HK1031722B - 3-amino-3-arylpropan-1-ol-derivates, their preparation and use - Google Patents

Description

The invention relates to 3-amino-3-arylpropan-1-ol derivatives of the general formula I, In which R1, R2, independently of each other, C1-6 alkyl or R1 and R2 together form a (CH2) 2-6 ring, which may also be benzo-condensed or phenyl substituteR3H, methylR4, R5, independently of each other, C1-6 alkyl, C3-C6-cycloalkyl, phenyl, benzyl, phenethyl or R4 and R5 together form a (CH2) 3-6 or CH2CH2OCH2CH2 ringA residue from the substituted phenyl group of formula XIII or is a single or multiple substitution of R6 to R10 with a furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, quinoline, isokinoline, phtalazinyl or chinazolinyl residue, wherein R6 to R10, independently of each other,H,F,Cl,Br,I,CF3,OH,OR11,OCF3,SR11,SO2CH3,SO2CF3,C1-6-alkyl,phenyl,CN,COOR11,NO2 or R6 and R7 or R7 and R8 together forming an OCH2O or OCH2CH2O ring,X a substituted benzyl of formula XI or a substituted benzoyl of formula XII where R12 to R14 are each independently H, F, Cl, Br, CHF2, CF3, OR11, SR11, OCF3, SO2CH3, SO2CF3, C1-6-alkyl, phenyl, CN, COOR11, NO2 withR11H, C1-6-alkyl, phenyl, benzyl, phenethyl, and their diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids, and their manufacture and use as medicinal products.

The treatment of chronic and non-chronic pain conditions is of great importance in medicine, as pain is one of the basic symptoms in the clinic. At present, there is a worldwide need for additional, not exclusively opioid, but well-effective pain therapy. The urgent need for action for patient-centred and targeted treatment of chronic and non-chronic pain conditions, including successful and satisfactory pain treatment for the patient, is documented in the large number of scientific papers that have recently appeared in the field of applied analytics or basic research Nociception.

Traditional opioids such as morphine are effective in the treatment of moderate to severe pain, but their use is limited by known side effects such as respiratory depression, vomiting, sedation, constipation, addiction, dependence and development of tolerance. They can therefore only be given under special precautions such as specific prescriptions over a longer period or at higher doses (Goodman, Gilgamman, The Pharmacological Basis of Therapeutics, Peron Press, New York 1990).

3-Amino-3-arylpropan-1-ol derivatives have already been described in the literature:

US 4 143 158 describes (1)-α-dimethylamino-α- ((cis-2-benzyloxycyclohexyl) -m-cresol as an inhibitor of prolactin release.

US 3 975 436 describes α-dimethylamino-α- ((cis-2-benzyloxycyclohexyl) -m-cresol for the antagonism of the pharmacological effects of narcotic drugs.

US 3 937 818 describes the compounds α-dimethylamino-α- ((cis-2-benzyloxycyclohexyl) -m-cresol and α-dimethylamino-α- ((cis-2-ethoxycyclohexyl) -m-cresol for antagonising the effects of a drug.

The purpose of the invention was to identify a new structural class of analgesic agents suitable for the treatment of pain, and to identify active substances also suitable for use as local anaesthetic and/or antiarrhythmic and/or antiemetic and/or nootropic (neurotropic) agents and/or for the treatment of: cardiovascular disease and/or urinary incontinence and/or diarrhoea and/or pruritus and/or inflammation.

The compounds of the generic formula I class have been found to have a marked analgesic effect. Furthermore, the compounds of the generic formula I class show a strong affinity for sodium channel binding site 2 (BTX binding) and benzothiazepine site of the L-type calcium channel (dilithiase binding). This makes the compound of the generic formula I class also suitable for use as a local anaesthetic and/or antiarrhythmic and/or antiemetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular disease and/or urinary disorders and/or diarrhoea and/or pruritus and/or inflammation.

The invention therefore concerns 3-amino-3-arylpropan-1-ol derivatives of the general formula I and their diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids.

Compounds of general formula I, in which R1 and R2 together form a (CH2) 2-6 ring, which may also be benzo-condensed or phenyl-substituted, are preferred, R3 to R5, A and X having the meanings as defined in general formula I, or Compounds of general formula I, in which R1 and R2 together form a (CH2) 4 ring, which may also be benzo-condensed or phenyl-substituted, R3 to R5, A and X having the meanings defined in general formula I, or Compounds of general formula I in which R3 is a residue of the hydrogen or methyl group, R1, R2, R4 to R5, A and X having the meanings as defined in general formula I; or Compounds of general formula Iin which A is a residue of the substituted phenyl group of formula XIII wherein R6 to R10, independently of each other, H, F, Cl, Br, I, CF3, OH, OR11, OCF3, SR11, SO2CH3, SO2CF3, C1-6 alkyl, phenyl, CN, COOR11, NO2 or R6 and R7 or R7 and R8 together form an OCH2O or OCH2CH2O ring,R11C1-6 means alkyl, phenyl, benzyl, phenethyl or thiophen or furan and R1 to R5 and X have the meaning as defined in the general formula I; or Compounds of general formula I, in which R1 and R2 together form a (CH2) 2-6 ring, which may also be benzo-condensed or phenyl-substituted, R3 being a residue from the hydrogen or methyl group,R4 to R5, A and X have the meanings as defined in the general formula I; or Compounds of general formula I, where R1 and R2 together form a (CH2) 4 ring, which may also be benzo-condensed or phenyl substitute, A a residue from the substituted phenyl group of formula XIII or thiophen or furan, R3 a residue from the hydrogen or methyl group, R4 to R5 and X having the meaning as defined in general formula I, or Compounds of general formula I, where R1 and R2 together form a (CH2) 4 ring, A a residue from the substituted phenyl group of formula XIII or thiophen or furan,R3 is a residue from the hydrogen or methyl group, R4 to R5 and X have the meanings as defined in the general formula I, or Compounds of general formula I, where R1 and R2 together form a (CH2) 4 ring, A thiophen, R3 a residue of the hydrogen or methyl group, R4 to R5 and X have the meanings as defined in general formula I, or Compounds of general formula I, where R1 and R2 together form a (CH2) 4 ring, A furan, R3 a residue from the hydrogen or methyl group, R4 to R5 and X have the meanings as defined in general formula I, or Compounds of general formula Iwhere X is a residue from the group of substituted benzyl of formula XI or substituted benzoyl of formula XII, R1 to R5 and A have the meanings given in claim 1.

Other preferred compounds include: Dimethyl-{[2-(2-methylbenzyloxy) cyclohexyl]phenylmethyl}amine and the corresponding hydrochloride[2-(dimethylbenzyloxy) cyclohexyl]-4-trifluoromethylbenzoate and the corresponding hydrochloride[2-(dimethylbenzyloxy) cyclohexyl]-4-methoxybenzoate and the corresponding hydrochloride{[2-(dimethylbenzyloxy) cyclohexyl]-dimethylphenyl) and the corresponding hydrochloride{2-dimethylbenzyloxy) cyclohexyl-methylphenyl]-{2-dimethylbenzyloxy) 4-methylbenzyloxy-methylbenzoate and the corresponding hydrochloride{2-dimethylbenzyloxy) 4-methylbenzyloxy dimethylphenyl dimethyl and the corresponding hydrochloride{2-dimethylbenzyloxy) dimethylphenylphenyl dimethyl and the corresponding hydrochloride{4-dimethylbenzyloxyfenzyloxy) dimethylphenylphenyl dimethyl) and the corresponding hydrochloride{2-dimethylbenzyloxyfenylphenylphenylphenylphenylphenylphenyl dimethyl) dimethyl and the corresponding hydrochloride{4-dimethylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenyl) dimethyl

In a particular embodiment of the invention, the enantiomers of a compound of the invention are used in a non-equimolar ratio, preferably between 5 and 45% by weight of one enantiomer in the enantiomeric mixture, as an active substance in a medicinal product which may contain additional active substances.

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

The present invention also relates to the production of compounds of general formula I. For the production of compounds of formula I, the Mannich bases of formula II are incorporated into a suitable nucleophile, such as a metal-organic compound (H3C) Y where Y means, for example, MgCl, MgBr, MgI or Li, or into a reducing agent such as sodium borohydride, sodium cyanoborohydride, lithium aluminium borohydride, diisobutylaluminium aluminium borohydride or a complex analogue of these compounds at temperatures between -70 °C and +110 °C. Ethers or esters of general formula I can be obtained from alkaloids by the corresponding standard methods by incorporation of alkaloids with the corresponding benzoyl benzoyl in the presence of organic compounds or organic esters. Other

The transformation of a Mannich base of formula II with a Grignard compound MeY, where Y stands for MgCl, MgBr or MgI, or with a lithium organic compound MeLi can be carried out in an aliphatic ether, such as diethyl ether and/or tetrahydrofuran, a hydrocarbon, such as hexane or toluene, or a mixture of hydrocarbons and aliphatic ethers, at temperatures between -70 °C and +110 °C. Lithium organic compounds MeLi can be obtained from organohalogen compounds MeZ, where Z stands for Cl, Br or I, by transformation with, for example, an n-lithium butyl/hexane solution by halogen exchange.

When a Mannich base of formula II is implemented with a metal-organic compound MeY, tertiary alcohols with the relative configuration of formula Ia, in which the aminoaryl methyl group cis is arranged to the hydroxyl group when R1 and R2 form a ring system, are obtained, depending on the reaction conditions, in preference. In open chain systems, the analogue relative stereochemistry is obtained, which is to be specified as anti. Compounds of formula Ia can be obtained by column chromatographic separation or by crystallization, including their salts, e.g. the hydrochloride, diastereomers. Other

The conversion of a Mannich base of formula II with a reducing agent may be carried out in alcohols, water, ether, hydrocarbon, halogen or mixtures of these solvents at temperatures between -70 °C and + 110 °C. The reaction conditions may be chosen to obtain either preference or exclusivity for one of the two possible stereoisomers Ib and Ic. Other

The Mannich bases of formula II can be obtained by conversion of enamines of formula III with an imminium salt of formula IV, where Y stands for e.g. Cl, AlCl4, Br or I-.

The enamines are produced by known methods from ketones of formula V and secondary amines, e.g. dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53). Other

The formula IV imminium salts do not need to be isolated, but can be produced in situ and converted with formula III enamines to Mannich bases of formula II (Angew Chem. 106 (1994) 2531-2533).

However, mannich bases of formula II can also be produced directly by conversion of enamines of formula III with an aromatic aldehyde of formula VIII and a secondary amine HNR4R5, also in the form of the corresponding hydrochloride HNR4R5, HCl, in the presence of triethylamine, chlorotrimethylsilan and sodium iodide (Synlett (1997) 974-976). Other

The Mannich bases of formula II are obtained by the above methods, depending on the reaction conditions, preferably with the relative configuration of formula IIa, in which the amino group anti is arranged in R1. Other

On the other hand, the representation of Mannich bases of formula II is less stereoselective by the 1,4-addition of secondary amines HNR4R5 to enones of formula IX, obtained from the aldol condensation of ketones of formula V with aromatic aldehydes of formula VIII (US Patent 4,017,637). Other

The value of the residues R1 to R5 and A respectively shall be the value given in formula I.

If chiral amines are used to represent enamines of formula III or imines of formula VII, the enantiomer-enriched to enantiomer-pure Mannich bases of formula II can be obtained in the subsequent Mannich reaction (Houben-Weyl - Methods of Organic Chemistry, E21b (1995) 1925-1929).

For example, 3-amino-3-arylpropan-1-ol derivatives of the general formula I substituted with a phenol can be prepared from the corresponding methyl ether derivatives with diisobutylaluminium hydride in an aromatic hydrocarbon, e.g. toluene, at a temperature between 60 and 130 °C (Synthesis (1975) 617-630).

The compounds of formula I can be known to be transferred to their salts by means of physiologically compatible acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, amber acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Preferably, the salination is carried out in a solvent such as diethyl, diisopropyl, acetic acid ester, acetone and/or 2-butanone.

The substances corresponding to formula I are toxicologically harmless and therefore suitable as pharmaceutical active ingredients in medicinal products. A further object of the present invention is therefore medicinal products containing at least one compound of general formula I as an active ingredient.

Biochemical studies have shown that the substances of the invention, in addition to their analgesic action, show a marked affinity for sodium channel binding site 2 (BTX binding) and benzothiazepine site of L-type calcium channel (Dilthiazem binding) and are therefore suitable for use as a local anaesthetic and/or antiarrhythmic and/or antiemetic and/or nootropic (neurotropic) and/or treatment/therapy of cardiovascular diseases and/or urethritis and/or diarrhoea and/or urethritis and/or inflammation.

The pharmaceutical formulations contain, in addition to at least one 3-amino-3-arylpropan-1-ol derivative of formula I, carrier materials, fillers, solvents, diluents, colours and/or binders. The choice of the excipients and the amounts to be used depend on whether the medicinal product is to be applied orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example to infections of the skin, mucous membranes and eyes. For oral application, preparations suitable for oral application are tablets, forms, capsules, granules, esters, syrups, syrups, syrups, syrup, syrup to be used in the form of oral solutions and, if necessary, in powdered or powdered form. The preparations may be used in a percutaneous form, or in a powdered form, or in a powdered form, or in a powdered form, or in a powdered form.

The dose to be administered to the patient will vary depending on the patient' s weight, type of application, indication and severity of the disease, and usually at least 0.5 to 500 mg/ kg of a 3-amino-3-arylpropan-1-ol derivative of formula I.

Pharmaceutical studies Analgesia test in the mouse writhing test

The analgesic efficacy study was performed in the mouse with phenylquinone-induced writhing (modified from I.C. Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240), using male NMRI mice weighing 25 to 30 g. Groups of 10 animals were given 0.3 ml/ mouse of a 0.02% aqueous solution of phenylquinone (Phenylbenzoquinone, Fa. Sigma, Deisenhofen; preparation of the solution with 5% ethanol and sublimation in water up to 45°C) 10 minutes after intravenous administration of the test substances. All animals were administered individually in an intra-abdominal application. A standard dose of co-extrusion was calculated at a rate of 0.3% per dose. The mean dose of phenylbenzoquinone (Phenylbenzoquinone, Fa. Sigma, Deisenhofen; preparation of the solution with 5% ethanol and sublimation in water up to 45°C) was obtained by measuring the following dose (in the case of animals with a control dose of 20 mg/kg) per dose. The mean dose of the test substance was calculated by measuring the number of animals (in the case of animals with a control dose of 20 mg/kg) of the substance (in the controlled substance) after administration of the test: $\text{\% Hemmung = 100 -}\frac{\text{Writhingreaktionen der behandelten Tiere}}{\text{Writhingreaktionen der Kontrolltiere}}\text{* 100}$

For some substances, the dose-dependent decrease in Writhing responses compared to parallel phenylquinone controls was used to calculate ED50 values with a 95% confidence interval for Writhing responses by regression analysis (evaluation programme Martens EDV Service, Eckental).

All the compounds tested showed a marked analgesic effect. The results are summarized in Table 1. Other Tabelle 1:

Analgesieprüfung im Writhing-Test an der Maus
Beispiel	%Hemmung der Writhingreaktion bei 10 mg/kg intravenös
1	85
2	48
3	43
4	32
5	74
6	68

The following are the main components of the test: Binding tests at the L-calcium channel: benzodiazepine binding site (dilithiase binding)

The biological membrane material was isolated from the rat cerebral cortex. [3H]-cis-(+) diltiazem (5 nM in the approach) was used as the ligand. Incubation for 20 minutes at 25 °C. Non-specific binding is defined as radioactivity measured in the presence of (±) diltiazem (10-6 M in the approach). The unbound portion of the radioactive ligand is separated after the end of incubation by a filtration process via Whatman fibres GF/B membranes. The membranes are then measured at the bottom of the β-process. The method is based on the publication of the Long Washer (H.S.N.S.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.S.N.E.N.S.N.E.S.N.E.N.S.N.E.N.S.N.S.N.E.N.S.N.S.N.N.S.N.N.S.N.S.N.N.S.N.N.S.N.S.N.N.S.N.N.S.N.N.S.N.S.N.N.S.N.N.S.N.N.S.N.S.N.N.S.N.N.S.N.N.S.N.N.S.N.N.S.N.N.N.S.N.N.S.N.N.N.S.N.N.S.N.N.S.N.N.S.N.N.S.N.N.N.N.S.N.N.N.S.N.N.S.N.N.S.N.N.S.N.N.N.S.N.N.N.S.N.N.N.S.N.N.S.N.N.N.N.N.S.N.N.

Binding tests at sodium channel: Binding point 2 (BTX binding)

The binding site 2 of the sodium channel is the so-called batrachotoxin-BTX binding site. The ligand was [3H]-batrachotoxin A20 α-benzoate (10 nM in the approach) These ion channel particles (synaptosomes) were enriched from the rat cerebral cortex by Gray and Whittaker (E.G. Gray and V.P. Whittaker (1962) J. Anat. 76, 79-88). As nonspecific binding is defined the radioactivity measured in the presence of veratridine (0.3 mM in the approach). Incubation at 37°C for 120 min. Assay conditions were performed after publication by Leuwels, Leuwels and Laduron (J. Pauwels, J. Pauwels, J. P.E. Pauron, J.M. 121-294, 1988) and Eurcol.

The KD value for this binding site is 24,63 ± 1,56 nM (N = 3, i.e. mean ± SEM values from 3 independent series of trials conducted in triple parallel).

The Commission has

Err1:Expecting ',' delimiter: line 1 column 235 (char 234)

The results of the biochemical tests are summarised in Table 2. Other Tabelle 2

Biochemie
Beispiel	Diltiazem-Bindung bei 10 µM	BTX-Bindung bei 10 µM
	82	99
		98
	65	89
	73	92
	89	98
	86	97

Examples

The following examples are intended to illustrate the process of the invention.

The yields of the compounds produced are not optimized.

All temperatures are uncorrected.

The term ether means diethyl ether.

The stationary phase for column chromatography was silica gel 60 (0.040 - 0.063 mm) from E. Merck, Darmstadt.

The thin-film chromatographic studies were carried out with HPTLC-prepared plates, silica gel 60 F 254, by E. Merck, Darmstadt.

Race separations were carried out on a 250 x 4.6 mm Chiracel OD column with a Daicel pre-column.

The mixing ratios of the media for all chromatographic studies are always given in volume/volume.

RT means room temperature, % volume, % m mass and %ee excess enantiomeric in percent.

Example 1 Dimethyl-{[2-[2-methyl-benzyloxy) cyclohexyl]phenylmethyl}amine hydrochloride The following is the list of active substances:

10 g (56 mmol) N,N,N',N'-tetramethyl-C-phenylmethandiamine (J. 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 mmol) acetyl chloride was dripped under nitrogen. After the first drops, a white salt was released, the temperature slightly increased. After 15 hours in RT, the solid was decanted, washed three times with 100 ml of ether, filtered under nitrogen using a protective gas filter and dried in the oil pump vacuum to weight. This resulted in 7.7 glidendimethylammonium benzyl ammonium (80.9% theoretically).

Stage 2 (dimethylaminophenylmethyl) cyclohexanone

7.1 ml (44 mmol) 1-Pyrrolidino) 1-cyclohexene was dissolved in 45 ml dichloromethane and cooled to -70 °C with nitrogen in a dry ice/isopropanol bath. 7.5 g (44 mmol) benzylidendimethylammonium chloride of grade 1 was added during stirring, the mixture was heated to -30 °C within two to three hours and stored at this temperature for 15 hours. 60 ml of semi-concentrated hydrochloric acid was added for processing and stirred for 5 minutes. RT was obtained by washing 50 ml of etheric acid in the water phase with 440 ml of an ammonium solution (25 vol. and rapidly added 150 ml of extra hydrochloric acid each. The organic extract was obtained by filtering the water by means of a mixture of 0.6 to 10.6 ml (42.8 mmol) of ammonium nitrate and 0.6 to 10.6 ml (42.8 to 10.6 mmol) of the ammonium nitrate. These were obtained by washing the water in a vacuum with 0.6 to 10.6 ml of the ammonium nitrate.

Stage 2 (dimethylaminophenylmethyl) cyclohexanol

The product was then agitated for 15 hours until it returned to the water. For the preparation, 13 ml of ethanol and 13 ml of water were slowly added, the suspension was stored for several hours at 0 °C, filtered by a glass fryer and washed several times with a small amount of toluene. The filtrate was compressed in the rotation vapor (500 to 10 mbar) and the solvent residues were removed in a high vacuum (approximately 0.1 mbar).

The following shall be indicated in the table for the determination of the concentration of the active substance:

The reaction mixture was heated for 30 minutes at 50°C, 904 mg (6.43 mmol) 2-methylbenzyl chloride was added and stirred for a further 15 hours at 50°C. 10 ml was added for processing and extracted three times with 15 ml of ether. The combined extracts were washed with 10 ml of potassium hydroxide solution (2 M) and water and extracted three times with 25 ml (5 mL) or more of alkaline sodium acid (3 mL) and extracted with 25 ml (10 mL) or more of hydrochloric acid (3 mL).The combined organic extracts were dried with sodium sulphate, filtered and pressurized in the rotary evaporator (500 to 10 mbar). 414 mg of raw base was obtained. The raw base was dissolved in 4 ml 2-butanone and added successively 11 μl (0.61 mmol) water and 155 μl (1.22 mmol) chlortrimethylsilan. The solution was stored for 15 hours at RT, the resulting solid was sucked out, washed with small portions of ether and dried in the oil pump vacuum to weight consistency. This obtained 221 mg of hydrochloride from dimethylben[{2-methylhexy) -cycloxy]phenylmethyl (13.8%) theoramine, which decomposes at 79 °C.

Example 2 [2-dimethylaminophenylmethyl) cyclohexyl]-4-trifluorethylbenzoate hydrochloride Stage 2 (dimethylaminophenylmethyl) cyclohexanol

80 g (299 mmol) of 2-dimethylaminophenylmethyl) cyclohexanone produced in step 2 was dissolved in 650 ml of methanol, added a total of 28,3 g (747 mmol) of sodium borohydride per serving and stirred for one hour. 680 ml of dilute hydrochloric acid (1 N) was added for processing and extracted with 500 ml of ether. The aqueous phase was alkalinized with ammonia solution (25 vol.%) (pH ≥ 10) and extracted three times with 250 ml of ether. The combined organic extracts were dried with sodium sulphate, filtered and diluted at the rotary vapour (500 to 10 mbar). 65.2 g (94%) of the 2-dimethylaminophenylmethyl) cyclohexanol was obtained.

The following substances are to be classified in the same category as the active substance:

1,34 g (6,43 mmol) 4-benzoyl chloride was dissolved in 4 ml dichloromethane and 870 mg (8,57 mmol) of triethylamine was added at - 10 °C (methanol/ice bath) and 1,0 g (4,29 mmol) 2-dimethylaminofenyl methyl) cyclohexanol dissolved in 2 ml dichloromethane was added, dripped and stirred for 15 hours. 2 ml of potassium hydroxide solution (0.5 N) was added to the treatment, the organic phase was removed, tricyclic sodium triphosphate was added, filtered and diluted at the rotary pump (500 to 10 mbar). 1,7 g of crude esamine were obtained.

Example 3 [2-dimethylaminophenylmethyl) cyclohexyl]-4-methoxybenzoate hydrochloride

1,06 g (6,43 mmol) 4-methoxybenzoyl chloride was dissolved in 4 ml dichloromethane and 870 mg (8,57 mmol) of triethylamine was added at - 10 °C (methanol/ice bath). Then 1,0 g (4,29 mmol) of 2-dimethylaminophenylmethyl) cyclohexanol produced in Step 2 (1st stage) was added, dripped and stirred for 15 hours. For processing, 2 ml of potassium hydroxide solution (0,5 N) was added, the organic phase was separated, dried in sodium sulphate, filtered and at the rotation point mbar (500 to 10 g) obtained. The raw water was obtained by pressing 1,78 g (4.00 g) of the 2-dimethylamethylmethyl methyl methyl methyl base in a base of 2-methyl methoxylamine (2-3% of the 2-methyl methyl base) at a temperature of 230 °C (52-dimethylamethyl methyl base).

Example 4 The following is added to the list of active substances: The following substances are to be classified in the same category as the active substance:

In case of ice-cooling, 24 ml (213 mmol) 2-chlorobenzaldehyde were added and further stirred for one hour. It was then re-cooled in an ice bath at 0°C, added 34 (213 mmol) 1-pyrrolidino-1-cyclohexane alkali rock and two hours each. To replace the solution, 300 ml (300 ml) of E-triethyl ether were diluted in a semi-concentrated solution at 10 °C (38.3%) without any further processing. These were diluted with 300 ml (300 ml) of E-triethyl ether (70%) and added to the solution for 10 minutes.

Stage 2 - Cyclohexanol hydrochloride

10.0 g (37.6 mmol) 2-[(2-Chlorphenyl) dimethylaminomethyl]-cyclohexanone was dissolved in 190 ml of methanol and 2.85 g (75.2 mmol) sodium borohydride was added per serving. 170 ml of hydrochloric acid (1 M) was added to the preparation during stirring and extracted with 100 ml of ether. 15 ml of ammonia solution (25 vol.%) was alkaline (pH ≥ 10) and extracted three times with 100 ml of ether. The combined extracts were dried over anhydrous sodium sulphate, filtered and pressed in the red-evaporation vapor (500 to 10 g) to obtain 8.10 mbar (80.3% of the raw base). 131 g (1,98.7 g) of base was extracted from this example (4.98 mmol/W) of 2-dimethylaminomethylanone was extracted with 2-dimethylamethyl gloride (72.74 g/W) in the 2-methyl-methyl-methyl-methyl-methyl-base of the hydrochloric acid.

The substance is to be classified in the immediate vicinity of the place of manufacture.

902 mg (5.60 mmol) 2-chlorobenzyl chloride and 1.0 g (3.73 mmol) 2-[(2-chlorophenyl) dimethylaminomethyl]cyclohexanol were dissolved in 6.0 ml of dimethyl sulfoxide p.a., added 503 mg (4.48 mmol) solid potassium tertiary butylate with nitrogen and heated to 100 °C for 15 hours. 10 ml of water were added for processing and extracted three times with 15 ml of ether each. The combined extracts were washed with 10 ml of dihydroxide (2 M) and water each and extracted three times with 25 ml of potassium alkyl acid (5 m mL) each. The combined extracts were obtained by adding three times (32 mL of dihydroxide (≥ 11.4%) dihydroxide of potassium tertiary nitrate) to the 150 ml of dihydroxide (2 mL) extracted from the 10 mg/mL of dihydroxyl sulfoxide (≥ 10.7%) and extracted from the 10 mg/mL of dihydroxyl sulfoxide (≥ 10.7%) of the raw sodium nitrate. The combined extracts were obtained by extracting 10 mg/m2 mg of dihydroxyl sulfoxide (≥ 10.7%) from the 10 mg/m2 ml of dihydroxyl sulfoxide (≥ 10.7%) and extracting 2 ml of dihydroxyl sulfoxide (≥ 10.2 mg/m2 mg/mL.

Example 5 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

1,00 g (4.29 mmol) of 2-dimethylaminophenylmethyl) cyclohexanol produced in step 1 (third step) was dissolved in 5 ml of dimethyl sulfoxide p.a. and added 503 mg (4.48 mmol) potassium tert-butylate at 50 °C. Then heated to 100 °C and added 323 μl (2.61 mmol) 3-fluorobenzyl chloride. This addition was repeated twice after two hours and the reaction mixture was then heated to 100 °C for a further 15 hours. The treatment was carried out after step 1 (fourth step) to obtain 166 mg (11%) of dimethyl dimethylamin hydrochloride (16%), which was heated at 203 °C.

Example 6 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

A suspension of 108 mg (4,48 mmol) sodium hydride in 1 ml of dimethylformamide p.a. was given a solution of 1,00 g (4,29 mmol) of 2-dimethylaminophenylmethyl) cyclohexanol prepared in step 1 in 5 ml of dimethylformamide p.a. The reaction mixture was heated to 100°C and 323 μl (2,61 mmol) 3-fluorobenzyl chloride was added. This addition was repeated twice after two hours and the reaction mixture was then heated to 100°C for a further 15 hours. The treatment was carried out in step 4 in step 1 and 393 mg (24-dimethylaminophenylhydrodioxyloxyhexycyclohexyphenylmethyl) was obtained at 210°C.

Claims (27)

1. 3-Amino-3-arylpropan-1-ol derivatives of the general formula I wherein

   R¹, R²   in each case independently of one another denote C_1-6-alkyl, or R¹ and R² together form a (CH₂)_2-6 ring, which can also be benzo-fused or phenyl- substituted,

   R³   denotes H or methyl,

   R⁴, R⁵   in each case independently of one another denote C_1-6-alkyl, C₃-C₆-cycloalkyl, phenyl, benzyl, phenethyl, or R⁴ and R⁵ together form a (CH₂)_3-6 or CH₂CH₂OCH₂CH₂ ring,

   A   denotes a radical from the group consisting of substituted phenyl of the formula XIII or represents a furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl radical which is mono- or polysubstituted by radicals chosen from the meanings given for R⁶ to R¹⁰, wherein

   R⁶ to R¹⁰   in each case independently of one another denote H, F, Cl, Br, I, CF₃, OR¹¹, OCF₃, SR¹¹, SO₂CH₃, SO₂CF₃, C_1-6-alkyl, phenyl, CN, COOR¹¹, NO₂, or R⁶ and R⁷ or R⁷ and R⁸ together form an OCH₂O or OCH₂CH₂O ring,

   R¹¹   denotes C_1-6-alkyl, phenyl, benzyl, phenethyl,

   X   denotes a substituted benzyl of the formula XI or a substituted benzoyl of the formula XII wherein

   R¹² to R¹⁴   in each case independently of one another denote H, F, Cl, Br, CHF₂, CF₃, OR¹¹, SR¹¹, OCF₃, SO₂CH₃, SO₂CF₃, C_1-6-alkyl, phenyl, CN, COOR¹¹, NO₂, where

   R¹¹   denotes H, C_1-6-alkyl, phenyl, benzyl, phenethyl,

   and diastereomers or enantiomers thereof, in the form of their bases or salts of physiologically acceptable acids.
2. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)_2-6 ring, which can be benzo-fused or phenyl-substituted, R³ to R⁵, A and X have the meaning according to claim 1.
3. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)₄ ring, which can be benzo-fused or phenyl-substituted, R³ to R⁵, A and X have the meaning according to claim 1.
4. Compounds according to claim 1, characterized in that R³ represents hydrogen, R¹, R², R⁴, R⁵, A and X have the meaning according to claim 1.
5. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)_2-6 ring, which can be benzo-fused or phenyl-substituted, R³ represents hydrogen, R⁴, R⁵, A and X have the meaning according to claim 1.
6. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)₄ ring, which can be benzo-fused or phenyl-substituted, A denotes a radical from the group consisting of substituted phenyl of the formula XIII or thiophenyl or furanyl, R³ to R⁵ and X have the meaning according to claim 1.
7. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)₄ ring, A denotes a radical from the group consisting of substituted phenyl of the formula XIII or thiophenyl or furanyl, R³ to R⁵ and X have the meaning according to the definition of claim 1.
8. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)₄ ring, A denotes thiophenyl, R³ to R⁵ and X have the meaning according to the definition of claim 1.
9. Compounds according to claim 1, characterized in that R¹ and R² together form a (CH₂)₄ ring, A denotes furanyl, R³ to R⁵ and X have the meaning according to the definition of claim 1.
10. Compounds according to claim 1, characterized in that X represents a radical from the group consisting of substituted benzyl of the formula XI, R¹ to R⁵ and A have the meaning according to claim 1.
11. Compounds according to claim 1:

    dimethyl-{[2-(2-methylbenzyloxy)cyclohexyl]phenylmethyl}amine and the corresponding hydrochloride

    [2-(dimethylaminophenylmethyl)cyclohexyl] 4-trifluoromethylbenzoate and the corresponding hydrochloride

    [2-(dimethylaminophenylmethyl)cyclohexyl] 4-methoxybenzoate and the corresponding hydrochloride

    {[2-(2-chlorobenzyloxy)cyclohexyl]-(2-chlorophenyl)-methyl}dimethylamine and the corresponding hydrochloride

    {[2-(3-fluorobenzyloxy)cyclohexyl]phenylmethyl}-dimethylamine and the corresponding hydrochloride

    {[2-(4-fluorobenzyloxy)cyclohexyl]phenylmethyl}-dimethylamine and the corresponding hydrochloride.
12. Medicaments comprising as an active compound at least one compound according to claims 1 to 11.
13. Medicaments comprising as active compounds a mixture of the enantiomers of a compound according to claims 1 to 11, wherein the two enantiomers are not present in equimolar amounts, and optionally further active compounds.
14. Medicaments comprising as active compounds a mixture of the enantiomers of a compound according to claims 1 to 11, wherein one of the enantiomers has a relative content of between 5 and 45 per cent by weight of the enantiomer mixture, and optionally further active compounds.
15. Process for the preparation of a compound according to claims 1 to 11, characterized in that a Mannich base of the general formula II wherein R¹ to R⁵ and A have the meaning according to the general formula I, is reacted with a Grignard compound of the general formula (H₃C)Y, wherein Y denotes MgCl, MgBr or MgI, or MeLi or a reducing agent, preferably from the group consisting of sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, diisobutylaluminium hydride or a complex analogue of these compounds, to give an alcohol of the general formulae 1d wherein R¹ to R⁵ and A have the meaning as in the general formula I, an alcohol of the general formulae 1d is reacted with HalX, wherein Hal has the meaning of halogens from the group consisting of F, Cl, Br or I and X has the meaning according to the general formula I, in the presence of inorganic or organic bases in a temperature range of 0°-150°C or is subjected to a condensation reaction with XOH in a temperature range of 0°-150°C and is thus converted into a compound of the general formula I.
16. Use of a compound according to claims 1 to 11 for the preparation of a medicament for combating pain.
17. Use according to claim 16 for the preparation of a medicament for combating neuropathic pain.
18. Use according to claim 16 for the preparation of a medicament for combating chronic pain.
19. Use of a compound according to claims 1 to 11 for the preparation of a medicament with a local anaesthetic action.
20. Use of a compound according to claims 1 to 11 for the preparation of a medicament with an antiarrhythmic action.
21. Use of a compound according to claims 1 to 11 for the preparation of a medicament with an antiemetic action.
22. Use of a compound according to claims. 1 to 11 for the preparation of a medicament with a nootropic (neurotropic) action.
23. Use of a compound according to claims 1 to 11 for the preparation of a medicament for treatment of cardiovascular diseases.
24. Use of a compound according to claims 1 to 11 for the preparation of a medicament for treatment of urinary incontinence.
25. Use of a compound according to claims 1 to 11 for the preparation of a medicament for treatment of diarrhoea.
26. Use of a compound according to claims 1 to 11 for the preparation of a medicament for treatment of pruritus.
27. Use of a compound according to claims 1 to 11 for the preparation of a medicament for treatment of inflammations.