0

C.

Example 22 2-[dimethylamino-( 4 -trifluoromethylphenyl)methyl]-- (3methoxybenzyl) cyclohexanol, hydrochloride S1 t Stage N,N,N' -tetramethyl-C- (4-trifluoromethylphlenyl) methanediamine 81 ml (0.632 mole) of dimethylamine solution (40 m- in water) were added to 55 g (0.315 mole) of 4-(trifluoromethyl) benzaldehyde while stirring and cooling in an ice bath, and the mixture was stirred for a further 15 hours at RT. The reaction mixture was worked up by adding 40 ml of saturated potassium carbonate solution and solid potassium carbonate until a pH of ca. 9 was reached. The reaction mixture was extracted three times, each time with 300 ml of ethyl acetate.

The combined organic extracts were dried over potassium carbonate, filtered, and concentrated by evaporation on a 15 rotary evaporator (500 to 10 mbar). 68.3 g of tetramethyl-C-(4-trifluoromethylphenyl) methanediamine (87.8% of theory) were obtained in this way.

2 n Stage 2-[dimethylamino-(4-trifluoromethylphenyl)methyl] cyclohexanone 63 g (2.56 mmole) of N,N,N',N'-tetramethyl-C-(4-trifluoromethylphenyl)methanediamine from stage 1 were dissolved in 25 450 ml of ether and cooled to 0°C in an ice bath. 18.3 ml (256 mmole) of acetyl chloride were added dropwise under nitrogen and the reaction mixture was stirred for 15 hours at RT. The solution was cooled to -70°C with a dry ice/isopropanol bath, 38.7 g (256 im ole) of l-(pyrrolidino)-1cyclohexene dissolved in 300 ml of dichloromethane were added dropwise, the mixture was heated to -30 0 C within three hours, and kept for 15 hours at this temperature. The reaction mixture was worked up by adding 200 ml of semi-concentrated hydrochloric acid and stirred for a further 5 minutes. The phases were separated and the aqueous solution was extracted at RT with 150 ml of ether, following which 400 ml of ammonia solution (5 vol. were added and the mixture was quickly extracted three times, each time with 400 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator without heating (500 to 10 mbar). 63.1 g of crude base (82.4% of theory) were obtained in this way. 51.4 g of the hydrochloride of 2-[dimethylamino-(4-trifluoromethylphenyl)methyl]cyclohexanone (59.8% of theory) having a melting point of 139-140 0 C were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

3 Stage 2-[dimethylamino- 4 -trifluoromethylphenyl)methyl (3- 15 methoxybenzyl)cyclohexanol, hydrochloride 0.29 g (12.0 rmmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.42 g (12.0 nmole) of 3-methoxybenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (10.0 munole) of the 2- [dimethyl-amino- (4-trifluoromethylphenyl) methyl] cyclohexanone prepared according to stage 2 were dissolved in 5 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 50 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mnbar) 5.60 g of crude base (133% of theory) were obtained. 3.26 g of 2-[dimethylamino- (4-trifluoromethyl-phenyl)methyl]-- (3methoxybenzyl)cyclohexanol, hydrochloride (70.9% of theory) were obtained from the crude base according to the procedure described in Example 1 (3 t stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 133°C.

Example 23 1- (4-chlorobenzyl) (dimethylaminophenylnmethyl) -1cyclohexanol, hydrochloride 0.38 g (15.6 inmole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 1.99 g (15.6 imuole) of 4-chlorobenzyl bromide dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred 15 for a further hour at RT. 3.0 g (13.0 mmole) of the .2-(dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 25 10 mbar) 4.48 g of crude base (96.5% of theory) were obtained. 1.74 g of 1- (4-chlorobenzyl) (dimethylaminophenylmethyl)-l-cyclohexanol, hydrochloride (34.0. of theory) were obtained from the crude base according to the procedure described in Example 1 3 stage) with chlorotrimethylsilane/ water in 2-butanone. The hydrochloride decomposes on heating above 208 0

C.

63 Example 24 2- (dimethylaminophenylmethyl) (2-fluorobenzyl) cyclohexanol, hydrochloride 0.38 g (15.6 mnole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 1.85 g (15.6 immole) of 2-fluorobenzyl bromide dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 immole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and 15 stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.50 g of crude base of theory) were obtained. 1.75 g of 2- (dimethylaminophenylmethyl)-1-(2fluorobenzyl)cyclohexanol, hydrochloride (35.7. of theory) were obtained from the crude base according to the procedure 25 described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 175 0

C.

Example 2- (dimethylaminophenylmethyl) -1-(4-fluorobenzyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 1.87 g (15.6 mmole) of 4-fluorobenzyl bromide dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2- (dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.51 g of crude base (102, of theory) were 15 obtained. 2.59 g of 2-(dimethylaminophenylmethyl)-1-( 4 fluorobenzyl)cyclohexanol, hydrochloride (52.8% of theory) were obtained from the crude base according to the procedure described in Example 1 3 stage) with chlorotrimethylsilane/ water in 2-butanone. The hydrochloride decomposes on heating above 203 0

C.

Example 26 25 1- 5-dimethoxyphenyl)-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmuole) of magnesium turnings was stirred in 15 ml of tetrahydrofuran of analysis purity. 3.39 g (15.6 nuuole) of l-bromo-2,5-dimethoxybenzene dissolved in 15 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further 1.5 hours at 65 0

C.

g (13.0 mmole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 15 ml of tetrahydro-furan, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated anunonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.17 g of crude base (108% of theory) were obtained. 4.43 g of 1-(2,5-dimethoxy-phenyl)-2- (dimethylainophenylimethyl) cyclohexanol, hydrochloride (84.27 of theory) with a melting point above 240°C were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotri-methylsilane/water in 2-butanone.

4 Example 27 1-(2-chloro-4-fluorobenzyl)-2-(dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.38 g (15.6 iunole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.79 g (15.6 muole) of 2-chloro-4-fluorobenzyl bromide dissolved in 10 ml of ether 25 "were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2-(dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in anl ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time witlh 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.52 g of crude base (92.8% of theory) were obtained. The crude base was dissolved in 45 ml of 2-butanone and some ethyl acetate, 0.11 ml (6.0 mmole) of water and 1.52 ml (12.0 immole) of chlorotrimethylsilane were added in succession, and the reaction mixture was kept for 15 hours at RT. The solvents were distilled off on a rotary evaporator (500 to 10 mbar), the residue was taken up in 20 ml of ether, the remaining solids were filtered off, washed with small portions of ether, and dried to constant weight in an oil pump vacuum. 4.45 g of 1-(2-chloro-4-fluorobenzyl)-2- (dimethylaminophenylmethyl)cyclohexanol, hydrochloride (83.2of theory) were obtained in this way. The hydrochloride decomposes on heating above 100'C.

15 Example 28 1- (4-tert. -butylbenzyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.33 g (13.5 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.46 g (13.5 mmole) of 4-tert.butylbenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was 25 stirred for a further hour at RT. 3.0 g (13.0 nmmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.18 g of crude base (98.1% of theory) were obtained. 2.16 g of 1-(4-tert.-butylbenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (46.2' of theory) with a melting point of 227-229 0 C were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 29 2-(dimethylaminophenylmethyl)-l-(3-fluorobenzyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 1.89 g (15.6 mmnole) of 15 3-fluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2- (dimethyl-aminophenylmethyl)cyclohexanone prepared according 20 to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 4.59 of crude base (104% of theory) were obtained, from which a hydrochloride was precipitated according to the procedure of Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 40 ml of water and 5 ml of caustic soda (32 mn), extracted three times, each time with 40 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.42 g of crude base (77.2% of theory) were obtained. 2.72 g of 2- (dimethylaminophenyllmethyl) (3-fluorobenzyl) cyclohexanol, hydrochloride (55.5% of theory) with a melting point of 146-147°C were obtained from the crude base according to the procedure described in Example 1 (3 stage) with chlorotrimethylsilane/water in 2-butanone.

Example 1- (2-chlorobenzyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 15 0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 2.0 ml (15.6 mmole) of 2-chlorobenzyl chloride dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and Sstirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ainmonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 4.50 g of crude base (97.0% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/ water in 2butanone. The base was freed from the hydrochloride with ml of water and 5 ml of caustic soda (32 mi), extracted three times, each time with 40 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar) 2.90 g of crude base were obtained, which were added to a 3.5 x 15 cm column filled with silica gel. Elution with ethyl acetate/n-hexane yielded 1.59 g of base, from which 1.75 g of 1-(2-chlorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (34.2% of theory) were obtained according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone.

The hydrochloride decomposes on heating above 130 0

C.

Example 31 l-benzo[1,3]dioxol-5-yl- 2 -[dimethylamino-(3- 15 methoxyphenyl)methyl]cyclohexanol, hydrochloride 2.61 g (13.0 mmole) of 4-bromo-1,2-methylenedioxybenzene were dissolved in 10 ml of tetrahydrofuran and cooled to -70 0

C

under nitrogen in a dry ice/isopropanol bath. 7.9 ml 20 (13.0 mmole) of n-butyllithium (1.6 M in hexane) were added dropwise while stirring so that the temperature did not rise above -60 0 C. The reaction mixture was stirred for a further 30 minutes and then 3.0 g (10.8 mmole) of the 2- [dimethylamino-(3-methoxyphenyl)methyl]cyclohexanone prepared according to Example 9 and dissolved in 10 ml of tetrahydrofuran were added dropwise while cooling in an ice bath, and the whole was heated to RT within two hours. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 20 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.10 g of crude base (98.8% of theory) were obtained, from which 1.96 g of l-benzo[l,3] dioxol-5-yl-2- [dimethylamino-(3-methoxyphenyl)methyl] cyclohexanol, hydrochloride (43.2% of theory) were obtained according to the procedure described in Example 1 (31 stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 109 0

C.

Example 32 1- (3-chlorobenzyl)-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml eeo of ther of analysis purity. 2.0 ml (15.6 mnuole) of 3-chlorobenzyl chloride dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After 15 completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 inmole) of the 2-(dimethyl-aminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and 20 stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated anunonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 4.55 of crude base (98.0% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 40 ml of water and 5 ml of caustic soda (32 extracted three times, each time with 40 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.87 g of crude base were obtained, to which were added 5 ml of ethyl acetate/n-hexane in a ratio of 2:5. The insoluble residue was filtered off and dried. 2.11 g of base was obtained, from which 1.68 g of 1-(3-chlorobenzyl)- 2 (dimethylaminophenylmethyl)cyclohexanol, hydrochloride (32.8% of theory) with a melting point of 185 0 C 188 0 C was precipitated according to the procedure described in Example 1 (3" stage) with chlorotrimethylsilane/water in 2-butanone.

Example 33 1- (2,4-dichlorobenzyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.04 g (15.6 mmole) of 2,4dichlorobenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 20 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwtse to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.14 g of crude base (97.0% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 3 ml of caustic soda (32 extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a 72 O rotary evaporator (500 to 10 mbar). 1.19 g of crude base were obtained, from which 0.45 g of 1- (2,4-dichlorobenzyl)-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride of theory) was obtained according to the procedure described in Example 1 stage) with chlorotri-methylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 140 0

C.

Example 34 l-benzyl-2- [dimethylaminophenyl- (3-phenoxyphenyl) methyl cyclohexanol, hydrochloride 15 1' Stage 2-[dimethylamino-(3-phenoxyphenyl)methyl]cyclohexanone 2.47 g (30.3 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 67 ml (66.6 mmole) 20 of sodium iodide solution (1 M in acetonitrile) cooled in an o S" ice bath to 0°C, following which 8 .4 ml (60.5 mmole) of triethylamine and 8.4 ml (66. 6 umnole) of chlorotrimethylsilane were added dropwise, and the whole was stirred for a further hour at RT. 6.0 ml (30.3 nunole) of 3phenoxybenzaldehyde were added to the reaction mixture while cooling in an ice bath, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C in an ice bath, and 4.58 g (30.3 imnole) of 1- (pyrrolidino)-1-cyclohexene were added and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 45 ml of semi-concentrated hydrochloric acid while cooling in an ice bath, stirred for minutes, washed twice each time with 45 ml of ether, and adjusted in the alkaline range (pH ca. 9) with 115 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times, each time with 45 ml of ether, and the 73 combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 7.41 g of crude base (75.7% of theory) were obtained in this way. 4.83 g of the hydrochloride of 2- [dimethylamino- (3-phenoxyphenyl) methyl] cyclohexanone (44.4% of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone.

2 nd Stage l-benzyl-2- [dimethylaminophenyl- (3-phenoxyphenyl) methyl] cyclohexanol, hydrochloride 0.27 g (11.1 iunole) of magnesium turnings was stirred in 5 ml 15 of ether of analysis purity. 1.90 g (11.1 mmole) of benzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. The base was freed with 30 ml of water and 5 ml 20 of ammonia solution (25 vol. from 3.7 g (11.4 mmole) of the hydrochloride of 2-[dimethylaminophenyl-(3-phenoxyphenyl) methyl] cyclohexanone obtained from stage 1, was extracted three times, each time with 30 ml of ether, and the combined Sorganic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 3.0 g (9.3 mmole) of this base were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.51 g of crude base (91.1% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with 9 74 chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, each time with ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.55 g of crude base (65.9% of theory) were obtained, which were added to a x 33 cm column filled with silica gel. Elution with ethyl acetate/n-hexane in a ratio of 1:4 yielded 1.92 g of base, from which 0.51 g of l-benzyl-2-[dimethylamino-phenyl-( 3 phenoxyphenyl)methyl]cyclohexanol, hydrochloride (12.1 of theory) with a melting point of 189-190"C was obtained according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone.

Example l-benzyl-2-[dimethylaminophenyl- (3-methoxyphenyl)methyl] cyclohexanol, hydrochloride 0.32 g (13.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.22 g (13.0 mmole) of benzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (10.8 mmole) of the 2-[dimethylaminophenyl- (3-methoxyphenyl)methyl]cyclohexanone prepared according to Example 9 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, with in each case 15 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to U 10 mbar). 3.58 g of crude base (93.74 of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, each time with ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.2 g of crude base (76.2% of theory) were obtained, which were added to a x 33 cm column filled with silica gel. Elution with ethyl acetate/n-hexane in a ratio of 1:4 yielded 1.69 g of base, from which 1.60 g of l-benzyl-2-[dimethylaminophenyl-(3methoxyphenyl)methyl] cyclohexanol, hydrochloride (38.0 of S 15 theory) having a melting point range of 101 0 C 115 0 C were obtained according to Example 1 (3 stage) with chlorotrimethylsilane/water in 2-butanone.

20 Example 36 0* 2- (dimethylaminophenyl-methyl) (3-trifluoromethylbenzyl) cyclohexanol, hydrochloride 0.33 g (13.5 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.62 g (13.5 mmtuole) of 3chloromethylbenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.60 g (11.2 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, O with in each case 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 4.49 g of crude base (1049 of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution vol. extracted three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.49 g of crude base were obtained, from which 1.80 g of 2-(dimethylaminophenylmethyl)-1- (3-trifluoromethylbenzyl) 15 cyclohexanol, hydrochloride (37.4% of theory) with a melting point of 184 0 C 186 0 C were obtained according to Example 1 (3 I stage) with chlorotrimethylsilane/water in 2-butanone.

Example 37 0 2- (dimethylamino-( 3-methoxyphenyl)methyl]-1- (3-methoxybenzyl)cyclohexanol, hydrochloride *0 0.32 g (13.0 ummole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.61 g (13.0 mmole) of 3-methoxybenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (10.8 mmole) of the 2- [dimethyl-amino-(3-methoxyphenyl)methyl]cyclohexanone prepared according to Example 9 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three Stimes at RT, each time with 15 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 3.87 g of crude base (101?. of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, each time with 15 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.34 g of crude base (61.2% of theory) were obtained, from which 2.04 g of 2-[dimethylamino- (3-methoxyphenyl) methyl] (3- S 15 methoxybenzyl)cyclohexanol, hydrochloride (48.4% of theory) were obtained according to Example 1 3 stage) with chlorotrimethylsil]ane/water in 2-butanone. The hydrochloride decomposes on heating above 75 0

C.

Example 38 2- (2-chlorophenyl) dimethylaminomethyl] -1-naphthalene-2ylcyclohexanol, hydrochloride 1 s' Stage 2- (2-chlorophenyl) dimethylaminome tlyl cyclohexanone 17.4 g (213 mmnole) of freshly dried dimethylamine hydrochloride were added while stirring to 471 ml (469 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to 0 C in an ice bath, followed by the dropwise addition of 60 ml (427 .mmole) of triethyalmine and 60 ml (469 mmole) of chlorotrimethylsilane, and the whole was stirred for one hour at RT.

24 ml (213 mmole) of 2-chlorobenzaldehyde were added while cooling in an ice bath, and the reaction mixture was stirred Sfor a further hour at RT. The reaction mixture was cooled once more to 0°C in an ice bath, following which 34 ml (213 mmole) of 1-(pyrrolidino)-l-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 300 ml of semiconcentrated hydrochloric acid while cooling with ice, stirring for 10 minutes, washing twice, each time with 300 ml of ether, and then adjusting to the alkaline range (pH ca. 9) with 770 ml of dilute ammonia solution (5 vol.r) The reaction mixture was extracted three times, each time with 300 ml of ether, and the combined organic extracts were dried over e sodium sulfate, filtered, and concentrated by evaporation on a *rotary evaporator (500 to 10 mbar) without heating. 38.3 g of crude base (67.5% of theory) were obtained in this way.

15 33.6 g of the hydrochloride of chlorophenyl)dimethylaminomethylJcyclohexanone (52. 0 of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone.

Stage (2-chlorophenyl) clime thylaminomethyl -1-naphthalene-2ylcyclohexanol, hydrochloride C 0.27 g (11.1 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.32 g (11.1 mmole) of 2-bromonaphthalene dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for one hour at RT. The base was freed from 3.0 g (11.2 mmole) of the hydrochloride of chlorophenyl)dimethylaminomethyl]cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation 0 on a rotary evaporator without heating (500 to 10 mbar).

2.50 g (9.3 rmnole) of this base were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath and was extracted three times at RT, each time with 15 ml of ether.

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 4.05 g of crude base (110% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia 15 solution (25 vol. extracted three times, each time with ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.2 g of crude base (60.0% of theory) were obtained, which were added to a 20 3 x 26 cm column filled with silica gel. Elution with ethyl °acetate/n-hexane yielded 0.95 g of base, from which 0.47 g of 2-[(2-chlorophenyl)dimethylaminomethyl]-1naphthalene-2-ylcyclohexanol, hydrochloride of theory)

C

with a melting point above 230°C were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 39 l-benzyl-2- 4-dichlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride 1 s t Stage 2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanone 7.92 g (97.1 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 214 ml (214 imuole) of sodium iodide solution (1 M in acetonitrile) cooled to 0 C with an ice bath, followed by the dropwise addition of 27 ml (194 mnnole) of triethylamine and 27 ml (214 mmole) of chlorotrimethylsilane, and the whole was stirred for a further hour at RT. 17.0 g (97.1 mmole) of 3,4-dichlorobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C with an ice bath, following which 14.7 g (97.1 mmole) of 1-(pyrrolidino)-1-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 130 ml of semiconcentrated hydrochloric acid, stirred for 10 minutes, washed 15 twice with in each case 125 ml of ether, and adjusted in the alkaline range (pH ca. 9) with 300 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 125 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar) without heating. 26.6 g of crude base (91. of theory) were obtained in this way. 26.7 g of the hydrochloride of 4-dichlorophenyl)dimethylaminomethyl] cyclohexanone(81.8% of theory) were obtained from the crude 25 base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

2 nd Stage 1-benzyl-2- 4-dichlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride The base was freed from 3.5 g (10.4 nunole) of the hydrochloride of 2- 4-dichlorophenyl)dimethylaminomethyl] cyclohexanone obtained according to stage 1 with 30 ml of water and 10 ml of anuonia solution (25 vol. extracted O three times, each time with 30 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar) 3.0 g (10.0 immole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling with an ice bath to 6.0 ml (12.0 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 15 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 3.05 g of crude base (77.9% of theory) were 15 obtained, from which 2.88 g of S"1 l-benzyl-2- 4-dichlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride (67.1% of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The 20 hydrochloride decomposes on heating above 200 0

C.

Example ee 4-dichlorophenyl)dimethylaminomethyl]-1phenethylcyclohexanol, hydrochloride g (10.0 mmole) of the 2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 39 were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 12.0 ml (12.0 mmole) of phenethylmagnesium chloride (1 M solution in tetrahydrofuran) and stirred for 15 hours at RT. The reaction solution was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 15 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator (500 to mbar). 3.88 g of crude base (95.5% of theory) were obtained from which, after adding 30 ml of n-hexane, an oil was obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/ water in 2-butanone.

After decanting the solvents the oil was stirred in 5 ml of water and 20 ml of ether, and the resultant precipitate was filtered off and dried. 3.04 g of dichlorophenyl) dimethylaminomethyl] -l-phenethylcyclo-hexanol, hydrochloride (68.7% of theory) were obtained in this way.

The hydrochloride decomposes on heating above 130°C.

15 Example 41 l-benzyl-2-[dimethylamino- (4-fluorophenyl) methyl] cyclohexanol, hydrochloride 20 1" V Stage 2-[dimethylamino-(4-fluorophenyl)methyl] cyclohexanone 19.7 g (242 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 532 ml (532 immole) of sodium iodide solution (1 M in acetonitrile) cooled to 0 C with an ice bath, followed by the dropwise addition of 67 ml (483 mmnole) of triethylamine and 67 ml (532 mmole) of chlorotrimethylsilane, and the whole was stirred for a further hour at RT. 30.0 g (242 mmole) of 4-fluorobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C with an ice bath, 36.6 g (242 nmmole) of 1-(pyrrolidino)-1cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 300 ml of semi-concentrated hydrochloric acid, while cooling with ice, stirred for 10 minutes, washed twice with in each case 250 ml of ether, and adjusted to the alkaline range (pH ca. 9) with 750 ml of dilute ammonia solution (5 vol. y).

The reaction mixture was extracted three times with 250 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by a rotary evaporator (500 to 10 mbar) without heating. 51.0 g of crude base (84.6% of theory) were obtained in this way. 41.7 g of the hydrochloride of 2-[dimethylamino-(4fluorophenyl)methyl]cyclohexanone (60.3% of theory) were obtained from the crude base according to the procedure described in Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

i Stage 0.

15 l-benzyl-2-[dimethylamino- (4-fluorophenyl) methylJ cyclohexanol, hydrochloride fee* The base was freed from 3.2 g (11.2 mmole) of the hydrochloride of 2-[dimethylamino-(4-fluorophenyl)methyl] e. 20 cyclohexanone obtained according to stage 1 with 30 ml of "water and 10 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.69 g (10.8 nmmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 6.5 ml (12.9 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath and was extracted three times at RT, with 15 ml of ether each time.

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.42 g of crude base (84.1% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

The base was freed from the hydrochloride with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 15 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 2.89 g of crude base (78.6' of theory) were obtained, from which 2.58 g of l-benzyl-2-[dimethylamino- (4-fluoro-phenyl)methyl]cyclohexanol, hydrochloride (63.3% of theory) having a melting point of 178 0 C were obtained according to the procedure described in Example 1 stage) 15 with chlorotrimethylsilane/water in 2-butanone.

Example 42 2- (3-chlorophenyl) (dimethylaminomethyl] -1-phenylcyclohexanol, hydrochloride 1t Stage 2- (3-chlorophenyl) (dimethylaminomethyl] cyclohexanone 3.48 g (42.7 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 94 ml (94 nimmole) of sodium iodide solution (1 M in acetonitrile), cooled to 0 C with an ice bath, followed by the dropwise addition of 12 ml (85.4 mmole) of triethylamine and 12 ml (94 immole) of chlorotrimethylsilane, and the whole was stirred for a further hour at RT. 4.8 ml (42.7 mmole) of 3-chlorobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C with an ice bath, 6.9 ml (42.7 minole) of 1-(pyrrolidino)- 1-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 60 ml of semi-concentrated hydrochloric acid, stirred for 10 minutes, washed twice with 60 ml of ether each time, and adjusted in the alkaline range (pH ca. 9) with 150 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 60 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 8.97 g of crude base (79.1% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone.

15 The base was freed from the hydrochloride with 90 ml of water and 15 ml of ammonia solution (25 vol. extracted three times with 50 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar) 7.05 g of crude base (62.1% of theory) were obtained, from which 7.38 g of the hydrochloride of 2- (3-chlorophenyl) (dimethylaminomethyl]cyclohexanone (57.2% of theory) were obtained according to the procedure described in Example 1 (2nd stage) with 25 chlorotrimethylsilane/water in 2-butanone.

2 nd Stage 2- (3-chlorophenyl) (dimethylaminomethyl] -1-phenylcyclohexanol, hydrochloride The base was freed from 2.5 g (8.27 imuole) of the hydrochloride of 2-[(3-chlorophenyl) (dimethylaminomethyll cyclohexanone obtained according to stage 1 with 30 ml o[ water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.0 g (7.5 mmole) of this base were dissolved in 5 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.5 ml (9.0 mmole) of phenylmagnesium chloride (2 M solution in tetrahydro-furan), and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time.

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary 15 evaporator (500 to 10 mbar). 2.30 g of crude base (88.8A of theory) were obtained, from which 2.18 g of 2- (3-chlorophenyl) dime thylaminomethyl -1-phenylcyclohexanol, hydrochloride (76.2% of theory) were obtained according to the procedure described in Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The hydrochloride decomposes on heating above 139 0

C.

Example 43 1- (2,4-dichlorophenyl) (3-dimethylaminomethyl) -1cyclohexanol, hydrochloride 0.76 g (31.2 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. A mixture of 1.34 ml (15.6 mmole) of dibromomethane and 3.52 g of l-bromo-2,4-dichlorobenzene dissolved in 10 ml of ether was added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour 87 7 at RT. 3.0 g (15.6 imole) of the 2(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise while cooling in an ice bath to the Grignard reagent, and the whole was stirred for hours at RT. The reaction mixture was worked up by adding ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 50 ml of ethyl acetate each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.92 g of crude base (100% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 15 (3 stage) with chlorotrimethylsilane/water in 2-butanone.

The base was freed from the hydrochloride with 40 ml of water and 5 ml of caustic soda (32 extracted three times, each time with 40 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar).

4.53 g of crude base were obtained, which were added to a 3.5 x 30 cm column filled with silica gel. Elution with ethyl acetate/n-hexane yielded 2.74 g of base, from which 2.46 g of 1- 4-dichlorophenyl) (3-dimethylaminonmethyl) 25 1-cyclohexanol, hydrochloride (45.6% of theory) having a melting point of 192 0 C 195 0 C were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

88

O

Example 44 l-benzyl-2- (3-chlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride g (7.5 mmnole) of the 2-[(3-chlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 42 were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.5 ml (9.0 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran) and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at 15 RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.61 g of crude base (97.0% of theory) were obtained, from which 1.24 g of 1-benzyl-2-[(3chlorophenyl)dimethylaminomethyl]cyclohexanol hydrochloride (41.8% of theory) having a melting point of 161°C 163°C were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example l-benzyl-2-[(2-chlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride 0.27 g (11.3 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.93 g (11.3 mmole) of benzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of 89 the addition the reaction mixture was stirred for a further hour at RT. 2.5 g (9.4 mmole) of the 2-[(2-chlorophenyl) dimethyl-aminomethyl]cyclohexanone prepared according to Example 38 were dissolved in 10 ml of ether, added dropwise while cooling in an ice bath to the Grignard reagent, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 3.18 g of crude base (94.4% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with 15 chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 Imar). 1.93 g of crude base were obtained, which were added to a 3 x 25 cm column filled with silica gel. Elution with ethyl acetate/n-hexane (1:4) yielded 0.92 g of base, from which 0.43 g of 1-benzyl-2-[ (2chlorophenyl)dimethylamino-methyl]cyclohexanol, hydrochloride 25 (11.5% of theory) having a melting point of 170 0 C were obtained according to the procedure described in Example 1 (3' 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 46 1-(4-tert.-butylbenzyl)-2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride 0.24 g (9.9 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.81 g (9.9 mmole) of 4-tert.butylbenzyl chloride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.48 g (8.3 immole) of the 2-[(3,4-dichlorophenyl)dimethylaminomethyl] cyclohexanone prepared according to Example 39 were dissolved in 10 ml of 15 ether, added dropwise while cooling in an ice bath to the Grignard reagent, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time.

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.69 g of crude base (99.6% of theory) were obtained, from which 1.54 g of l-(4-tert.butylbenzyl) 4-dichlorophenyl) dimethylamino- 25 methyl]cyclohexanol, hydrochloride (38.3% of theory) were obtained according to the procedure described in Example 1 3 r Stage) with chlorotrimethylsilane/water in 2-butanone.

The hydrochloride decomposes on heating above 210'C.

0 Example 47 2-[dimethylamino-(4-fluorophenyl) methyl]-l-(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride 0.29 g (12.1 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.35 g (12.1 mmole) of 3-chlorobenzotrifluoride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.51 g (10.1 mmole) of the 2-[dimethylamino-(4-fluorophenyl)methyl]cyclohexanone prepared according to Example 41 were dissolved in 5 ml of ether, added 1: dropwise to the Grignard reagent while cooling in an ice bath, 15 and stirred for 15 hours at RT. The reaction mixture was S. worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 4.15 g of crude base (101?° of theory) were obtained, from which 3.10 g of 2-[dimethylamino-(4fluorophenyl)methyl]-1-( 3 -trifluoromethylbenzyl) cyclo-hexanol, hydrochloride (69.1% of theory) were obtained according to the 25 procedure described in Example 1 3 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 210 0

C.

Example 48 2-(dimethylaminophenylmethyl)bicyclohexyl-l-ol, hydrochloride g (13.0 mmole) of the 2 -(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 7.8 ml (15.6 mmole) of cyclohexylma gnesium chloride (2 M solution in tetrahydrofuran), and stirred for hours at RT. The reaction mixture was worked up by adding ml of saturated ammonium chloride solution while cooling in an ice bath and extracted three times at RT, with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.03 g of crude base (98.5% of theory) were obtained, from which 2.22 g of 2-(dimethylaminophenylmethyl)bicyclohexyl-l-ol, hydrochloride (48.5% of theory) with a melting point of 220 0 C 223 0 C were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 49 2- (dimethylaminophenylmethyl) (4-methoxybenzyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml of tetrahydrofuran of analysis purity. 2.44 g (15.6 ummole) of 4-methoxybenzyl chloride dissolved in 15 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled 25 gently. After completion of the addition the reaction mixture was stirred fora further 1.5 hours at 65 0 C. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example I were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to the Grignard reagent, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.26 g of crude base (93.0% of theory) were obtained, from which 2.87 g of 2-(dimethylaminophenylmethyl) (4-methoxybenzyl)cyclohexanol, hydrochloride (56.8% of theory) were obtained according to the procedure described in Example 1 (31 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 130 0

C.

Example 1- (2,4-difluorobenzyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.29 g (11.9 mmnole) of magnesium turnings was stirred in 5 ml 15 of ether of analysis purity. 2.47 g (11.9 mmole) of 2,4-difluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.30 g (9.9 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while 25 cooling in an ice bath, and extracted three times at RT with ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.78 g of crude base (49.9% of theory) were obtained. The aqueous solution was extracted three times with 15 ml of ether and ml of dichloromethane each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 1.31 g of crude base (36.7% of theory) were obtained. The hydrochloride was precipitated from both bases according to Example 1 3 1 stage) with chlorotrimethylsilane/water in 2-butanone. 0.95 g of 1-(2,4difluorobenzyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride (20.2% of theory) was obtained from the first base, and 1.27 g of 1-( 2 ,4-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (32.4s of theory) with a melting point of 178 0 C was obtained from the second base.

Example 51 1- (4-tert. -butylbenzyl) (3-chlorophenyl) dimethylaminomethyl]cyclohexanol, hydrochloride 15 0.22 g (9.0 immole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.65 g (9.0 mmole) of 4-tert.butylbenzyl chloride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.0 g (7.5 mmole) of the 2- (chloro-phenyl)dimethylaminomethyl cyclohexanone obtained according to Example 38 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.50 g of crude base (80.1% of theory) were obtained, from which 1.03 g of 1-(4-tert.-butylbenzyl)-2-[(3chlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride (30.5% of theory) having a melting point above 225 0 C were obtained according to the procedure described in Example 1 3 rd Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 52 2- [dimethylamino- (3-phenoxyphenyl) methyl] -1-phenethylcyclohexanol, hydrochloride g (6.2 mmole) of the 2-[dimethylamino-( 3 -phenoxyphenyl)methyl]cyclohexanone prepared according to Example 34 were dissolved in 9 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 7.4 ml (9.0 mmole) of phenethylmagnesium chloride (1 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 10 ml of ether each time. The combined 15 organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.55 g of crude base (96.0% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3" stage) with chlorotrimethylsilane/water in 2-butanone. The base was Freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, each time with ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation 25 on a rotary evaporator (500 to 10 mbar). 1.51 g of crude base (56.8% of theory) were obtained, from which 1.31 g of 2- [dimethylamino-(3-phenoxyphenyl)methyl]-1phenethylcyclohexanol, hydrochloride (45.2% of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

The hydrochloride decomposes on heating above 120 0

C.

SExample 53 2- [dimethylamino- (3-phenoxyphenyl)methyl] (3-trifluoromethylbenzyl)cyclohexanol, hydrochloride 0.18 g (7.4 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.44 g (7.4 mmole) of 3-chloromethylbenzotrifluoride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was stirred for one hour at RT. 2.0 g (6.2 ummole) of the 2-[dimethylamino-(3-phenoxyphenyl) methyl]cyclohexanone prepared according to Example 34 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium Schloride solution while cooling in an ice bath, and was extracted three times at RT with 10 ml of ether each time.

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.85 g of crude base (95.3% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of anmmonia 25 solution (25 vol. extracted three times, each time with ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.94 g of crude base (31.4% of theory) was obtained, from which 0.35 g of 2- [dimethylamino-(3-phenoxyphenyl)methyl]-1-(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride (10.8' of theory) was obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. In order to purify the hydrochloride the latter was stirred with 120 ml of cyclohexane at 50 0 C, cooled in an ice bath, decanted, and the residue was dried. 0.27 g of hydrochloride of theory) was obtained in this way.

Example 54 1- (2,5-difluorobenzyl) (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.29 g (11.9 munole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.47 g (11.9 mmole) of bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was 15 stirred for a further hour at RT. 2.30 g (9.9 immole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT

S

•with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 3.49 g 25 of crude base (97.8% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and ml of ammonia solution (25 vol. extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.75 g of crude base (77.0% of theory) were obtained, from which 2.21 g of 1-(2,5-difluoro-benzyl)-2- (dimethylaminophenylmethyl)cyclohexanol, hydrochloride (56.4% of theory) with a melting point of 219°C 221°C were obtained according to the procedure described in Example 1 3 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 1- 4-difluorobenzyl)-2- (dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.29 g (11.9 itunole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.47 g (11.9 mmole) of 3,4difluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred 15 for a further hour at RT. 2.30 g (9.9 mmole) of the 2- (dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mnbar). 3.58 g 25 of crude base (100% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 30 ml of water and ml of ammonia solution (25 vol. extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.31 g of crude base (64.7% of theory) were obtained, from which 2.0 g of 1-(3,4-difluoro-benzyl)-2- (dimethylaminophenylmethyl)cyclohexanol, hydrochloride (51.0% of theory) with a melting point of 185 0 C 188°C were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 56 1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl) cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.79 g (15.6 mmole) of 2-chloro-6-fluorobenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for one hour at RT. 3.00 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammionium chloride solution while cooling in an ice bath, and was extracted three times at RT with 30 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.92 g 25 of crude base (101% of theory) were obtained, from which 3.28 g of 1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (61.2, of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 225 0

C.

Example 57 1-(2,3-difluorobenzyl)-2-(dimethylaminophenylmethyl) cyclohexanol, hydrochloride 100 0 0.41 g (16.8 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.47 g (16.8 mmnole) of 2,3difluorobenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.23 g (14.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts 15 were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.13 g of crude base (102% of theory) were obtained, from which 1.67 g of 1-(2,3-difluorobenzyl)-2-(dimethylamino-phenylmethyl)cyclohexanol, hydrochloride (30.0% of theory) were obtained according to the procedure described in Example 1 3 Stage) with chlorotrimethylsilane/water in 2-butanone.

The hydrochloride decomposes on heating above 140 0

C.

Example 58 l-benzyl-2- (4-chlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride 1 Stage (4-chlorophenyl) dimethylaminomethyl] cyclohexanone 15.1 g (185 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 407 ml (407 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to 0 C in an ice bath, following which 52 ml (370 nunole) of triethylamine and 52 ml (407 mmole) of chlorotrimethylsilane were added dropwise and the whole was stirred for a further hour at RT. 26.0 g (185 nmmole) of 4-chlorobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C with an ice bath, 12.0 ml (185 mmole) of 1-(pyrrolidino)- 1-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 280 ml of semi-concentrated hydrochloric acid while cooling in an ice bath, stirred for 10 minutes, washed twice with 280 ml of ether each time, and then adjusted to the alkaline range (pl-I ca. 9) with 700 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three 15 times with 280 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 16.2 g of crude base (33.0 of theory) were obtained, from which 14.8 g of the hydrochloride of (4-chlorophenyl)dimethylaminomethyl cyclohexanone (57.2% of theory) were obtained according to the procedure described in Example 1 (2nd Stage) with chlorotrimethylsilane/water in 2-butanone.

a 25 Stage l-benzyl-2- (4-chlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride The base was freed from 2.5 g (8.27 mmole) of the hydrochloride of 2-[(4-chlorophenyl)dimnethylaminomethyl] cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. was extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 1.80 g (6.75 mmole) of this base 102 9were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.05 ml (8.13 mmole) of benzylmagnesium chloride (2 M solution in tetrahydro-furan), and stirred for 15 hours at RT. 2.30 g of crude base (94.9% of theory) were obtained, from which 1.24 q of l-benzyl-2- (4-chlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride (46.7% of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 130 0

C.

Example 59 15 1-dimethylamtino-3-ethyl-2-nmethyl-l, 5-diphenylpentan-3-ol, hydrochloride 1 st Stage 1-(l-ethylpropenyl)pyrrolidine 99 g (1.39 mole) of pyrrolidine dissolved in 460 ml of n-pentane were added dropwise to 40 g (0.464 mole) of 3pentanone dissolved in 1600 ml of n-pentane, and the solution o was cooled to 0°C in an ice bath. 48.4 g (0.255 mole) of titanium tetrachloride dissolved in 480 ml of n-pentane were added dropwise at 0°C 10°C within one hour, the mixture was stirred for two further hours at RT, and the suspension was filtered. The filtrate was concentrated by evaporation on a rotary evaporator (500 to 10 iibar) and 44.3 g of l-(1-ethylpropenyl)pyrrolidine (68.6! of theory) were obtained in this way.

Stage l-dimethylamino-2-methyl-l-phenylpentan-3-one 103 25.9 g (318 mmnole) of freshly dried dimethylamine hydrochloride were added while stirring to 700 ml (700 mmnole) of sodium iodide solution (1 M in acetonitrile) cooled to 0"C in an ice bath, followed by the dropwise addition of 89 ml (636 Iruole) of triethylamine and 89 ml (700 mmole) of chlorotrimethylsilane, and the whole was stirred for a further hour at RT. 33.8 g (318 mmole) of benzaldehyde were added while cooling with ice, and the mixture was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C in an ice bath, 44.3 g (318 irunole) of 1-(l-ethylpropenyl) pyrrolidine from stage 1 were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 480 ml of semi-concentrated hydrochloric acid while cooling with ice, stirred for 10 minutes, washed 15 twice with 480 ml of ether each time, and adjusted to the alkaline range (pH ca. 9) with 1200 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 480 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 1 0 mbar) without heating. 51.3 g of crude base (73.6Y, of theory) were obtained, from which 26.5 g of the hydrochloride of l-dimethylamino-2-methy-l-phlenyl-pentan-3-one (32.6- of theory) were obtained according to the procedure described in 25 Example 1 (2nd Stage) with chlorotrimethylsilane/water in 2-butanone.

3r' Stage l-dimethylamino-3-ethyl-2-methyl-1, 5-diphenylpentan-3-ol, hydrochloride The base was freed from 2.5 g (9.77 mniole) of the hydrochloride of l-dimethylamino- 2-methyl-l-phenylpentan-3-one obtained according to stage 2 with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.90 g (8.7 munole) of this base were dissolved in 13 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 10.4 ml (10.4 mmole) of phenethylmagnesium chloride (I M solution in tetrahydrofuran), and stirred for 15 hours at RT.

The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.96 g of crude base (69.6% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with 15 chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of anuonia solution (25 vol. extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.72 g of crude base was obtained, which was added to a 3.5 x 25 cm column filled Swith silica gel. Elution with ethyl acetate/n-hexane (1:4) yielded 0.41 g of base, from which 0.19 g of 1-dimethylamino- 3-ethyl-2-methyl-l, 5-diphenylpentan- 3 -ol, hydrochloride 25 of theory) having a melting point of 63 0 C 66°C was obtained according to the procedure described in Example 1 3 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 1- (2-chlorobenzyl) (2-chlorophenyl)dimethylaminomethyl] cyclohexanol, hydrochloride 105 0.22 g (9.0 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.45 g (9.0 imnole) of 2-chlorobenzyl chloride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.00 g (7.5 mmole) of the 2-[(2-chlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 38 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by 15 evaporation on a rotary evaporator (500 to 10 mbar). 2.57 g of crude base (87.1% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3' stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of anmmonia solution (25 vol. extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 0.74 g of crude base was obtained, which was added 25 to a 3 x 15 cm column filled with silica gel. Elution with ethyl acetate/n-hexane yielded 0.60 g of base, from which 0.42 g of 1-(2-chlorobenzyl)-2- [(2-chlorophenyl) dimethylaminomethyl] cyclohexanol, hydrochloride (12.9 of theory) having a melting point of 146-147C was obtained according to the procedure described in Example 1 (3 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 61 1-benzyl-2- (4-bromophenyl) dimethylaminomethyl ]cyclohexanol, hydrochloride 1 Stage 2- (4-bromophenyl) dimethylaminomethyl cyclohexanone 2.64 g (32.4 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 71 ml (71 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to 0°C in an ice bath, followed by the dropwise addition of 9.0 ml (65 mmole) of triethylamine and 9.0 ml (71 mmole) of 15 chlorotrimethylsilane, and the whole was stirred for a further hour at RT. 6.0 g (32.4 mmole) of 4-bromobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C with an ice bath, 5.2 ml (2.45 mmole) of 1-(pyrrolidino)- 20 1-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 50 ml of semi-concentrated hydrochloric acid while cooling in an ice bath, stirred for 10 minutes, washed twice with 50 ml of ether each time, and then adjusted to the 25 alkaline range (pH ca. 9) with 120 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 50 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 7.37 g of crude base (73.3% of theory) were obtained, from which 6.48 g of the hydrochloride of 2- [(4-bromophenyl)dimethylaminomethyl]cyclohexanone (57.6% of theory) were obtained according to the procedure described in Example 1 (2nd Stage) with chlorotrimethylsilane/water in 2-butanone.

2' Stage l-benzyl-2- (4-bromophenyl)dimethylaminomethyl] cyclohexanol, hydrochloride The base was freed from the 2.0 g (5.77 mmole) of the hydrochloride of (4-bromophenyl) dimethylaminomethyl] cyclohexanone obtained according to stage 1 with 20 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar) 1.70 g (5.5 imnole) of this base were dissolved in 8.5 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 3.3 ml (6.6 mmole) of 15 benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 10 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.91 g of crude base (86.6% of theory) were obtained, from which 0.86 g of l-benzyl-2-[ (4-bromophenyl) dimethylamionomethyl]cyclohexanol, hydrochloride (35.9" of theory) were obtained according to the procedure described in Example 1 Stage) with chloro-trimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 151 0

C.

108 Example 62 2- (4-chlorophenyl) dimethylaminomethyl] (4trifluoromethylphenyl)cyclohexanol, hydrochloride 0.22 g (9.0 nmnole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.03 g (9.0 mmole) of 4-bromobenzotrifluoride dissolved in 5 nil of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.00 g (7.5 nunole) of the (4-chloro-phenyl) dimethylaminomethyl] cyclohexanone prepared according to Example 58 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice 15 bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated armnonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 2.65 g of crude base (85.4% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) 0.50 g of crude base (16.2% of theory) was obtained, from which 0.20 g of chlorophenyl) dimethylaminomethyl (4trifluoromethylphenyl)cyclohexanol, hydrochloride of theory) with a melting point above 240 0 C was obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

109 Example 63 (4-chlorophenyl) dimethylamoiomethyl] (3-trifluoromethylbenzyl)cyclohexanol, hydrochloride 0.22 g (9.0 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.76 g (9.0 mmuole) of 3-chloromethylbenzotrifluoride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.00 g (7 .5 immole) of the chlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 58 were dissolved in 10 ml of ether, 15 added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ainmonium chloride solution while cooling in an ice bath, and was extracted three "times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.46 g of crude base (45.69; of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 15 ml of water and 5 ml of aimmonia solution (25 vol. extracted three times with 15 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.33 g of crude base (10.3% of theory) was obtained, from which 0.12 g of chlorophenyl) dimiethylaminomethyl]- (3trifluoromethylbenzyl)cyclohexanol, hydrochloride of theory) was obtained according to the procedure described in Example 1 3 r Stage) with chlorotrimethylsilane/water in 2butanone. The hydrochloride decomposes on heating above 115 0

C.

110 Example 64 1- (4-tert.-butylbenzyl) [climethylamino- (3-phenoxyphenyl) methyl]cyclohexanol, hydrochloride 0.15 g (6.3 mmnole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.15 g (6.3 imiole) of 4-tert.butylbenzyl chloride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 1.70 g (5.3 nuuole) of the 2- [dimethyl-amino-(3-phenoxyphenyl)me thyl] cyclohexanone prepared i: 15 according to Example 34 were dissolved in 5 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 10 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 2.01 g of crude base (68.6? of theory) were .:obtained, from which a hydrochloride was precipitated '25 according to Example 1 stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of anmmonia solution (25 vol. extracted three times with 15 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.70 g of crude base was obtained, which was added to a 3 x 15 cm column filled with silica gel. Elution with ethyl acetate/n-hexane yielded 0.40 g of base, from which 0.22 g of 1-(4-tert.-butylbenzyl)-2-[dimethylamino-(3-phenoxyphenyl) methyl]cyclohexanol, hydrochloride of theory) having a melting point of 192-195 0 C was obtained according to the procedure described in Example 1 (3 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 92 0

C.

Example 4- dimethylamino-[2-hydroxy-2-(4-trifluoromethylphenyl) cyclohexyl]methyl}benzonitrile, hydrochloride 1"L Stage 4- [dimethylamino- (2-oxocyclohexyl]methyl}benzonitrile 15 2.8 g (34.3 ruuole) of freshly dried dimethylamine hydrochloride were added while stirring to 75 ml (75 iimole) of sodium iodide solution (1 M in acetonitrile) cooled to 0°C in an ice bath, followed by the dropwise addition of 9.6 ml •09 (68.6 unole) of triethylamine and 9.5 ml (75.5 mmnole) of chlorotrimethylsilane, and the whole was stirred for one hour at RT. 4.50 g (34.3 mmole) of 4-cyanobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to S0C in an ice bath, 5.5 ml (34.3 mmnole) of 1-(pyrrolidino)-1- 0.

25 cyclohexene were added, and the reaction mixture was stirred for a further two hours at RT. The reaction mixture was worked up by adding 50 ml of semi-concentrated hydrochloric acid while cooling with ice, stirred for 10 minutes, washed twice with 50 ml of ether each time, and adjusted to the alkaline range (pH ca. 9) with 130 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 50 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 8.2 g of crude base (93% of theory) were obtained, from which 6.75 g of the hydrochloride of 112 S4-[dimethylamino-(2-oxocyclohexyl] methyl}benzonitrile of theory) were obtained according to the procedure described in Example 1 (2nd Stage) with chlorotrimethylsilane/water in 2-butanone.

Stage 4- {dimethylamino- [2-hydroxy-2- (4-trifluoromethylphenyl) cyclohexyl]methyl}benzonitrile, hydrochloride 0.34 g (14.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.16 g (14.0 mmole) of 4-bromobenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred 15 for a further hour at RT. The base was freed from 3.5 g (12.0 mmuole) of the hydrochloride of 4- [dimethylamino- (2oxocyclohexyl)methyl]benzonitrile obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution vol. extracted three times with 30 ml of ether each 20 time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 3.0 g (11.7 imnole) of this base were dissolved in 10 ml of ether, S"added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 3.52 g of crude base (74.7% of theory) were obtained, from which 0.17 g of 4-{dimethylamino-[2-hydroxy-2- (4-trifluoromethylphenyl) cyclohexyl] methyl }-benzonitrile, hydrochloride of theory) having a melting point above 250 0 C was obtained according to the procedure described in 113 Example 1 (3L' Stage) with chlorotrimethylsilane/ water in 2butanone.

Example 66 2- (dimethylamino-o-tolylmethyl) -1-phenylcyclohexanol, hydrochloride 1"L Stage 2- (dimethylamino-o-tolylmethyl) cyclohexanone 6.79 g (83.2 imnole) of freshly dried dimethylamine hydrochloride were added while stirring to 183 ml (183 rmmole) 15 of sodium iodide solution (1 M in acetonitrile) cooled to 0 C in an ice bath, following which 23 ml (166 mmole) of triethylamine and 23 ml (183 iunole) of chlorotrimethylsilane were added dropwise and the whole was stirred for one hour at RT. 10.0 g (83.2 mmole) of 2-tolualdehyde were added while 20 cooling with ice, and the reaction mixture was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C in an ice bath, 13.4 ml (83.2 mmole) of 1-(pyrrolidino)-lcyclohexene were added, and the whole was stirred for a S: further two hours at RT. The reaction mixture was worked up by adding 125 ml of semi-concentrated hydrochloric acid while cooling with ice, stirred for 10 minutes, washed twice with 125 ml of ether each time, and adjusted to the alkaline range (pH ca. 9) with 310 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 125 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar) 11.8 g of crude base (57.8% of theory) were obtained, from which 10.4 g of the hydrochloride of 2-(dimethylamino-o-tolylmethyl)cyclohexanone (44.4% of theory) were obtained according 114 to the procedure described in Example 1 (2nd Stage) with chlorotrimethylsilane/water in 2-butanone.

2"' Stage 2- (dimethylamino-o-tolylnmethyl) -1-phenylcyclohexanol, hydrochloride The base was freed from 3.0g (10.6 mmole) of the hydrochloride of 2-(dimethylamino-o-tolylmethyl) cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried .over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar).

15 2.50 g (10.2 mmole) of this base were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 6.1 ml (12.2 mmole) of phenylmagnesium chloride (2 M solution in tetrahydro-furan) and stirred for 15 hours at RT.

The reaction mixture was worked up by adding 15 ml of saturated aimmonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.12 g of crude base (94.5% of theory) were obtained, from which 1.97 g of 2- (dimethylamino-o-tolylmethyl)-1 -phenylcyclohexanol, hydrochloride (53.7% of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 137 0

C.

115 O Example 67 l-benzyl-2- (dimethylamino-o-tolylmethyl) cyclohexanol, hydrochloride g (7.5 mmole) of the 2-(dimethylamino-o-tolylmethyl) cyclohexanone prepared according to Example 66 were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 6.1 ml (12.2 rmnole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 158 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over 15 sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.39 g of crude base (98.5% of theory) were obtained, from which 0.83 g of 1 -benzyl- 2 (dimethylamino-o-tolylme thyl)cyclo-hexanol, hydrochloride (21.8% of theory) having a melting point of 180-183C was obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/ water in 2butanone.

Example 68 2- (dimethylaminophenylmethyl) (3-phenylpropyl) cyclohexanol, hydrochloride 0.32 g (13.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.58 g (13.0 mmole) of 1-bromo-3-phenylpropane dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.8 mmole) of the 116 0 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.73 g of crude base (98.2% of theory) were obtained, from which 2.92 g of 2- (dimethylaminophenylmethyl)-l-(3phenylpropyl)cyclohexanol hydrochloride (67.7% of theory) were obtained according to the procedure described in Example 1 (3 Stage) with chlorotrimethylsilane/water in 2-butanone.

15 The hydrochloride decomposes on heating above ~Example 69 20 2- (2-chlorophenyl)dimethylami nomethyl]-- (4fluorophenyl) ethyl] cyclohexanol, hydrochloride 0.22 g (9.0 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 1.83 g (9.0 mmole) of l-(2-bromomethyl)-4-fluorobenzene dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.00 g (7.5 mmole) of the 2- (2-chlorophenyl) dimethylaminomnethyl] cyclohexanolle prepared according to Example 38 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time.

The combined organic extracts were dried over sodium sulfate, 117 O filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.85 g of crude base (97.2% of theory) were obtained, from which 1.74 g of 2-[(2-chlorophenyl)dimethylaminomethyl]-1-[2-(4-fluorophenyl)ethyl] cyclohexanol, hydrochloride (54.1% of theory) were obtained according to the procedure described in Example 1 3 -1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 170 0

C.

Example 2- [dimethylaminothiophen-2-ylrmethyl]-- (3-trifluoromethyl benzyl)cyclohexanol, hydrochloride 1" Stage 2- [dimethylaminothiophen-2-ylmethyl] cyclohexanone 4.36 g (53.5 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 118 ml (118 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to 0 C in an ice bath, following which 15 ml (107 mmuole) of triethylamine and 15 ml (118 mmole) of chlorotrimethylsilane were added dropwise and the whole was stirred for a further hour at RT. 6.0 g (53.5 mmole) of thiophene-2-carboxaldehyde were added while cooling with ice, and the reaction mixture was stirred for a further hour at RT. The reaction mixture was cooled again to O°C with an ice bath, 8.6 ml (53.5 mmole) of l-(pyrrolidino)-l-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 80 ml of semi-concentrated hydrochloric acid while cooling with ice, stirred for minutes, washed twice with 80 ml of ether each time, and adjusted to the alkaline range (pll ca. 9) with 200 ml of dilute ammonia solution. The reaction mixture was extracted three times with 80 ml of ether each time, and the combined 118 organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar) without heating. 8.09 g of crude base of 2- (dimethylaminothiophen-2-yliethyl) cyclohexanone (63.7' of theory) were obtained.

2 d Stage 2-(dimethylaminothiophen)-2-ylmethyl]-1-(3-trifluoromethylbenzyl)cyclohexanol, hydrochloride 0.31 g (12.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.46 g (12.6 mmole) of 3-chloromethylbenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled 15 gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.5 mmole) of the 2-(dimethylaminothiophen-2-ylmethyl)cyclohexanone prepared according to stage 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, 20 and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammuonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar) 3.33 g of crude base ('79.6 of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3' stage) with chlorotrimethylsilane/ water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.63 g of crude base (15.0% of theory) was obtained, from which 0.39 g of 2- [dimethylaminothiophen-2-ylmethyl] (3- 119 0 trifluoromethylbenzyl)cyclohexanol, hydrochloride of theory) was obtained according to the procedure described in Example 1 (3'1 Stage) with chloroLrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 98 0

C.

Example 71 Methyl-4-[2-(dimethylaminophenylmethyl)-1-hydroxycyclohexyl]benzoate, hydrochloride 5.6 ml (10.4 mmole) of isopropylmagnesium chloride (2 M solution in ether) were added to 2.72 g (10.4 mmole) of methyl-4-iodobenzoate dissolved in 20 ml of ether and cooled 15 to -40 0 C with a dry ice/isopropanol bath, and the whole was stirred for a further hour. 2.0 g (8.65 mmuole) of the 2-(dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent at -40°C and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.19 g of crude base (100% of theory) were obtained, from which 3.49 g of methyl-4-[2- (dimethylaminophenylmethyl)-l-hydroxycyclohexyl] benzoa e, hydrochloride (57.3% of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/ water in 2-butanone. The hydrochloride decomposes on heating above 140 0

C.

120 Example 72 1-benzyl-2- (dimethylaminophenylmethyl) -4-phenylcyclohexanol, hydrochloride 1 Stage 1- (4-phenylcyclohex-l-enyl)pyrrolidine 36.8 g (0.517 mole) of pyrrolidine dissolved in 170 ml of n-hexane were added dropwise to 30.0 g (0.172 mole) of 4-phenylcyclohexanone dissolved in 860 ml of n-hexane, and the solution was cooled to 0 0 C in an ice bath. 18.0 g (0.095 mole) of titanium tetrachloride dissolved in 140 ml of n-hexane were added dropwise within one hour at 0 0 C 10 0

C,

15 stirred for a further two hours at RT, following which the suspension was filtered. The filtrate was concentrated by evaporation on a rotary evaporator (500 to 10 mbar), and the remaining oil was purified by distillation at a pressure of less than 1 mbar; the main fraction boiled at 135 0 C. 22.2 of 20 crude product were obtained, which on account of incomplete conversion underwent, in the cold, the addition of 27.2 g (0.379 mole) of pyyrolidine dissolved in 125 ml of n-hexane and 13.1 g (0.069 mole) of titanium tetrachloride dissolved in 140 ml of n-hexane, and the mixture was then heated under reflux for two hours. 20.2 g of 1- (4-phenylcyclohex-1enyl)pyrrolidine (51.7% of theory) were obtained in this way.

2"' i Stage 2- (dimethylaminophenylmethyl) -4-phenylcyclohexanone 2.15 g (26.4 mmnole) of freshly dried dimethylamine hydrochloride were added while stirring to 58 ml (58 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to 0°C in an ice bath, following which 7.4 ml (52.8 mmole) of triethylamine and 7.3 ml (58.0 mmole) of chlorotrimethylsilane were added dropwise and the whole was stirred for a further 121 Shour at RT. 2.80 g (26.4 runole) of benzaldehyde were added while cooling with ice, and the reaction mixture was stirred for a further hour at RT. The reaction mixture was cooled again to 0°C with an ice bath, 6.00 g (26.4 nunole) of 1-(4phenyl-cyclohex-l-enyl)pyrrolidine from stage 1 were added, and the reaction mixture was stirred for a further two hours at RT. The reaction mixture was worked up by adding 40 ml of semi-concentrated hydrochloric acid while cooling with ice, stirred for 10 minutes, washed twice with 40 ml of ether each time, and adjusted to the alkaline range (pH ca. 9) with ev 100 ml of dilute ammonia solution (5 vol. The reaction mixture was extracted three times with 40 ml of ether each time, and the combined organic extracts were dried over sodium Ssulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 6.77 g of crude base (83.5% of theory) were obtained, from which 5.95 g of the hydrochloride of 2-(dimethylaminophenylmethyl)-4phenylcyclohexanone (65.5% of theory) were obtained according to the procedure described in Example 1 Stage) with 20 chlorotrimethylsilane/water in 2-butanone.

3'- 1 Stage l-benzyl-2- (dimethylaminophenylmethyl) -4-phenylcyclohexanol, hydrochloride The base was freed from 2.5g (7.27 mmole) of the hydrochloride of 2- (dimethylaminophenylmethyl) -4-phenylcyclo-hexanone obtained according to stage 2 with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to mbar). 2.00 g (6.51 mmole) of this base were dissolved in ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 3.9 ml (7.8 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at S RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.12 g of crude base (84.6% of theory) were obtained, from which 1.67 g of 1benzyl-2- (dimethylaminophenylmethyl) -4-phenylcyclohexanol, hydrochloride (60.7% of theory) with a melting point above 240 0 C was obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

15 Example 73 1- (4-bromophenyl) -2-dimethylaminophenylmethyl) cyclohexanol, hydrochloride 2.78 g (9.8 mmole) of 1-bromo-4-iodobenzene were dissolved in ml of ether and cooled in an ice bath (methanol/ice) to and 5.45 ml (10.1 unole) of isopropylmagnesium chloride (2 M solution of tetrahydrofuran) were added dropwise. After S' stirring for one hour at 0 C, 2.5 g (10.8 imnole) of the 2- (dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 30 ml of ether and added dropwise, and the whole stirred for 15 hours at RT. The reaction mixture was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 40 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 4.13 g of crude base (98.4% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 25 ml of water and 5 ml of ammonia solution (25 vol. extracted three times, with 25 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.07 g of crude base (54.4% of theory) was obtained, from which 2.01 g of 1-(4bromophenyl)-2-dimethylaminophenylmethyl) cyclohexanol, hydrochloride (43.8% of theory) were obtained according to the procedure described in Example 1 (3' Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 165 0

C.

Example 74 2-(dimethylaminophenylmethyl)-l-naphthalene-l-ylcyclohexanol, o* hydrochloride 0.824 g (3.24 mmole) of 1-iodonaphthalene were dissolved in 20 2 ml of ether, cooled to -10 0 C, and 1.62 ml (3.24 mmnole) of *o •isopropylmagnesium chloride (2 M solution in tetrahydro-furan) were added dropwise. After stirring for one hour at 0°C, 0.50 g (2.16 mmole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 and dissolved in 2 ml of ether were added dropwise, and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 2 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 5 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.00 g of crude base (129% of theory) was obtained, from which 0.23 g of 2-(dimethylaminophenylmethyl)-1-naphthalene-lylcyclohexanol, hydrochloride (17.9% of theory) having a melting point above 250 0 C was obtained according to the 124 O procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Example 2-(dimethylaminophenylmethyl) (2-methylsulfanylphenyl) cyclohexanol, hydrochloride 0.811 g (3.24 mmnole) of 2-methylmercaptoiodobenzene were dissolved in 2 ml of ether, cooled to -10 0 C, and 1.62 ml (3.24 nunole) of isopropylmagnesium chloride (2 M solution in tetrahydrofuran) were added dropwise. After stirring for one hour at oC, 0.50 g (2.16 mmole) of the 2-(dimethylamino- S 15 phenylmethyl)cyclohexanone prepared according to Example 1 and dissolved in 2 ml of ether was added dropwise, and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 2 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three eo 20 times at RT with 5 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.84 g of crude base (109?. of theory) was obtained, Sfrom which 0.483 g of 2-(dimethylaminophenyl-methyl)-1-(2methylsulfanylphenyl)cyclohexanol, hydrochloride (38.0 of theory) was obtained according to the procedure described in Example 1 3 Stage) with chlorotrimethylsilane/ water in 2-butanone. The hydrochloride decomposes on heating above 230 0

C.

Example 76 1-benzyl-2- (dimethylaminonaphthalene-2-ylmetlyl) cyclohexanol, hydrochloride S1 Stage 2- (dimethylaminonaphthalene-2-ylmethyl) cyclohexanone 19.3 g (237 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 520 ml (520 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to o C with an ice bath, following which 66 ml (474 mmole) of triethylamine and 66 ml (521 mmole) of chlorotrimethylsilane were added dropwise and the whole was stirred for a further hour at RT. 37.0 g (237 nmnole) of 2-naphthaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0 0 C with an ice bath, 38 ml (237 tnole) of 1-(pyrrolidino)-1cyclohexene were added, and the whole was stirred for two 15 hours at RT. The reaction mixture was worked up by adding 350 ml of semi-concentrated hydrochloric acid while cooling .with ice, stirred for 10 minutes, washed twice with 350 ml of ether each time, and adjusted to the alkaline range (pH ca. 9) with 890 ml of dilute ammonia solution. The reaction mixture 20 was extracted three times with 350 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 54.7 g of crude base (82.1% of theory) were obtained, from which 50.8 g of the hydrochloride of 2-(dimethylaminonaphthalene-2ylmethyl)cyclohexanone (67.5 of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Stage 1-benzyl-2- (dimethylaminonaphthalene-2-ylmethyl) cyclohexanol, hydrochloride The base was freed from 3.0 g (9.44 mmole) of the hydrochloride of 2-(dimethylaminonaphthalene-2-ylmethyl) cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.5 g (8.9 mmole) of this base were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 5.3 ml (10.7 imnole) of benzylmagnesium chloride (2 M solution in tetrahydro-furan), and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time.

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary 15 evaporator (500 to 10 mbar). 3.17 g of crude base (99.2" of theory) were obtained, from which 2.4 g of l-benzyl-2-(dimethylaminonaphthalene-2-yl-methyl)cyclohexanol, hydrochloride (68.1% of theory) were obtained according to the procedure described in Example 1 Stage) with 20 chlorotrimethylsilane/water in 2-butanone. The hydrochloride I* decomposes on heating above 180 0

C.

Example 77 l-benzyl-2- (dimethylaminopentafluorophenylmethyl) cyclohexanol, hydrochloride 1 Stage 2- (dimethylaminopentafluorophenylmethyl) cyclohexanone 10.4 g (128 rmmole) of freshly dried dimethylamine hydrochloride were added while stirring to 280 ml (280 inmole) of sodium iodide solution (1 M in acetonitrile) cooled to O°C with an ice bath, following which 35.5 ml (255 mmole) of triethylamine and 35.5 ml (280 nmole) of chlorotrimethyl- U silane were added dropwise and the whole was stirred for a further hour at RT. 25.0 g (128 nunole) of pentafluorobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0 C with an ice bath, 20.5 ml (128 mmole) of 1-(pyrrolidino)-1-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 190 ml of semiconcentrated hydrochloric acid while cooling with ice, stirred for 10 minutes, washed twice with 190 ml of ether each time, and adjusted to the alkaline range (pll ca. 9) with 480 ml of dilute ammonia solution (5 vol. T) The reaction mixture was extracted three times with 190 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, 15 filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 30.2 g of crude base (73.7% of theory) were obtained, from which 14.7 g of the hydrochloride of 2- (dimethylaminopentafluorophenylmethyl) cyclohexanone (32.3% of theory) were obtained according to the 20 procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone.

Stage 1-benzyl-2- (dimethylaminopentafluorophenylmethyl) cyclohexanol, hydrochloride The base was freed from 3.0 g (8.39 nunole) of the hydrochloride of 2- (dimethylaminopentafluorophenylmethyl) cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.5 g (7.8 mmole) of this base were dissolved in 12 ml of tetrahydrofuran, added dropwise to 4.7 ml (9.3 mmole) of benzylmagnesium chloride (2 M solution 128 S in tetrahydrofuran) while cooling in an ice bath, and then stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated armmonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.46 g of crude base (76.4% of theory) were obtained, from which 0.68 g of l-benzyl-2-(dimethylaminopentafluorophenylmethyl)cyclohexanol, hydrochloride of theory) was obtained according to the procedure described in Example 1 3 Stage). The hydrochloride decomposes on heating above 100 0

C.

S" Example 78 1-benzyl-2 (phenylpiperidin-1-ylmie thyl) cyclohexanol, hydrochloride 1 1- Stage 2- (phenylpiperidin-1-ylmethyl) cyclohexanone 10 g (47.7 munole) of l-benzylidenepiperidinium chloride were dissolved in 20 ml of dichloromethane and cooled to -70 0 C in a cooling bath (isopropanol/dry ice) 7.21 g (47.7 mmole) of 1-(pyrrolidino)-1-cyclohexene were added and stirred for a further 15 hours at RT. The reaction mixture was worked up by adding 70 ml of'semi-concentrated hydrochloric acid while cooling with ice, stirred for 10 minutes, washed twice with ml of ether each time, and adjusted to the alkaline range (pH ca. 9) with 180 ml of dilute aummonia solution (5 vol. The reaction mixture was extracted three times with 70 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating.

129 8.73 g of crude base (67.5% of theory) were obtained, from which 6.3 g of the hydrochloride of 2- (phenylpiperidin-1ylmethyl)cyclohexanone (42.9' of theory) were obtained according to the procedure described in Example 1 2 Stage) with chlorotrimethylsilane/water in 2-butanone.

Stage l-benzyl- 2 (phenylpiperidin-l-ylmethyl) cyclohexanol, hydrochloride The base was freed from 2.5 g (8.12 mmnole) of the hydrochloride of 2-(phenylpiperidin-1-ylmethyl)cyclohexanone obtained according to stage 1 with 25 ml of water and 5 ml of ammonia solution (25 vol. extracted three times with 30 ml 1 5 of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to mbar). 2.00 g (7.4 mmole) of this base were dissolved in 0 ml of tetrahydrofuran, added dropwise to 4.4 ml (8.8 mmole) 20 of benzylmagnesium chloride (2 M solution in tetrahydrofuran) while cooling in an ice bath, and stirred for 15 hours at RT.

The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator (500 to 10 mbar). 2.29 g of crude base (85.4% of theory) were obtained, from which 1.05 g of l-benzyl- 2 (phenylpiperidin-l-ylmethyl) cyclohexanol, hydrochloride (35.'7 of theory) was obtained according to the procedure described in Example 1 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 218 0

C.

130 O Example 79 4- tdimethylaminophenyllmethyl) (4-trifluoromethylphenyl) cyclohexanol, hydrochloride 0.76 g (31.0 mmole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 4.46 ml (31.0 imnole) of 4-bromobenzotrifluoride dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 6.0 g (26.0 mmole) of the 2-{dimethylaminophenylimethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and i 15 stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 50 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by 20 evaporation on a rotary evaporator (500 to 10 mbar). 8.49 g of crude base (86.7' of theory) were obtained, from which 6.62 g of 2-{dimethylaminophenylmethyl)-l.-(4- S. trifluoromethylphenyl)cyclohexanol, hydrochloride (61.7. of theory) were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 170 0

C.

Example 3- (4-tert.-butylbenzyl) [dimethylamino-2-methyl-lphenylpentan-3-ol, hydrochloride 0.33 g (13.7 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.50 g (13.7 mmole) of S4-tert.-butylbenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently.

After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.60 g (11.2 mnmole) of the l-{dimethylamino-2-methyl-l-phenylpentan-3-one prepared according to Example 59 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.93 g of crude base (93.8% of theory) were 15 obtained, which were added to a 3.5 x 30 cm column filled with silica gel. Elution with ethyl acetate/ hexane yielded ooo* 0.59 g of base, from which 0.26 g of 3- (4-tert.-butylbenzyl) -1-dimethylainino-2-methyl-l-phenylpentan-3-ol, hydrochloride 6% of theory) were obtained 20 according to the procedure described in Example 1 Stage) •The hydrochloride decomposes on heating above 91°C.

Example 81 2- (dimethylamino-o-tolylmethyl)-1 -phenylcyclohexanol, hydrochloride 2.50 g (9.3 mmole) of the 2- (diimethylainio-o-tolylmethyl) cyclohexanone prepared according to Example 66 were dissolved in 10 ml of tetrahydrofuran, added dropwise to 12.2 ml (12.2 mmole) of phenethylmagnesium chloride (1 M solution in tetrahydrofuran) while cooling in an ice bath, and stirred for hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of 132 W ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 Lo 10 imbar). 3.32 g of crude base (92.7% of theory) were obtained, from which 2-(dimethylamino-o-tolylmethyl) -1-phenylcyclohexanol, hydrochloride (52.9% of theory) with a melting point of 187" were obtained according to the procedure described in Example 1 Stage) with chlorotrimethylsilane/water in 2butanone.

Example 82 1- (4-tert. -butylbenzyl) [dime thylaminothiophen-2- S* 15 ylmethyl]cyclohexanol, hydrochloride 0.31 g (12.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.30 g (12.6 mmole) of 4-tert.-butylbenzyl bromide dissolved in 10 ml of ether were 20 added dropwise so that the reaction mixture boiled gently.

o* After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.5 Iuole) of tlie S' 2-(dimethylaminothiophen-2-ylmethyl)cyclohexanone prepared according to Example 70 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to mbar). 3.69 g of crude base (90.7% of theory) were obtained, from which 1.16 g of 1-(4-tert.-butylbenzyl)-2- [dimethylaminothiophen-2-ylmethyl] cyclo-hexanol, hydrochloride (26.2% of theory) were obtained according to the procedure described in Example 1 (3 1 Stage) with 133 chlorotriinethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 210'C.

0 .0 00*.

0000 00000

Claims

1. Substituted 3-aiino-3-ar-ylpropan--l-ols of the general formula I, R 3 OH A R 4 2N R N R 1 C C wherein R I RI denote, in each case iindepenidently of one an.othier, C 1 -r alkyl or R' and R, together denote a ring that may also be substituted by phenyl, denotes alkyl, cycloalkyl, aryl with optionally heteroatons in the ring system and the substituents R" to R" on the aryl ring, or a substituted Cj-, alkylphenyl of the formula XII, 6 n 1, 2 or 3 XI 1 4 5 R R denote, in each case independently of one another, CI-c alkyl, cycloalkyl, phenyl, benzyl, phenethyl or R and R" together form a (C'H 2 ring or CII,,CH 2 ,OC:11 2 CH. ring, denote;, in each case independently of one another, H, F, C1, Br, CHF:, CF,, OH, OCF-,, OR Ii, NR''RL", sR 11 phenyl, SO 2 SO. 2 Cl-- alkyl, CN, CQQR 1 R 1 to R' 135 W CONR"R' or R' and R together form a OCII 0, OCII CH O, CH=CHO, CH=C(CI-H)O or (CH ring, wherein R 1 denotes alkyl, phenyl, benzyl, phenethyl, and R, R 1 denote, in each case independently of one another, H, alkyl, phenyl, benzyl, phenethyl, and A denotes an aryl radical that may optionally contain 10 heteroatoms in the ring system and/or that may optionally be substituted, *and their diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids, whereas 1- benzyl-2- (dcimethylaminophenylmethyl) cyclohexanol, its diastereomers and its enantiomers in the form of their bases as well as its reaction product with methyliodide are disclaimed. 20 2. Compounds according to claim 1, characterised in that R' and R: together form a ring that may be substituted by phenyl, and R' to R' and A have the meanings according to claim 1.

3. Compounds according to claim 1, characterised in that R' and R- together form a ring that may be substituted by phenyl, and R' to R" and A have the meanings according to claim 1.

4. Compounds according to claim 1, characterised in that R denotes a substituted Ci-i-alkylphenyl of the formula XII, and R 1 R 2 R' to R" and A have the meanings according to claim 1. Compounds according to claim 1, characterised in that R' denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R' to R S on the aryl ring, 136 and R' to R' and A have the meanings according to claim 1.

6. Compounds according to claim 1, characterised in that A denotes a radical from the group of substituted phenyl of the formula XI R 1 1 R 10 R 12 see**: Be 0 oe *0 5 *S oo.0 XI, wherein R" to R'" OS*SS S 0 0 denote, in each case independently of one another, H, F, Cl, Br, I, CF,, OH, OR OCF, SR", SO.CH,, SO.:CF,, Ci--alkyl, phenyl, CN, COOR'', NO. or R' and R' or and together form a OCH 0 or OCH CII O ring, denotes Ci-. alkyl, phenyl, benzyl, phenethyl, R" or A denotes an unsubstituted or substituted thiophene or unsubstituted or substituted furan, and R' to R" have the meanings according to claim 1.

7. Compounds according to claim 1, characterised in that R' and R' together form a ring that may be substituted by phenyl, R' denotes a substituted Ci_, alkylphenyl of the formula XII, and R to R" and A have the meanings according to claim 1.

8. Compounds according to claim 1, characterised in that R' and R- together form a ring that may be substituted by phenyl, R' denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R' to R on the aryl ring, and R' to R' and A have the meanings according to claim 1.

9. Compounds according to claim 1, characterised in that R' and R 2 together form a i ring that may be substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstituted or substituted furan, R' denotes a substituted CI- alkylphenyl of the formula XII, and R' to R have the meanings according to claim 1. Compounds according to claim 1, characterised in that R' and R together form a (CIH). 1 ring that may be substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted 20 thiophene or unsubstituted or substituted furan, R 3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R to R" on the aryl ring, and R' to R have the meanings according to claim 1.

11. Compounds according to claim 1, characterised in that R' and R together form a ring, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene, R- denotes a substituted C3_, alkylpheny]. of the formula XII, and R' to R have the meanings according to the definition of claim 1.

12. Compounds according to claim 1, characterised in that R' and R 2 together form a ring, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene, R 3 denotes an aryl radical with optionally heteroatoms in the ring system and the 138 substituents R" to R' on the aryl ring, and R' to R: have the meanings according to the definitions of claim 1.

13. Compounds according to claim 1, characterised in that R' and R together form a ring, A denotes unsubstituted or substituted thiophene, R' denotes a substituted Cj-, alkylphenyl of the formula XII, and R' to R have the meanings according to the definitions of claim 1.

14. Compounds according to claim 1, characterised in that R and R" together form a (CIH.) ring, A denotes unsubstituted or substituted thiophene, R: denotes an aryl radical with optionally heteroatoims in the ring system and the substituents R" to R" on the aryl ring, and R' to R have the meanings 15 according to the definitions of claim 1.

15. Compounds according to claim 1, characterised in that R and R together form a ring, A denotes unsubstituted or substituted furan, R' denotes a substituted CI-, alkylphenyl of 20 the formula XII, and R' to R- have the meanings according to the definitions of claim 1.

16. Compounds according to claim 1, characterised in that R and R- together form a ring, A denotes unsubstituted or substituted furan, R' denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R to RP on the aryl ring, and R to R" have the meanings according to the definitions of claim 1.

17. Compounds according to claim 1: 2- (dimethylamiinophenylmne thyl) (3-methoxyphenyl) cyclohexanol and the corresponding hydrochloride 2- (dimethylaminophenylmethyl)-1-(3-fluorophenyl) cyclohexanol and the corresponding hydrochloride 139 2- (dilnethylamfiflophenlmfethyl) -1-phenylcyclohexaflol and the correspondingj hydrochloride 3- (dirnethiylauinophenylfe thyl) -l-hydroxycyclohexyl] phenol and the corresponding hydrochloride 2- (cimethylaiinophenylmethyl) -1-(4-inethoxypheflyl) cyclohexanol and the corresponding hydrochloride 1- (4-chiorophenyl) -2-(dimnethylanuifophenYlmfethYl) cyclohexanol and the corresponding hydrochloride (dimethylaninophenlmfe thyl) -1-(4-fluorophenyl) cyclohexanol and the corresponding hydrochloride (dirnethylaminophenylmfethYl) -1-p-tolylcyc.ohexanoI and the corresponding hydrochloride 1- (3-chiorophenyl) [dimethylainino- (3-methoxypheflyl) methyl] cyclohexanol and the corresponding hydrochloride 0:001- (4-dimethylaminophelyl) (dirnethylaminopheflylme thyl] cyclohexanol and the corresponding hydrochloride l-benzo[1i, 3] dioxol-4-y1- 2 -(dime thylaminophenylmnethyl) cyclohexanol and the corresponding hydrochloride 1- 4 -dime thioxyphenyl) (dime thylami nophienylme thyl) cyclohexariol and the corresponding hydrochloride 2- (dimethylaminophenyilfethyl) -1-(3-methoxybefizyl) cyclohexanol and the corresponding hydrochloride l-benzyl-2- (dimethylarninopheriyllfethyl) cyclohexaflol; hydrochloride 140 2- (diinethiylaiiinophen-yliuiethiy-) (4-f lioro-3- triflIuoroD- mte thyilphenyl-)cycloliexaniol a-nd the corresponding hydrochloride 2- (dimie thylaininioplienylm-ethyl) -1-(4-trifluoromethoxy- benzyI) cyclohexanol and the corresponding hydrochloride 2 -(dime thyl aminophenylmte thy 1) -1 furan- 3- ylcycilohexa no I and the corresponding h-ydrochloride I1-butyi-2 -(dime thyl aminrophenylmnethyl) cyclohexanol anid the corresponding hydrochlo ride 15 1- 4-dichiorophenyl) (cdime Lhylaininophenyimethyl) cyclohexanol and the corresponding hydrochloride M+ 4-dichiorophenyl) (dlime thyl ami nophenyl methyl) cyclohexanol and the corresponding hydrochloride 4-cli.chloroplienyi) (dimethylaminopheny- methyl) cyclohexanol and the corresponding hydroch!Lor-Ide 4- (diinethiylaiinioplheryline thyl) -1-hydroxycycioliexyl]1 phenol and the corresponding hydrochloride 2- (diiinetlhylainiophieny-iiuethiyl) 1 -naphthalene- 2 ylcyclohexanol I and the corresponding hiydrochloridle 2- dime tlyl amino- tri.fluoromethiyihenyl iethyl] (13- methoxybenzyl) cycloliexaiiol ind the corresponding hydrochloride 1- (4-chlorobenzyl) (di-methylamin-oph-eniyljinethyl) -1- cyclohexanol and the corresponding hydrochloride 2- (dime thyl aminophenyliethyl1) (2-fluorobenzyi) cyclohexanol and the corresponding hydlrochilor-ide 2- (diimethiylamninophienylae tiyl1) -i1- (4-f Iluorobeiizyl) cyclohexanol anid the corresponding hydrochloride 1- 5-diiinethoxypheiiyl) (dimte thylaininophenylme thyl1) cyclohexanol and the corresponding hydrochloride 1- (2-chloro-4--fluorobenzyl) (dime th ylami nophenyl methyl) cyclohexanol and the corresponding hydrochloride 1- (4-tert.-butylbenzylI) (dime thylaininophenylitiethyl) cyciohexanol anid the corresponding hydrochloride 2(dimie thiyLaiuiinophienylimethyl) -I (3-f luorobenzyl) cyclohexanol and. the corresponding hydrochloride 1- (2-chlorobenzyl) (dimiethiylaininophenylinethyl) cyclohexanol and. the corresponding hydrochloride 1-Ibenzo 1, 3]dioxo I-5-y.L- [dime thylamino(3 imetlhoxyph-eniyl) meth-yl] cycioh-exaliol and the corresponding hydrochloride 1- (3-chlorobenzyl) (diiethylarntinophenylmiethiyl) cyclohexanol and the corresponding hydrochloride 1- 4-dichlorobenzyl) (clirethylaininophenyitie thyl) cyclohexanol and the corresponding hydrochloride l-benzyl-2- Idimethiylaminophenyl- (3-phenoxyphenyl) methyllcyclohexanol arid the corresponding hydrochloride l-benzyl-2- (dime thyl aminophenyl -(3-r-nethioxyphenyl) methyl] cyclohexanol and the corresponding hydrochloride 14 2 2 (dimne th ylamninoph e nyle thIyi 1 1- r iflIuo roie LIiyl benzyl) cyciohexanol arid the corresponding hydrochiloride 2 (dimne th yIari no 3-menethoxyph enyl1) me thIiyl] -1I- (3 inethoxybenzyl) cyciohexanol and the corresponding hydrochloride 2- (2-chiorophenyl) diruethylaminonetihyl -1-naphthaiene-2- ylcyclohexanoi and the corresponding hydrochloride 1 -benzyl-2 4 -dichiorophienyl) dime thylaminomeethyl] cyclohexanol anid the corresponding hydrochloride .is1 2- 4-dichiorophenyl) (dimethylaminomethyl] -1.-phenethyl cyclohexanol and the corresponding hydrochloride 1 -b enz y 1- 2 dimeth yamin o (4 fuoro ph en yI )le L Iiy1 cyclohexanol and the corresponding hydrochloride 2- (3-chiorophenyl) (dimethylaininornethyl] -1-ph-enlyl cyclohexanol anid the cor responding hyclroclbride *a1- 4-dichiorophienyl) (3-'-di-mueth-ylainin-omiethyl) -1- cyclohexanol anid the corresponding hydrochloride 1-benzyl-2- (3-chiorophenyl) diiuethylaminotriethyi I cyclohexanol and the corresponding hydrochloride 1-benzyl-2- (2-chlorophenyi)cliiethylaminoluethyl] cyclohexanol and the corresponding hydrochloride 1- tert. -butylbenzyl) 4 -cichiorophenyl) dime thylainiinornethyl) cycloh-exan-ol and the corresponding hydrochloride 1413

42- [dimnethylamino- (4-fluorophenyl) mnethyI]l] (3- tri fluoromethylbenzyl) cyclohexanol and the correspondincg hydrochloride 2- (diiinethylaintoph-eniylinethyl) bicyclohexyl-I--ol and the corresponding hydrochloride 2- (dime thyl aminophenyline thyl) (4-me thoxybenzyl) cyclohexanol and the corresponding hydrochloride 4-di fluorobenzyi) (climethiylaminophien-yine thyl-) cyclohexanol and the corresponding hydrochloride 1- (4-tert.-butyibenzyl) (3-chilorophenyl) djimehyl- 15 aminomethyl] cyclohexanol and the corresponding hydrochloride 2- [diimiethylainino- (3-plienoxyphenyl )methyl] -1-phenethyl- cyclohexanol and t1he corresponding hydrochloride 29. [dli me th yl1ain irno 3 -ph en o xyphe nylI mnet hyl -1I- tnri- fluoromuethylbenizy-) cyciohlexanol- and the coruresponding hydrochloride 1- 5-difiuorobenzyl) (dlime thylamninophenyimethyl.) cyclohexanol and the corr-espondinig hydrochloride 1- 4-dif luorobenzyl) (dlim~e thylainiophienyiine tliyi) cyclohexanol and the corresponding hydrochloride 1- (2-chloro-6-fluorobenzyl)-2- (dimethylamino- phienylmethyl) cyclohexanol and the corresponding hydrochloride 1- 3-clifluorobenizyl) (diruethylaminophenyimethyl) cyclohexanol and the corresponding hydrochloride 1 /1 4 1-benzyl-2- (4-chiorophenyl) climie thylaminometLhyl]I cyclohexanol and the corresponding hiydrochloride -dimnethylaiiiio-3-ethyl-2 methiyl-i, 5-dliplienylpentane-3-ol and the corresponding hydrochlo ride 1- (2-chlorobenzyl) (2-ciocrophenyl) -diinethyl- aminomnethyl] cyclohexanol and thie corresponding hydrochloride 1-benzyl-2- (4-broinophienyl) climethylaminoinethyl]I cyclohexanol and the corresponding hydrochloride 15 2- (4-chiorophenyl) dime thylaminioretiyl]I (4-trifluoro- inethyiphenyl) cyclohiexanol and the correspondingq hydrochloride 2 (4 c hio rop he nyl1) d i we thIiylaini no nethIiy] 11- (3 -t r iflIuo ro me thylbenzyl) cyclohexanol and the corresponding hiydr o c hl0ride (4-tert. -butylberizyl) [dimethylamiino- (3-phenoxy- *phen-yl) methyl Icyclohexanol-) arid the corresponding hydrochloride 4 t dime thylamtino- [i 2-hydroxy- 2- (4 -tri fluoroutetLhyl- phenyl) cyclohiexyl] methyl beu-zoni tryl and the corresponding hydrochloridle 2- (dimnethylamnino-o-tolylmethyl) -phienylcyclohiexanol and the corresponding hydrochloride 1-benzyl-2-(dimethylamino-o-tolyl-methiyl)cyclohexaniol and the corresponding hydrochloride 145 2- (cdime thylaiinophienylitie L hyl) (3-pheiiyipropyl) cyclohexanol and the corresponding hydrochloride 2- (2-chlorophienyl) diuethylaminoitiethyl] (4-fluoro- phenyl) ethyl] cyclohexanol and the corresponding hydrochloride 2- [dimethylaininothiioph-eni-2-ylinethiyl] -1-(3-trifluoro- inethylbenzyl) cyclohexanol. and the corresponding hydrochloride .Methyl-4- (dimethI-ylarini-oph-en-ylmiethiyl) -1-hydroxycyclo- hexyl 3benzoate and the correspondinig hydrochloride **is 1 1-benzyl-2- (dime thyl aminophenylme thyl) -4-phenylcyclo- hexanol and the co rres pondcing hydrochloride -bromophenyl) 2- (climie thyl aiinophenylme th yl) cyc lo- hexanol and the corresponding hydrochloride 2 (diimethiylaiinoplhenyl-niethyl) -i-naphthalene-i-ylcyclo- hexanol and the corresponding hydrochloride (rietlmcs,1,noph~ni,1nn-1t l(2-ine cnyisulfaianylpnen~yl cyclohexanol and the corresponding hydrochloride i-benzyl-2- (dimtetliylarainoniaphtlhaiene-2-ylimeth-yl) cyclohexanol and the corresponding hydrochloride 1-benzyl-2- (dime thylatinonapenta.f luorophenylute hyl) cyclohexanol and the corresponding hydrochloride 1-benzyl--2-(phien-ylpipericini- -ylinethyl) cyclohexanol and the corresponding hydrochloride 146 2- (dimethylaminophenylmethyl) (4-trifluoromethyl- phenyl)cyclohexanol and the corresponding hydrochloride 3- (4-tert.-butylbenzyl) -l-dimethylamino-2-methyl-l- phenylpentan-3-ol and the corresponding hydrochloride 2-(dimethylamino-o-tolylmethyl) -1-phenethylcyclohexanol and the corresponding hydrochloride 1- (4-tert.-butylbenzyl) [dimethylaminothiophen- 2 ylmethyl]cyclohexanol and the corresponding hydrochloride e* 18. Medicinal drug containing as active agent at least one compound according to claims 1 to 17 including the disclaimed 15 compounds according to claim 1. 19. Medicinal drug containing as active agent a mixture of the enantiomers of a compound according to claims 1 to 17 including the disclaimed compounds according to claim 1, the '20 two enantiomers not being present in equimolar amounts, and optionally further active agents. 20. Medicinal drug according to claim 19, characterized in that one of the enantiomers is being present in an amount of between 5 and 45 wt. relative to the enantiomer mixture. 21. Process for preparing a compound according to claims 1 to 17, characterised in that a Mannich base of the general formula II O A R4 R R R R S S 147 wherein R' to R' and A have the meanings according to the general formula I, is reacted with an organometallic compound R 3 Y, wherein Y denotes MgCl, MgBr, Mgl or Li and R 3 is according to formula I, to form an alcohol of the general formula I R 3 OH A R l R 4 R R wherein R' to R and A have the meanings according to formula I. 22. A substituted 3 -amino-3-arylpropan-l-ol of the general formula I substantially as hereinbefore described with reference to any one of the Examples. 23. A compound according to any one of claims 1 to 17 when prepared by the I, process of claim 21. 24. Use of at least one compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim I for preparing a medicinal drug to relieve pain. Use according to claim 24 for preparing a medicinal drug to relieve neuropathic pain. 26. Use according to claim 24 for preparing a medicinal drug to relieve chronic pain. 27. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug 20 having a local anaesthetic effect. 28. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug having an anti-arrhythmic action. 29. Use of at least one compound according to any one of claims I to 17, 22 or 23 _s including the disclaimed compounds according to claim 1 for preparing a medicinal drug having an anti-emetic action. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim I for preparing a medicinal drug having a nootropic (neurotropic) action. o' 31. Use of at least one compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim I for preparing a medicinal drug for treating cardiovascular conditions. 00.06 0: 0 a 5 a S IR \I.IVV]O2157.docnic 148 32. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for treating urinary incontinence. 33. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for trcating diarrhoea. 34. Use of at least one compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for treating pruritis. 11 35. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for treating alcohol dependence. 36. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for Is treating narcotics dependence. S* 37. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for treating drug dependence. 38. Use of at least one compound according to any one of claims I to 17, 22 or 23 2 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for o* treating inflammations. 39. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim I for preparing a medicinal drug for treating depression. 40. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for improving libido. 41. Use of at least one compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1 for preparing a medicinal drug for improving alertness and attentiveness. 42. A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used in the treatment of pain.

43. A compound according to claim 42 wherein said pain is neuropathic pain or chronic pain. IR \1.11VV]02157 doc nic 149 44 A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used as a local anaesthetic. A compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used as an anti-arrhythmic.

46. A compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used as an anti-emetic. 1 47. A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to 20 having a nootropic (neurotropic) action.

48. A compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to i 2\0. when used in the treatment of cardiovascular conditions.

49. A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to 20. when used in the treatment of urinary incontinence. A compound according to any one of claims 1 to 17, 22 or 23 including the 1 0 disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to 20, when used in the treatment of diarrhoea.

51. A compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used in the treatment of pruritis.

52. A compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used in the treatment of alcohol dependence.

53. A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim I, or a drug according to any one of claims 18 to S 20. when used in the treatment of narcotics dependence.

54. A compound according to any one of claims I to 17. 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used in the treatment of drug dependence. (R \l.BVV|02157 doc:nic 150 A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used in the treatment of inflammations.

56. A compound according to any one of claims I to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used in the treatment of depression.

57. A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to when used for improving libido. i 58. A compound according to any one of claims 1 to 17, 22 or 23 including the disclaimed compounds according to claim 1, or a drug according to any one of claims 18 to 20. when used for improving alertness and attentiveness.

59. A method of treating pain comprising the administration of an effective amount ol a compound according to any one of claims 1 to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof. The method of claim 59 wherein said pain is neuropathic pain or chronic pain.

61. A method of treating arrhythmia comprising the administration of an effective amount of a compound according to any one of claims 1 to 17, 22 or 23, including the 2 disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

62. A method of providing an anti-emetic comprising the administration of an effective amount of a compound according to any one of claims 1 to 17, 22 or 23, including o the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

63. A method of providing a neutropic comprising the administration of an effective amount of a compound according to any one of claims I to 17. 22 or 23. including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

64. A method of treating cardiovascular conditions comprising the administration of an effective amount of a compound according to any one of claims 1 to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof. A method of treating urinary incontinence comprising the administration of an effective amount of a compound according to any one of claims 1 to 17. 22 or 23, including (K \I.IIVV 102157 doc.nic 151 the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

66. A method of treating diarrhoea comprising the administration of an effective amount of a compound according to any one of claims I to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

67. A method of treating pruritis comprising the administration of an effective amount of a compound according to any one of claims I to 17, 22 or 23. including the disclaimed compounds according to claim 1, or an effective amount of a drug according to i any one of claims 18 to 20 to a patient in need thereof.

68. A method of treating alcohol dependence comprising the administration of an effective amount of a compound according to any one of claims 1 to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

69. A method of treating narcotics dependence comprising the administration of an c efective amount of a compound according to any one of claims 1 to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof. A method of treating drug dependence comprising the administration of an 2 effective amount of a compound according to any one of claims 1 to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof. *fee:

71. A method of treating inflammation comprising the administration of an effective 4 amount of a compound according to any one of claims I to 17, 22 or 23, including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

72. A method of treating depression comprising the administration of an effective amount of a compound according to any one of claims I to 17, 22 or 23. including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof.

73. A method of improving libido comprising the administration of an effective amount of a compound according to any one of claims 1 to 17, 22 or 23. including the disclaimed compounds according to claim 1, or an effective amount of a drug according to any one of claims 18 to 20 to a patient in need thereof. I K \I.I VVjI)21 7 dc.nijc 152

74. A mnethod of improving alertness and attentiveness comprising the administration of an effective amount of a compound according to any one of claims 1 to 1 7. 22 or 23, 1Ciluding the disclaimed compounds according to claim 1, or an effective Zamo01int ol'a druLg according to any one of'claimns 18 to 20 to a patient in need thiereof. Dated 31 March, 2000 Grunenthal GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 00 0 1k \1-1IIVV102157 1 c