HK1031864B - Dimethyl-(3-aryl-but-3-enyl) amine derivatives with analgesic activity - Google Patents
Dimethyl-(3-aryl-but-3-enyl) amine derivatives with analgesic activity Download PDFInfo
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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 - (1RS, 2RS)-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 known side effects of 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-methyltrol, which is also present as an enantiomeric enantiomer.
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 and R2 together constitute - ((CH2)2-4-, - ((CH2)2-CHR7 or - ((CH2-CHR7-CH2-), R3 H means C1-5 alkyl, R4 and R5 together -CH=C(R9)-O- or -CH=C(R9)-S means provided that R6 is H, or R5 and R6 together -CH=CH-C(OR10) = CH- means provided that R4 is H, R7 means C1-8 alkyl, C3-8 cycloalkyl, O-C1-4 alkyl, O-benzyl, CF3, Cl or F, R9 means H or C1-4 alkyl, R10 means H1-3 or C1-3 alkyl, in their base and/or enzyme forms, as salts, racemates or enantiomers.
The preferred dimethyl ((3-aryl-3-but-3-enyl) amines correspond to formula I with R1 and R2 together - ((CH2)2-4- or - ((CH2)-2-CHR7, R3H or C1-3-alkyl, R4 and R5 together -CH=C(R9) -O- or -CH=C(R9) -S-, provided that R6 is H, or R5 and R6 together -CH=CH-C(OR10) =CH-, provided that R4 is H, and R7 C1-4-alkyl, CF3, Cl3 or F. In particular, dimethyl-aryl-but-3-enyl) amines of formula I, where R1 and -CH2 together - ((CH2) -CH2-3-CHCHCH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH-CH
The present invention also relates to a method for the preparation of dimethyl ((3-aryl-but-3-enyl) amines of formula I, where R1 and R2 together constitute - ((CH2)2-4-, - ((CH2) 2-CHR7 or - ((CH2-CHR7-CH2-), R3 H or C1-5 means alkyl, R4 and R5 together - CH=C(R9) -O- or - CH=C(R9) -S, provided that R6 is H, or R5 and R6 together - CH=CH-COR10) = CF, provided that R4 is H, R7 C1-8-alkyl, C3-8-cycloalkyl, O-C1-4-benzyl, O-alkyl, Cl3, or Fok, or R9 H1-4 or C10 C1-3-alkyl, or C1-alkyl, or C1-alkyl, which means β-methyl, and is denoted by the symbol H-Alkyl, which is a dimethyl,
a thickness of not more than 0,05 mm,
where Z stands for MgCl, MgBr, Mgl 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-dimethylamine 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 done 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 brithium, clithium or J, with, for example, an n-butylum/hexane halogen exchange solution by L/L.
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 compounds of the formula 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, diisopropylkylyl, acetic acid ether, acetone and/or 2-butanone.
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.
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.
27 g (1.11 mol) of magnesium flakes were stirred in 150 ml of tetrahydrofuran and 207.6 g (1.11 mol) of 1-bromo-3-methoxybenzene, dissolved in 400 ml of tetrahydrofuran, were dripped. It was heated for one hour under reflux and then cooled to a temperature between 5°C and 10°C. At this temperature 128.30 g (0.89 mol) (RS) -dimethylamino-2-methylpentane-3-one, dissolved in 400 ml of tetrahydrofuran, were dripped. The reaction mixture was stopped and then cooled again to a temperature between 5°C and 10°C. After adding 300 g of tetrahydrofuran, 20 g of hydrochloric acid was diluted with 400 ml of ether (1,111 g) of ethyl sulphate. The second solution was obtained by adding 12 g (12.8 g) of ammonium tetrahydrochloride to a solution of 200 ml of ether (12.8 g) of ammonium tetrahydrochloride and 12 g (12.8 g) of ethyl sulphate (2,2 g) of ammonium tetrahydrofuran.
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 I of ice water and set to a pH of 13 with 10 molar sodium salts. After extraction with ether, drying 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 - 170 °C were obtained.
1,6 I 20 wt. % diisobutylaluminium hydride solution in toluol was dripped at room temperature to 182 g (Z) ((RS) [3-(3-Methoxy-phenyl) -2-methyl-pent-3-enyle] dimethylamine dissolved in 360 ml toluol. Then heated for 11 hours under reflux. After cooling to 0 °C, 450 ml of ethanol were dripped under refrigeration. Then stirred for 15 minutes and diluted with 1 I toluol. Then 450 ml of an ethanol/water mixture (1: 1) were added under refrigerated drop acid. 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 resulting 1667 g (97.6%) of the ethanol was dissolved in a crystalline solution of 1616 g (66.6%) of the hydrochloric acid with a crystalline base of 1667 °C (1,67% of the sodium) and obtained by dissolving it in a crystalline base of 1667 g (1,65%) of the hydrochloric acid.
Enantiomers of (3):
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
The base was removed from the hydrochloride (3) obtained by dichloro-methane/aqueous sodium hydrocarbonate solution as shown in example 2. After drying the solution, the 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 yield is 44% of the theory.
[α]RTDThe following table shows the results of the analysis:
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 dried by tritium sulphate. The solution of the aqueous solution was obtained from a solution of 1,68 g (58 g) of ethyl ethyl alcohol obtained from a solution of 0,68 g (84 °C) of the raw base obtained by dissolving the base of the ethyl chloride in a solution of 0,68 g of ethyl ethyl chloride.
75 g (0.26 mol) (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl) 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) of the raw base ((Z) isomer (2) : (E) isomer (5) = 6 base 4) were obtained. The raw base was placed on a column filled with diesel. The elution was filled with 7 g of methanol: 7 g/W (134 g/W) of theoretical base (134 g/W) of theoretical base (134 g/W) of theoretical base (134 g/W) of theoretical base) was obtained in a 140 °C (218 °C) bath of trimethanol (234 g/W) with a base of trimethanol.
The base was removed with dichloromethane/sodium sulphate and, after drying the solution, the dichloromethane distillate.
Enantiomers of (6):
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
From the hydrochloride obtained in Example 6 (6), the base was released 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 with a melting point of 154 - 155°C.
[α]RTD+36.3° (c = 0.96; methanol) ((-6)): yield: 44 % of the theory
[α]RTDThe following formulae are used:
(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 -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.
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.
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, hydrochloride (9) under the conditions specified in Step 1 (2RS, 3RS) with concentrated hydrochloric acid, at a yield of 36% (depending on the alcohol used) and a melting point of 172°C, under the conditions specified in Step 2 (9).
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.
7.0 g (34 mmol) 1-bromo-3-difluormethylbenzene produced from 3-bromobenzaldehyde and diethylamino sulphur trifluoride according to 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-on. dissolved in 15 ml of dry tetrahydrofuran were added. The reaction chamber 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.
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 crude base were obtained by applying to a column filled with silica gel. The dilution point with diisopropyl/ethyl alcohol = 7 = 1 g (3.0 g) was obtained by distillation of trimetyl chloride/water in a solution of 2,162 g (2,4 g/m2 of theoretical) with a pH of 161°C.
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 and a melting point of 207 to 208 °C under the conditions given in Example 1 (Stage 2).
(E) - (RS) - (E) - (Methoxyphenyl) - (E) - (Methoxyphenyl) - (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 (E) -E) -E
and ((Z) - ((RS) -[3- (3-) -methoxyphenyl) -methyl-hex-3-enyl]-dimethylamine, hydrochloride (15)
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% from the (2RS, 3SR)-3-dimethylamino-1-one and 1-bromo-propane) at a melting point of 131 to 132 °C, under the conditions specified in Step 1 of Example 1. 30 g (0,1 mol) of the compound (16) were converted into 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 given on a column filled with water. The elution was filled with diesel g (Z) 7 g/methoxyethylene: 7 g/methoxyethylene (Z) 7 g/methoxyethylene (Z) 7 g/methoxyethylene (Z) 7 g/methoxyethylene) 14 g/methoxyethylene (Z) 7 g/methoxyethylene) 14 g/methoxyethylene (Z) 5 g/methoxyethylene) 5 g/methoxyethylene (Z) 5 g/methoxyethylene) 5 g/methoxyethylene (Z) 7 g/methoxyethylene) 14 g/methocyl) was obtained in the resulting from the combination of the compound with the base (15).
The melting point is 154° C. The yield is 15.8 g (56% of the theory).
The melting point is 110 to 112 °C.
The base was removed with dichloromethane/sodium chloride 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.
The base was removed with dichloromethane/sodium chloride solution 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.
From (RS)-2-dimethylaminomethyl-1- ((3-methoxy-phenyl) -pentan-1-one and methyliodide, using ether as solvent (2RS, 3SR) -dimethylaminomethyl-2- ((3-methoxy-phenyl) -hexane-2-ol), hydrochloride (20) was obtained at a yield of 76%, with a melting point of 137 to 138 °C, under the conditions specified in Step 1 of Example 1. 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 = 121 g: 24 g were obtained with trimethyl chloride/water in 2-methyl methanol (2,3 g/water) (23,4 g/mol) obtained from a solution of 120 °C (74 g/mol) of methyl methyl base.
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 to 179 °C (23) using ether as solvent (2RS, 3SR) -4-dimethylamino-2- (((3-methoxyphenyl) -3-methylbutan-2-ol, hydrochloride) 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 the vacuum. 23,7 g (0,1 mol) of the base was converted with diisobutyinium lalalum hydrochloride as described in Step 2 of Example. In this way, 18,5 g (71 mol) of the hydrochloromethane (22) were obtained with a melting point of 183 °C.
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 by concentrated hydrochloric acid in acetone.
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 on a column filled with elution. The solution with diisopropyl ether/methanol base = 7 : 1 yielded 19 g (77 % of the theory) as a bright oil gel.
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.
(RS) 2-dimethylaminomethyl-cyclopentane and 1-brom-4-trifluorethylbenzene were converted under the conditions given in example 1 (step 1). 30 g of the resulting raw product were transferred to a column filled with silica gel. Elution with acetic acid ethyl ester/methanol = 5 : 1 yielded 11.6 g of base, which was filled with trimethyl chloride Elu/water in 2-Bilanon in 12.0 g (21 % of the theory) (1 RSRS) 2-dimethylamethyl-1-trifluorethylphenyl-cyclopentane, hydrochloride (28) with a melting point of 213 - 214 °C. 32.4 g of amethyl hydrochloride (28) were transferred to the column filled with concentrated acetic acid (0,5 g) in accordance with example 5 : 450 ml. The resulting base was transferred to a column filled with trimetyl chloride Elu/water in 2-Bilanon (29 °C) (29.9 g/methanol), which was filled with a mixture of 220 g of diethyl methanol (29 °C) The base was transferred to a column filled with trimetyl chloride (29 g/metyl methyl methyl isothenol) in a base, which was filled with a mixture of 2,9 - 9%, which was mixed with diethyl methanol (29 = 7 °C) (29 = 9 g/metyl methyl is obtained in a base, which was mixed with a mixture of 220 g of trimetyl methanol (29 = 9 g/metyl methanol, 2 = 7%) The base was transferred to a column filled with a mixture of water (29 g/metyl methanol (29 = 9 g/metyl methanol, which was mixed with trimetal (29 = 7 g/metyl methanol, which was mixed with trimetal)
Enantiomers of (27):
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
and ((-) - ((R) -dimethyl-[2- (trifluoromethylphenyl) -cyclopent-2-enylmethyl]amine, hydrochloride (-27)
The base was released from (27) with dichloromethane/sodium salts. 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 obtained by conversion into acetone with concentrated hydrochloric acid at a melting point of 244 to 246 °C.
(+27): yield: 42% of the theory
[α]RTDThe yield is 44% of the theory.
[α]RTDThe following formulae are used:
From (RS)-2-dimethylaminomethyl cyclohexanone and 1-bromo-2-methoxybenzene, the base was released with dichloromethane/sodium sulphate. After drying the solution, dichloromethane was distilled in the solution. 30,0 g (0,1 mol) of the base were converted to diisobutylaluminium according to step 2. 22,7 g (18,8 of the theoretical point) (1,2 RS)-2-dimethylaminomethyl cyclohexanol was obtained from (47%) (30). The base was filled with dichloromethane/sodium sulphate. After drying the solution, dichloromethane was distilled in the solution.
Enantiomers of (29):
(-) - R) -2-dimethylaminomethyl cyclohex-1-enyle) phenol, hydrochloride (-29)
and+ (S) - (S) -2- (D) -6-dimethylaminomethyl-cyclohex-1-enyle) phenol, hydrochloride (+29)
The base was released from (29) 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 271 to 272°C.
(+29): yield: 43 % of the theory
[α]RTDThe yield is 44% of the theory.
[α]RTDThe following formulae are used:
(RS) 2-dimethylaminomethyl-cyclohexane and 1-brom-4-trifluorethylbenzene were converted under the conditions given in example 1 (step 1). 30 g of the raw product were placed on a column filled with silica gel. Elution with acetic acid ethyl ester/methanol = 5 : 1 yielded 18.9 g of base, which was filled with trimethyl chlorosylane/water in 2-butane in 16.4 g (37% of the theory) (1 RSRS) 2-dimethylaminomethyl-1-trifluorethylphenyl) cyclohexane, hydrochloride (33) with a melting point of 234 °C. 33.7 g of ammonium hydroxide (33) were placed on a column filled with concentrated acetic acid in accordance with example 5 : 1 . The base was placed on a column filled with trimetyl chlorosyl ether (32.0 g/mol/W) and silica gel (32.0 g/W) The samples were obtained in a column filled with methanol, diethyl ether (32.0 g/W) and silica gel with a melting point of 20.5 °C.
(RS) 2-Dimethylaminomethyl-cyclohexanone and 4-Brom-2-methyl-benzo[b]thiophen were converted under the conditions given in Example 1 (step 1) using ether as solvent and 1,2-Dibromethane as carrier. 25 g of the raw product were placed on a column filled with silica gel. Elution with acetic acid ethyl ester/methanol = 1 : 1 yielded 12.6 g, which was converted into trimethyl basechloricyl sulphate/water in 2-butane in 10,4 g (29% of the theory) (1RS,2RS) 2-Dimethylaminomethyl-1-methyl-benzo[b]thiophen-point) Trimethyl-cyclohexanol, hydrochlorohexanol (35) with a melting point of 204°C. These were added to a column of 17,8 g (14,0 g) of water (34,0 g) in a molar form containing 17,8 g (34,0 g) of ammonium hydrochlorohexanol (28,5 g) in a molar form containing 450 ml (28,4 g) of ammonium sulphate.
(-) - 3S,6R) - 3-6-dimethylaminomethyl-3-methyl-cyclohex-1-enyl) phenol, hydrochloride (-36)
and+ (() - ((3R,6S) 3- ((6-Dimethylaminomethyl-3-methyl-cyclohex-1-enyle) phenol, hydrochloride (+36)
95 ml (750 mmol) 1-bromo-3-methoxybenzole was dissolved in 425 ml of dry tetrahydrofuran and cooled to -75°C. After adding 750 mmol of 1.6 molar n-butyllithium solution to hexane, it was stirred for one hour at -75°C. Then 82 g (484 mmol) (2RS,5SR) 2-dimethylaminomethyl-5-methylcyclohexane, produced from 3-methylcyclohexane, dimethylaminohydrochloride and paraformaldehyde, was added to ice acid dissolved in 120 ml of dry tetrahydrofuran. The room was heated up to room temperature within 2.5 hours.
For processing, 200 ml of water were added under freezing to keep the internal temperature at 15°C. After phase separation, the aqueous phase was extracted three times with 50 ml of acetic acid ethyl ester. The combined organic phases were dried with sodium sulphate. After the solvent was removed by a nitrating agent, the residue was dissolved in 700 ml of acetone and added to trimethyl chlorosilane/water. At 4-5°C, 67 g (48% of the theory) of hydrochloride (37) with a melting point of -173°C crystallized.
Enantiomers of (37):
(+) - 1 R,2R,5S) - 2-dimethylaminomethyl-1- ((3-methoxyphenyl) -5-methylcyclohexanol, hydrochloride (+37)
and ((-) - ((1S,2S,5R) -dimethylaminomethyl-1- ((3-methoxyphenyl) -5-methylcyclohexanol, hydrochloride (-37)
The base was released from (37) with dichloromethane/sodium sulphate. After drying the solution, dichloromethane was distilled in a vacuum. The racemate was then separated on the chiral HPLC column. From the enantiomers obtained, the hydrochlorides were isolated by conversion to 2-butanone with trimethyl chlorosilane/water at a melting point of 151-153°C.
(+37): yield: 43 % of the theory
[α]RTDThe yield is 44% of the theory.
[α]RtDThe following formulae are used:
(-) - 1R,4S) - [2-3-methoxyphenyl]-4-methyl-cyclohex-2-enylmethyl]dimethylamine, hydrochloride (-38)
and+() - 1S,4R) -[2- (3-methoxyphenyl) -4-methyl-cyclohex-2-enylmethyl]dimethylamine, hydrochloride (+38)
The methoxy compounds (-37) and (+37) from step 2 were converted to the hydrochlorides (+38) and (-38) at a yield of 87% of the theory and a melting point of 122 to 123°C under the conditions given in example 5.
(-) - 3S,6R) - 3-6-dimethylaminomethyl-3-methyl-cyclohex-1-enyl) phenol, hydrochloride (-36)
and+ (() - ((3R,6S) 3- ((6-Dimethylaminomethyl-3-methyl-cyclohex-1-enyle) phenol, hydrochloride (+36)
From the bases obtained after step 3, the hydrochlorides (-36) and (+36) were obtained at a yield of 79% of the theory and a melting point of 131 to 133°C by transformation with diisobutylaluminiumhydride and subsequent hydrochloride precipitation with trimethylchlorsilane/water in 2-butanone under the conditions given in example 2.
(-36):[α]RTDThe following is added to the list of active substances:RTDThe following formulae are used:
28.8 g (0.1 mol) (+) - 1R,2R) - 3-(2-Dimethylaminomethyl-1-hydroxycyclohexyl) phenol hydrochloride was dissolved in 450 ml of concentrated formic acid and heated for two hours under return flow.
(-39):[α]RTDThe following formulae are used:
Under the conditions given in example 26, hydrochloride obtained from 28,8 g (0.1 mol) (-) - ((1 S,2S) -3- ((2-Dimethylaminomethyl-1-hydroxy-cyclohexyl) phenol, hydrochloride 21,8 g (81,4% of the theory) hydrochloride (+39) with a melting point of 216 to 217 °C.
(+39):[α]RTDThe following formulae are used:
The analgesic effect was studied in the 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.
Other 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 |
| 20 (+)-Enantiomer | 1,40 |
| 22 (-)-Enantiomer | 2,12 |
| 1,35 | |
| 25 (-)-Enantiomer | 0,90 |
| 26 (-)-Enantiomer | 1,04 |
| 27 (+)-Enantiomer | 1,60 |
| zum Vergleich: Tramadol | 3,68 |
Claims (7)
- Dimethyl-(3-arylbut-3-enyl)amine compounds of the formula I in which R1 and R2 together represent -(CH2)2-4-, -(CH2)2-CHR7 or -CH2-CHR7-CH2-, R3 means H or C1-5 alkyl, R4 and R5 together mean -CH=C(R9)-O- or -CH=C(R9)-S-, with the proviso that R6 is H, or R5 and R6 together mean -CH=CH-C(OR10)=CH-, with the proviso that R4 is H, R7 means C1-8 alkyl, C3-8 cycloalkyl, O-C1-4 alkyl, O-benzyl, CF3, Cl or F, R9 means H or C1-4 alkyl, R10 means H or C1-3 alkyl, in the form of the bases thereof and/or salts of physiologically acceptable acids, as enantiomers or racemates.
- Dimethyl-(3-arylbut-3-enyl)amine compounds according to claim 1, characterised in that R1 and R2 together mean -(CH2)2-4- or -(CH2)2-CHR7, R3 means H or C1-3 alkyl, R4 and R5 together mean -CH=C(R9)-O- or -CH=C(R9)-S-, with the proviso that R6 is H, or R5 and R6 together mean -CH=CH-C(OR10)=CH-, with the proviso that R4 is H, and R7 means C1-4 alkyl, CF3, Cl or F.
- Dimethyl-(3-arylbut-3-enyl)amine compounds according to claim 1 or 2, or characterised in that R1 and R2 together mean -(CH2)2-3- or -(CH2)2-CHR7, R3 means H, CH3 or CH2CH3, R4 and R5 together represent -CH=C(CH3)-S-, with the proviso that R6 is H, or R5 and R6 together mean -CH=CH-C(OH)=CH-, with the proviso that R4 is H.
- A process for the production of a dimethyl-(3-arylbut-3-enyl)amine compound of the formula I [in which] R1 and R2 together represent -(CH2)2-4-, -(CH2)2-CHR7 or -CH2-CHR7-CH2-, R3 means H or C1-5 alkyl, R4 and R5 together mean -CH=C(R9)-O- or -CH=C(R9)-S-, with the proviso that R6 is H, or R5 and R6 together mean -CH=CH-C(OR10)=CH-, with the proviso that R4 is H, R7 means C1-8 alkyl, C3-8 cycloalkyl, O-C1-4 alkyl, O-benzyl, CF3, Cl or F, R9 means H or C1-4 alkyl and R10 means H or C1-3 alkyl, characterised in that a β-dimethylaminoketone of the formula II is reacted with an organometallic compound of the formula III in which Z means MgCl, MgI or Li, to yield a tertiary alcohol of the formula IV which is subsequently dehydrated to yield a compound of the formula I.
- A pharmaceutical preparation containing as pharmaceutical active ingredient at least one dimethyl-(3-arylbut-3-enyl)amine compound of the formula I according to claim 1 in the form the base thereof and/or the salt thereof of a physiologically acceptable acid, as an enantiomer or racemate and optionally further active ingredients and/or auxiliary substances.
- A pharmaceutical preparation according to claim 5 for the treatment of pain.
- Use of at least one dimethyl-(3-arylbut-3-enyl)amine compound of the formula I according to claim 1 in the form of the base thereof and/or the salt thereof of a physiologically acceptable acid as an enantiomer or racemate for the production of a pharmaceutical preparation for the treatment of pain.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19609847 | 1996-03-13 | ||
| DE19609847A DE19609847A1 (en) | 1996-03-13 | 1996-03-13 | Dimethyl- (3-aryl-but-3-enyl) amine compounds as active pharmaceutical ingredients |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1031864A1 HK1031864A1 (en) | 2001-06-29 |
| HK1031864B true HK1031864B (en) | 2004-11-19 |
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