HK1026197B - Pharmaceutically-active dimethyl-(3-aryl-but-3-enyl)-amine compounds - Google Patents

Description

The invention relates to dimethyl ((3-aryl-but-3-enyl) amine compounds, their manufacturing process and their use in medicinal products.

The treatment of chronic and non-chronic pain conditions is of great importance in medicine. At present, there is a worldwide need for additional, not exclusively opioid-based but highly effective pain therapy. The urgent need for patient-centred and targeted treatment of chronic and non-chronic pain conditions, including successful and satisfactory pain management for the patient, is documented by the large number of scientific papers published recently in the field of applied analgesics and basic research on nociception.

Opioids have been used for many years as analgesics to treat pain, although they cause a range of side effects, such as addiction and dependence, respiratory depression, gastrointestinal inhibition and constipation, and therefore can only be given under special precautions, such as specific prescriptions over a longer period or at higher doses (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990).

Tramadol hydrochloride - (1 RS, 2 RS) 2-dimethylaminomethyl-1- ((3-methoxyphenyl) cyclohexanol, hydrochloride - occupies a special position among the centrally acting analgesics because it produces a strong analgesic effect without the side effects known for opioids (J. Pharmacol. Exp. Ther. 267, 331 (1993)). Tramadol is a racemate and consists of equal amounts of (+) and (-) enantiomers. In vivo the active substance forms the metabolite O-methyl-tramadol, which is also present as an enantiomeric compound. Studies have shown that both the enantiomers of Tramadol and the enantiomers of Tramadol are involved in the analgesic effect (J. Pharmacol. Exp. 260, 275 (1992)).

Err1:Expecting ',' delimiter: line 1 column 67 (char 66)

EP 693 475 A1 of Grünenthal GmbH describes pharmacologically active 1-phenyle-3-dimethylamino-propane compounds.

Err1:Expecting ',' delimiter: line 1 column 57 (char 56)

The purpose of the invention was to develop analgesic agents which would be suitable for the treatment of severe pain without causing the side effects typical of opioids, and the substances to be developed should not have the side effects which may occur during treatment with tramadol, such as nausea and vomiting.

It was found that certain dimethyl ((3-aryl-but-3-enyl) amines fulfilled the requirements for the substances to be developed, and these substances have a marked analgesic effect, which is significantly enhanced compared with tramadol.

The invention is therefore concerned with dimethyl ((3-aryl-but-3-enyl) amino compounds of formula I, where R1 is C1-5 alkyl and R2 means H or C1-5 alkyl, R3 H or C1-5 alkyl, R4 H, OH, C1-4 alkyl, O-C1-4 alkyl, O-benzyl, CF3, O-CF3, Cl, F or OR8 means R5 H, OH, C1-4 alkyl, O-C1-4 alkyl, O-benzyl, CHF2, CF3, O-CF3, Cl, F or OR8 and R6 H, OH, C1-4 alkyl, O-C1-4 alkyl, O-benzyl, CF3, O-CF3, Cl, F or OR8 means, provided that the R4, R5 or R6 H are two routes or routes together and R5 - CHR=CHR-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCH-OCHO-OCH-OCH-OCH-OCH-OCHO-OCH-CHO-OCHO-CHO-OCHO-CHO-CHO-CHO-CHO-CHO-O-CHO-CHO-CHO-CHOCHO-CHO-CHO-OCHO-CHO-CHO-CHO-CHO-CHO-CHO-OCHO-CHO-CHO-CHO-CHO-CHO-O-CHOCHO-CHO-CHOCHOCHO-CHO-CHOCHO-R4H is, R8 CO-C1-5-alkyl, PO ((O-C1-4-alkyl) 2, CO-C6H4-R11, CO ((O-C1-5-alkyl), CO-CHR12-NHR13, CO-NH-C6H3-(R14) 2 means a pyridyl, thienyl, thiazoyl or phenyl group, R9 H means a C1-4-alkyl, R10 H or C1-3-alkyl means an R11 OC ((O) C1-3-alkyl in ortho position or CH2-N-(R15) 2 means a meta or para position, where R15C1-4-alkyl or both R15 residues together with the N4-morpholine residue, mean R12 and are equal or different and R13 C-61 or C-63 cycloalkyl or R14 C-83 or R14 R-C-14, mean R13 R-83 or R14 R-C-14, or R-71 or R-72 together with their salts, means that the two residues are equal or different and R13 C-61 or C-83 cycloalkyl, R13 C-14, R13 C-14, R13 C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14, R13 O-C-14,The enantiomers or racemates are the same.

Preferred dimethyl ((3-aryl-3-but-3-enyl) amines conform to formula I with R1 C1-3 alkyl and R2 H or C1-3 alkyl, R3 H or C1-3 alkyl, R4 H, OH, CF3, Cl, F or OR8, R5 H, OH, C1-4 alkyl, O-C1-4 alkyl, O-benzyl, CHF2, CF3, Cl, F or OR8 and R6 H, OH, O-C1-4 alkyl, O-benzyl, CF3, Cl, F or OR8, provided that two of the residues are R4, R5 or R6 H, or R4 and R5 together - CH=CHR9) - O-CHR or - CH=CHR-S9) provided that R6 is combined with H, CH=CHR5 - CH=CHR6 - CHR3 and R3 - CHR3 - CHR3 and R3 - CHR3 - CHR3 - CHR3 - CHR3 and R3 - CHR3 - CHR3 - CHR3 - CHR3 and R3 - CHR3 - CHR3 - CHR3 - CHR3 and R3 - CHR3 - CHR3 - CHR3 - CH3 and R3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 - CH3 -CH3 or CH2CH3 means R4H or OH, R5H, OH, OCH3, CHF2 or OR8 and R6H means OH, OH or CF3 provided that two of the residues are R4, R5 or R6H, or R4 and R5 together mean -CH=C(CH3)-S- provided that R6H, or R5 and R6 together mean -CH=CH-COH) =CH- provided that R4H, and R8 means CO-C6H4-R11 with R11 OC1 to OR1 to OR1 to OR1 to OR1 to OR3O. In particular, dimethyl-methyl-butyl-3amines with CH1 or CH3 or R3, or R3, or R3, or R4, or H8, are preferred.R6H and R8 CO-C6H4-R11 with R11 OC ((O)CH3 in ortho position.

The invention also relates to a method for the production of dimethyl ((3-aryl-but-3-enyl) amines of formula I, where R1 is C1-5-alkyl and R2 H or C1-5-alkyl means R3 H or C1-5-alkyl means R4 H, C1-4-alkyl means O-C1-4-alkyl means O-benzyl, CF3, O-CF3, or F means R5 H, C1-4-alkyl means C, O-C1-4-alkyl means O-benzyl, CHF2, Cl3, O-CF3, or F, and R6 H, C1-4-alkyl means O-C1-4-alkyl, O-benzyl means CF3, O-CF3, or Cl1 means F, where R5 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H, R1 H a thickness of not more than 0,05 mm, where Z stands for MgCl, MgBr, MgI or Li, to a tertiary alcohol of formula IV The chemical is then dehydrated to a compound of formula I.

The reaction of a β-dimethylamino ketone with a Grignard compound of formula III, where Z means MgCl, MgBr or MgJ, or with a lithium organic compound of formula III, can be carried out in an aliphatic ether, e.g. diethyl ether and/or tetrahydrofuran, at temperatures between -70° and +60° C. The transformation with a Grignard compound can be carried out with or without the addition of a carrier reagent, preferably 1,2-dibromethane. Lithium organic compounds of formula III can be obtained by transformation of a compound of formula III, where Z means Cl, Cl or J, with, for example, a n-butylum/hexane-lithium halogen exchange solution.

The resulting tertiary alcohols of formula IV can be dehydrated with acids, in particular formic acid or hydrochloric acid, at temperatures between 0 and 100 °C.

The subject matter of the invention is also a method for the preparation of a dimethyl ((3-aryl-but-3-enyl) amine compound of formula I, in which R1 is a C1-5 alkyl and R2 H or C1-5 means an alkyl, R3 H or C1-5 means an alkyl, one of the residues means R4, R5 or R6 OH and the other two residues are H, which is characterized by the formation of a compound of formula I, in which one of the residues means R4, R5 or R6 O-CH3 and the other two residues are Huty, converted into aluminium diisobutane hydride, or one of the compounds I, in which one of the residues R4, R5 or R6 means O-benzyl and the other two residues is H, reductant debonyl.

The implementation of a dimethyl ((3-aryl-but-3-enyle) amine compound with diisobutylaluminium hydride is usually carried out in an aromatic hydrocarbon, e.g. toluene, at a temperature between 60 and 130 °C (Synthesis 1975, 617; DE 24 09 990, DE 24 09 991; Chem. abstract 84, 59862 (1974)). Reductive debenzylation of a compound of the invention of formula I, where one of the residues R4, R5 or R6 is O-benzyl, can be performed in the presence of platinum or palladium on a carrier material, e.g. activated carbon, in the presence of hydrogen in a solvent, e.g. acetic acid or C1-4 alkyl alcohol, at pressures between 1 and 100 bar and temperatures between 20 and 100 °C.

Dimethyl ((3-aryl-but-3-enyl) amines of general formula I, where one or more of the aromatic substituents R4, R5 and R6 are OR8 and OR8 is a phosphate, carbonate, carbamat, carboxylate or aryloxy or heteroaryloxy group, can be obtained by conversion of a corresponding dimethyl ((3-hydroxyphenyl) but-3-enyl) amines of formula I, where R4, R5 and/or R6 are an OH group, into an alkaline salt with a dialkyl chlorophosphate, with an alkyl or copper tetrafluorate, with an aryl or heteroaryl carboxy group, with a heterohydroxy or heterohydroxy group, or with a heterohydroxy or heterohydroxy group. These additives are usually carried out in a solution of 37,5 °C (1971, 47,3 °C) or between 30,7 °C (1977, 47,3 °C) and 47 °C (1978,4 °C) or in a solution of J. or J. or J. (for example, J. or J. or J. or J. or J. or J. or J. or J. or J. respectively) at a temperature of between 47 °C. and 47 °C. These additives are carried out in a solution of 47,7 °C. and 47 °C. These additives are used as a diethyl or or or or J. (for example, J. or J. or J. or J. or J. or J. or J. respectively) at temperatures of between 30,7 °C. and 47 °C. and 70 °C.

Dimethyl ((3-aryl-but-3-enyl) amines of formula I, where OR8 is an α-aminocarboxylate group, are obtained by conversion of a corresponding dimethyl ((3-hydroxy-phenyl) but-3-enyl) amines of formula I, where R4, R5 and/or R6 are an OH group, with a corresponding 2-t-butoxycarbonylaminocarboxylic acid using triethylamine and coupling reagents such as benzotriazole-1-oxy-tripyrrolidinophosphoniumhexafluorophosphat in a solvent such as dichloromethane.

The compounds of formula I can be transferred to their salts in a known manner with 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 ether, diisopropyl ether, ester of acetic acid, acetone and/or 2-butanone. In addition, trimethyl chloride is obtained in aqueous solution to produce the hydrochlorides.

The compounds of the invention have a marked analgesic effect and are toxicologically harmless. They are therefore suitable as pharmaceutical active substances. Accordingly, the subject of the invention is also the use of a dimethyl- ((3-aryl-but-3-enyl) -amine compound of formula I as an active substance in medicinal products, preferably as an active substance in painkillers.

In addition to at least one dimethyl ((3-aryl-but-3-enyl) amine compound of formula I, the invention's medicinal products contain carriers, fillers, solvents, diluents, colours and/or binders. The choice of excipients and the amounts to be used depend on whether the medicinal product is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example to treat infections of the skin, mucous membranes or eyes. For oral application, preparations are suitable in the form of tablets, drops, capsules, granules, syrups, syrups and syrup, which can be used in the form of oral or percutaneous solutions. The main examples of preparations which are suitable for oral or percutaneous application are preparations in the form of syrups, syrups, syrups, syrups and syrup, if necessary, percutaneous or percutaneous solutions.

The amount of active substance to be administered to the patient will vary depending on the patient' s weight, the type of application, the indication and the severity of the disease.

Examples Manufacture of compounds of the invention

The term ether means diethyl ether.

The stationary phase for column chromatography was silica gel 60 (0.040 - 0.063 mmm) 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 separation was carried out on a Chiracel OD column of Daicel Chemical Industries, LTD.

The mixing ratios of the solvents for all chromatographic studies are given in volumes.

Example 1 (Z) - (RS) - (Z) - (Methoxyphenyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) Stage one The following substances are to be classified in the same heading as the active substance:

At this temperature, 128.30 g (0.89 mol) (RS) 1-Dimethylamino-2-methylpentan-3-one, dissolved in 400 ml of tetrahydrofuran, were dripped. The reaction was stopped and then cooled again at 5 to 10 °C. After adding 300 ml, 20 ml of ammonium chloride solution was diluted with 400 ml of etheric acid. The solution was diluted with 200 g (1,880 ml) of ethyl etheric acid and obtained in a second solution containing 12 g (1,260 ml) of the extracted etheric acid and 12 g (1,880 ml) of the extracted etheric acid.

Stage two: (Z) - (RS) - (Z) - (Methoxyphenyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-3-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-ethyl) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-) - (Pent-)

200 g (0.69 mol) of hydrochloride (2) were dissolved in one litre of concentrated hydrochloric acid and left to stand at room temperature. The hydrochloric acid was removed in a vacuum distillation. The residue was dissolved in 1 l of ice water and set to a pH of 13 with 10 molar sodium salts. After extraction with ether, drying of the organic phase and distillation of the solvent, 162 g of raw product were obtained, which was purified by crystallization. 79 g (42% of the theory) of hydrochloride (1) with a melting point of 169 °C to 170 °C were obtained.

Example 2 (Z) - (RS) -3-[1- (2-Dimethylamino-1-methyl-ethyl) -propenyl]-phenol, hydrochloride (3)

After cooling to 0 °C, 450 ml of ethanol were added by cooling. After 15 minutes of stirring and dilution with 1 l of toluol, 450 ml of an ethanol/water mixture (1: 1) were added by refrigerating with a dropper. After one hour of stirring at room temperature, the defective aluminium hydroxide was evaporated and removed from the organic solvent phase of the distillation. The result was 167 g (97.6%) of the ethanol solution (66 g) dissolved in a crystalline solution of the solvent with a crystalline base of 1.67 g (61.6%) of the hydrochloric acid obtained from the crude acetone.

Example 3 Enantiomers of (3): It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (-) - (Z) - (R) -3-[1- (2-Dimethylamino-1-methyl-ethyl) -propenyl]-phenol, hydrochloride (-3)

The base was released from the hydrochloride (3) obtained by using dichloromethane/aqueous sodium hydrocarbonate solution. After drying the solution, dichloromethane was distilled in a vacuum. The racemate was then separated on a chiral HPLC column. From the enantiomers obtained, the hydrochlorides were isolated by conversion into acetone with concentrated hydrochloric acid at a melting point of 166 to 167 °C. (+3): yield: 42 % of the theory [α]RTDThe following table shows the results of the analysis:RTDThe following table shows the results of the analysis:

Example 4 (Z) - (RS) -2-acetoxybenzoic acid 3-[1-dimethylamino-1-methyl-ethyl) -propenyl]-phenylester, hydrochloride (4)

From the hydrochloride (3), prepared as in example 2, the base was released with dichloromethane/aqueous sodium hydrocarbonate solution and the dichloromethane distillate was removed after drying the solution. 0,67 g (3.0 mmol) of the obtained base was dissolved in 7 ml of dry dichloromethane and at room temperature with 0,6 g (3.24 mmol) 2-acetyl benzoyl chloride dissolved in 3 ml of dry dichloromethane. After 20 hours of stirring at room temperature, the reaction engine was stirred with 20 ml of sodium hydrocarbonate solution and the aqueous phase was doubled with 10 ml of additional dichloromethane. The organic phases were combined and dehydrated by tri sulphate. The solution of the aqueous solution was obtained from a solution of 0,68 g (5-88 °C) of ethyl ethyl ethyl alcohol obtained from 0,68 g of the raw base, with a solution of ethyl ethyl ethyl ethyl ethyl ethyl (4) obtained at a temperature of 86 °C.

Example 5 (E) - (RS) - (E) - (Methoxyphenyl) - (E) - (Methoxyphenyl) - (E) - (E) - (E) - (E) - (RS) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) - (E) -E) -E) - (E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E) -E -E -E -E -E -E -E -E -E -E

75 g (0.26 mol) (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, hydrochloride (1) from example 1 (stage 1) were dissolved in one litre of concentrated formic acid and heated for two hours under return flow. The formic acid was then distilled in a water jet vacuum, the residue was absorbed in ice water and mixed with baking soda/ether. After drying the organic phase and distillate removal of the solvent, 60 g (98% of the theoretical base) (2 (Z) isomer): (E) isomer (5) = 6 (4) was obtained. The raw base was placed on a column filled with diesel. The elution was filled with 7 g of methanol/W (140 g of methanol/W) = 18 g of trimethanol (213 g of theoretical base) with a base of theoretical (134 g of trimethanol) (5).

Example 6 (E) - (RS) -3-[1- (2-Dimethylamino-1-methyl-ethyl) -propenyl]-phenol, hydrochloride (6)

The base was removed with dichloromethane/sodium sulphate and, after drying the solution, the dichloromethane distillate was removed.

Example 7 Enantiomers of (6): It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (-) - E) - S) - 3-[1-2-dimethylamino-1-methyl-ethyl) -propenyl]-phenol, hydrochloride (-6)

The base was released from the hydrochloride obtained in Example 6 (6) with dichloromethane/aqueous sodium hydrocarbonate solution. After drying the solution, dichloromethane was distilled in a vacuum. The racemate was then separated on a chiral HPLC column. From the enantiomers obtained, the hydrochlorides were isolated by conversion into acetone with concentrated hydrochloric acid at a melting point of 154-155 °C. (+6): yield: 42 % of the theory [α]RTDThe following table shows the results of the analysis:RTDThe following formulae are used:

Example 8 (Z) - (RS) -4-[1- (2-Dimethylamino-1-methyl-ethyl) -propenyl]-phenol, hydrochloride (7) Stage one:

(Z) - ((RS) - ((3-)) 4-Methoxyphenyl) -2-methyl-pent-3-enyl) -dimethylamine (8) Based on (RS) -1-Dimethylamino-2-methyl-pentan-3-one and 1-Brom-4-methoxybenzole, obtained under the conditions specified in Step 1 (2RS, 3RS) -1-Dimethylamino-3- ((4-Methoxyphenyl) -2-methyl-pentan-3-ol), hydrochloride at a yield of 44%, and a melting point of 188-189 °C obtained under the conditions specified in Step 2 (RS) - (Z) - ((RS) - ((3-)) 4-Methoxyphenyl) -2-methyl-pent-3-dimethylamine (8) was obtained as a 46% solution in a solution of oil.

Stage two: (Z) - (RS) -4-[1- (2-Dimethylamino-1-methyl-ethyl) -propenyl]-phenol, hydrochloride (7)

The base obtained from step 1 yielded the hydrochloride (7) at 79% of the theoretical yield and a melting point of 203 °C under the conditions given in example 2.

Example 9 The chemical composition of the product is determined by the following equation:

From (RS)-1-Dimethylamino-2-methylpentan-3-one and 3-bromotoluol, hydrochloride obtained at a yield of 24% and a melting point of 154-155 °C was converted to (RS)-1-Dimethylamino-2-methylpentan-3- ((m-tolyl) -pentan-3-ol) in the conditions given in Step 1 (2RS, 3RS) with concentrated hydrochloric acid into (RS) -dimethyl- (((2-methyl-3-m-tolylpentan-3-enyl) -amin) -pentan-3-pentan-pentan-pentan (9) at a yield of 36% (depending on the alcohol used) at a melting point of 172 °C at the conditions given in Step 2.

Example 10 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

Based on (2RS, 3RS)-1-dimethylamino-2-methyl-3 ((m-tolyl) -pentan-3-ol, hydrochloride, which was produced in accordance with example 9, the hydrochloride (10) was obtained at a yield of 36% at a melting point of 153 °C under the conditions given in example 5.

Example 11 (Z) - (RS) - (Z) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D) (D (D) (D) (D) (D) (D) (D) (D (D) (D) (D (D) (D) (D) (D) (D (D) (D) (D) (D (D) (D) (D (D) (D) (D Stage one: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

7,0 g (34 mmol) 1-bromo-3-difluormethylbenzene produced from 3-bromobenzaldehyde and diethylamino sulphur trifluoride as described in Org. React. 35, 513 (1988), were dissolved in 110 ml of dry tetrahydrofuran and cooled to -75 °C. After adding 34 mmol of 1.6-molar n-butyllithium solution in hexane, they were stirred for one hour at -75 °C. Then 4,8 g (34 mmol) (2RS) 1-dimethylamino-2-methylpentan-3-one dissolved in 15 ml of dry tetrahydrofuran was added. The reaction table was heated to room temperature within 2.5 hours.

The organic phase was extracted with 40 ml of 5% hydrochloric acid. The combined aqueous phases were washed twice with 50 ml of ether. To release the base, concentrated baking soda was added and dichloromethane was extracted. This resulted in 7.8 g of raw product, which was added to a column filled with silica gel.

Stage two: (Z) - (RS) - (Z) - (RS) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluorophenyl) - (Difluor) - (Difluor) - (Difluor) - (Difluor) -) - (Difluor) - (Difluor) - (Difluor) -) - (Difluor) - (Difluor) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D) - (D)

10 g (32 mmol) (2RS, 3RS) 3-(3-Difluormethylphenyl) 1-dimethylamino-2-methylpentan-3-ol, hydrochloride (12) of step 1 was dissolved in 150 ml of concentrated formic acid and heated for two hours under return flow. The formic acid was then distilled in a water jet vacuum, the residue was absorbed in ice water and mixed with baking soda/ether. After drying the organic phase and distillation of the solvent, 9.1 g (97% of the theory) of the raw base were obtained by applying to a column filled with silica gel. The elution point with diisopropyl/ethyl ethanol 7 = 1 g (3.0 g) was obtained by distillation of trimetyl/ethyl ethanol base in a 2-g (2,3 g/water) solution of 2,0 °C (24-1.3 g) of the methylamine hydrochloride.

Example 12 (Z) - (RS) -6-[1- (2-Dimethylamino-1-methyl-ethyl) -propenyl]-naphth-2-ol, hydrochloride (13)

From (1RS, 2RS)-6- ((3-Dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -naphth-2-ol, hydrochloride, produced according to Chirality 6, 389 (1994), hydrochloride (13) has been obtained at 39% yield at a melting point of 207 to 208 °C under the conditions given in Example 1 (step 2).

Example 13 (E) - (RS) -[3- (3-) -methoxyphenyl) -2-methyl-hex-3-enyl]-dimethylamine, hydrochloride (14) and (Z) - (RS) - (Z) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxyphenyl) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) - (Methoxy) -Methoxy) - (Methoxy) -Methoxy) - (Methoxy) -Methoxy) -Methoxy) -Methoxy (Methoxy) -Methoxy (Methoxy) -Methoxy (Methoxy) -Methoxy) -Methoxy (Methoxy) -Methoxy (Methoxy) -Methoxy (Methoxy) -Methoxy) -Methoxy (Methoxy) -Methoxy (Methoxy

From (2RS)-3-dimethylamino-1- (((3-methoxyphenyl) --2-methylpropan-1-one and 1-bromo-propane, the (2RS, 3SR)-1-dimethylamino-3- ((3-methoxyphenyl) --2-methylhexane-3-ol, hydrochloride (16) was obtained at a yield of 81% at a melting point of 131 °C to 132 °C using ether as the solvent under the conditions specified in Example 1 (step 1). 30 g (0,1 mol) of the compound (16) were converted to 450 ml of concentrated formic acid as in Example 5. The raw base (28 g) obtained in this way, consisting of a (Z) /E) base isomer, was placed on a column filled with water. The elution was filled with diesel: 7 g/methoxyethylene (1 g/E) = 7 g/methoxyethylene (1 g/E) 14 g/B) in combination with the base compound. The base (28) was given in a base (1 g) /E) isomeric solution. (14) Yield: 5.9 g (21 % of the theory) The maximum melting point is 154 °C (15).The yield is 15.8 g (56% of the theory).

Example 14 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The base was removed with dichloromethane/sodium sulphate and, after drying the dichloromethane distillate solution, the resulting base was obtained from the hydrochloride (17) at a yield of 86% of the theoretical and a melting point of 214 °C under the conditions given in example 2.

Example 15 The following shall be indicated in the column for the product:

The base was removed with dichloromethane/sodium sulphate and, after drying the dichloromethane distillate solution, the resulting base was obtained from hydrochloride (18) at a yield of 86% of the theoretical and a melting point of 120-121 °C under the conditions given in example 2.

Example 16 (RS) [3-[3-Methoxyphenyl) 2-propyl-but-3-enyl]-dimethylamine, hydrochloride (19)

From (RS)-2-dimethylaminomethyl-1- ((3-methoxy-phenyl) -pentan-1-one and methyliodide, using ether as solvent (2RS, 3SR) as the first step, 3-dimethylaminomethyl-2- ((3-methoxy-phenyl) -hexane-2-ol, hydrochloride (20) was obtained at a yield of 76% with a melting point of 137 °C to 138 °C. 30 g (0,1 mol) of the compound (20) were converted to 300 ml of concentrated formic acid as in example 5. The resulting crude base was given on a column filled with methyl gel. The silica elution with diisopropyl methanol/thermal base = 7 1 : 24 g was obtained with trimethyl chloride/water in 2-methyl methanol (23,1 g/water) at a temperature of 120 °C to 23,1 g (1,4 mol) of the hydrochloride base obtained from a solution of methyl methanol (121 °C to 23,1 g/water) at 120 °C (19).

Example 17 (RS) 3-[1-[2-Dimethylamino-1-methyl-ethyl]-vinyl]-phenol, hydrochloride (21) Stage one: The following substances are to be classified in the same heading as the active substance:

From (RS)-3-dimethylamino-1- (((3-methoxyphenyl) --2-methylpropan-1-one and methyliodide, the base was obtained at a yield of 46% with a melting point of 178 °C to 179 °C (23) using ether as solvent (2RS, 3SR) -4-dimethylamino-2-(3-methoxyphenyl) -3-methylbutan-2-ol, hydrochloride (23) under the conditions specified in Step 1 of Example 1. The base was released with dichloromethane/sodium chloride. After drying the solution, the dichloromethane was destilated in vacuum. 23,7 g (0,1 mol) of the base was converted with diisobutinium lalalum hydrochloride as described in Step 2 of Example. In this way 18,5 g (71 mol) of the hydrochloride (22) were obtained with a melting point of 183 °C to 184 °C.

Stage two: (RS) 3-[1-[2-Dimethylamino-1-methyl-ethyl]-vinyl]-phenol, hydrochloride (21)

10 g (37 mmol) of hydrochloride (22) of stage 1 were dissolved in 150 ml of concentrated formic acid and reheated for two hours under return flow. The formic acid was then distilled in a water jet vacuum, the residue was absorbed in ice water and mixed with baking soda/ether. After drying the organic phase and distillation of the solvent, 9.1 g of crude base were obtained, from which 7.5 g (83% of the theory) of hydrochloride (21) with a melting point of 228 to 230 °C was obtained with concentrated hydrochloric acid in acetone.

Example 18 (RS) 3-[1-[2-Dimethylamino-1-methyl-ethyl) 2-methyl-propenyl]-phenol, hydrochloride (24) Stage one: The following substances are to be classified in the same heading as the active substance:

Based on (RS)-1-dimethylamino-2,4-dimethylpentan-3-one and 1-bromo-3-methoxybenzene, under the conditions specified in Step 1 (2RS, 3RS) 1, dimethylamino-3- (((3-methoxyphenyl) --2,4-dimethylpentan-3-ol, hydrochloride (26) was obtained at a yield of 44% with a melting point of 180-181 °C. 30 g (0.1 mol) of the compound (26) were converted to 450 ml of concentrated formic acid as shown in Example 5. The resulting crude base was given to a column filled with elution. The solution with diisopropyl ether/methanol base = 7 yielded 19 g (77 % of the theory) as a light oil gel.

Stage two: (RS) 3-[1-[2-Dimethylamino-1-methyl-ethyl) 2-methyl-propenyl]-phenol, hydrochloride (24)

The base obtained from step 1 yielded hydrochloride (24) at 84% of the theoretical yield and a melting point of 176 to 177 °C under the conditions given in example 2.

Pharmaceutical studies Analgesia test in the mouse writhing test

The analgesic effect was studied in phenylquinone-induced writhing in mice modified to I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237 - 240 (1959) using male NMRI mice weighing 25 - 30 g. Groups of 10 animals per dose were analysed 10 minutes after intravenous administration of a compound of the invention 0.3 ml/mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, ED. Fa. Sigma, Deisenhofen; preparation of the solution under addition of 5% ethanol and storage in a water bath at 45 °C) by apperitally. The number of animals was studied in parallel with the observation of the individual doses.

All compounds tested showed a marked analgesic effect, which was enhanced compared to tramadol.

The results are summarised in the following table. Tabelle:

erfindungsgemäße Verbindung hergestellt nach Beispiel
2	1,37
3 (+)-Enantiomer	2,25
3 (-)-Enantiomer	0,98
4	1,64
12	0,97
13	2,96
15	1,33
18	2,07
zum Vergleich: Tramadol	3,68

Claims (9)

1. Dimethyl-(3-aryl-but-3-enyl)-amine compounds of formula I where R¹ is C_1-5 alkyl and R² denotes H or C_1-5 alkyl, R³ denotes H or Ci-s alkyl, R⁴ denotes H, OH, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CF₃, O-CF₃, Cl, F or OR⁸, R⁵ represents H, OH, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CHF₂, CF₃, O-CF₃, Cl, F or OR⁸, and R⁶ denotes H, OH, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CF₃, O-CF₃, Cl, F or OR⁸, with the proviso that two of the radicals R⁴, R⁵ or R⁶ are H, or R⁴ and R⁵ together denote -CH=C(R⁹)-O- or -CH=C(R⁹)-S-, with the proviso that R⁶ is H, or R⁵ and R⁶ together denote -CH=CH-C(OR¹⁰)=CH-, with the proviso that R⁴ is H, R⁸ denotes CO-C_1-5 alkyl, PO(O-C_1-4 alkyl)₂, CO-C₆H₄-R¹¹, CO(O-C_1-5 alkyl), CO-CHR¹²-NHR¹³, CO-NH-C₆H₃-(R¹⁴)₂ or a pyridyl, thienyl, thiazoyl or phenyl group, R⁹ denotes H or C_1-4 alkyl, R¹⁰ denotes H or Ci-3 alkyl, R¹¹ denotes OC(O)-C_1-3 alkyl in the ortho position or CH₂-N-(R¹⁵)₂ in the meta or para position, wherein R¹⁵ denotes C_1-4 alkyl or both radicals R¹⁵ form the 4-morpholino radical together with N, R¹² and R¹³ are the same or different and denote H, C_1-6 alkyl or C_3-8 cycloalkyl, or R¹² and R¹³ together denote -(CH₂)_3-8-, R¹⁴ denotes H, OH, C_1-7 alkyl, O-C_1-7 alkyl, phenyl, O-aryl, CF₃, Cl or F, with the proviso that the two radicals R¹⁴ are the same or different, in the form of their bases and/or salts of physiologically compatible acids, as enantiomers or racemates.
2. Dimethyl-(3-aryl-but-3-enyl)-amine compounds according to claim 1, characterised in that R¹ is C_1-3 alkyl and R² denotes H or C_1-3 alkyl, R³ denotes H or Ci-3 alkyl, R⁴ denotes H, OH, CF₃, Cl, F or OR⁸, R⁵ represents H, OH, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CHF₂, CF₃, Cl, F or OR⁸, and R⁶ denotes H, OH, O-C_1-4 alkyl, O-benzyl, CF₃,Cl, F or OR⁸, with the proviso that two of the radicals R⁴, R⁵ or R⁶ are H, or R⁴ and R⁵ together denote -CH=C(R⁹)-O- or -CH=C(R⁹)-S-, with the proviso that R⁶ is H, or R⁵ and R⁶ together denote -CH=CH-C(OR¹⁰)=CH-, with the proviso that R⁴ is H.
3. Dimethyl-(3-aryl-but-3-enyl)-amine compounds according to claim 1 or 2, characterised in thatR¹ represents CH₃ or C₃H₇ and R² represents H, CH₃ or CH₂CH₃, R³ denotes H, CH₃ or CH₂CH₃, R⁴ denotes H or OH, R⁵ denotes H, OH, OCH₃, CHF₂ or OR⁸ and R⁶ denotes H, OH or CF₃, with the proviso that two of the radicals R⁴, R⁵ or R⁶ are H, or R⁴ and R⁵ together represent -CH=C(CH₃)-S-, with the proviso that R⁶ is H, or R⁵ and R⁶ together represent -CH=CH-C(OH)=CH-, with the proviso that R⁴ is H, and R⁸ represents CO-C₆H₄-R¹¹, where R¹¹ represents OC(O)-C_1-3 alkyl in the ortho position.
4. Dimethyl-(3-aryl-but-3-enyl)-amine compounds according to one or more of claims 1 to 3, characterised in that R¹ denotes CH₃ and R² denotes H or CH₃, R³ denotes H or CH₃, R⁴ is H, R⁵ denotes OH or OR⁸, R⁶ is H, and R⁸ denotes CO-C₆H₄-R¹¹, where R¹¹ represents OC(O)-CH₃ in the ortho position.
5. A method of preparing a dimethyl-(3-aryl-but-3-enyl)-amine compound of formula I where R¹ is C_1-5 alkyl and R² denotes H or C_1-5 alkyl, R³ denotes H or C_1-5 alkyl, R⁴ denotes H, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CF₃, O-CF₃, Cl or F, R⁵ represents H, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CHF₂, CF₃, O-CF₃, Cl or F, and R⁶ denotes H, C_1-4 alkyl, O-C_1-4 alkyl, O-benzyl, CF₃, O-CF₃, Cl or F, with the proviso that two of the radicals R⁴, R⁵ or R⁶ are H, or R⁴ and R⁵ together denote -CH=C(R⁹)-O- or -CH=C(R⁹)-S-, with the proviso that R⁶ is H, or R⁵ and R⁶ together denote -CH=CH-C(OR¹⁰)=CH-, with the proviso that R⁴ is H, R⁹ denotes H or C_1-4 alkyl, and R¹⁰ denotes H or C_1-3 alkyl, characterised in that a β-dimethylaminoketone of formula II is reacted with an organometallic compound of formula III where Z denotes MgCl, MgBr, MgI or Li, to form a tertiary alcohol of formula IV which is subsequently dehydrated to form a compound of formula I.
6. A method of preparing a dimethyl-(3-aryl-but-3-enyl)-amine compound of formula I where R¹ is C_1-5 alkyl and R² denotes H or C_1-5 alkyl, R³ denotes H or C_1-5 alkyl, one of the radicals R⁴, R⁵ or R⁶ denotes OH and the other two radicals are H, characterised in that a compound of formula I, in which one of the radicals R⁴, R⁵ or R⁶ denotes O-CH₃ and the other two radicals are H, is reacted with diisobutylaluminium hydride, or a compound of formula I, in which one of the radicals R⁴, R⁵ or R⁶ denotes O-benzyl and the other two radicals are H, is reductively debenzylated.
7. A drug containing, as a pharmaceutical active ingredient, at least one dimethyl-(3-aryl-but-3-enyl)-amine compound of formula I according to claim 1, in the form of its base and/or salt of a physiologically compatible acid, as an enantiomer or racemate, said drug optionally containing further active ingredients or adjuvants.
8. A drug according to claim 7 for controlling pain.
9. Use of at least one dimethyl-(3-aryl-but-3-enyl)-amine compound of formula I according to claim 1, in the form of its base and/or salt of a physiologically compatible acid, as an enantiomer or racemate, for producing a drug for controlling pain.