MXPA00003286A - 3-amino-3-arylpropan-1-ol-compounds, their preparation and use - Google Patents
3-amino-3-arylpropan-1-ol-compounds, their preparation and useInfo
- Publication number
- MXPA00003286A MXPA00003286A MXPA/A/2000/003286A MXPA00003286A MXPA00003286A MX PA00003286 A MXPA00003286 A MX PA00003286A MX PA00003286 A MXPA00003286 A MX PA00003286A MX PA00003286 A MXPA00003286 A MX PA00003286A
- Authority
- MX
- Mexico
- Prior art keywords
- medicament
- substituted
- preparing
- compound according
- meaning
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 33
- 230000000875 corresponding Effects 0.000 claims abstract description 17
- -1 aryl radical Chemical class 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 239000000126 substance Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 208000002193 Pain Diseases 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000036407 pain Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 230000000202 analgesic Effects 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000005842 heteroatoms Chemical group 0.000 claims description 5
- 206010012735 Diarrhoea Diseases 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 208000003251 Pruritus Diseases 0.000 claims description 4
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- 230000003474 anti-emetic Effects 0.000 claims description 4
- 201000008286 diarrhea Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 4
- TZJNJXWEBVVSRG-UHFFFAOYSA-N 1-[2-[(4-fluorophenyl)methoxy]cyclohexyl]-N,N-dimethyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1C(N(C)C)C1CCCCC1OCC1=CC=C(F)C=C1 TZJNJXWEBVVSRG-UHFFFAOYSA-N 0.000 claims description 3
- 241000349731 Afzelia bipindensis Species 0.000 claims description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 3
- VFJVOUALZFHZDG-UHFFFAOYSA-N [2-[dimethylamino(phenyl)methyl]cyclohexyl] 4-(trifluoromethyl)benzoate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(N(C)C)C1CCCCC1OC(=O)C1=CC=C(C(F)(F)F)C=C1 VFJVOUALZFHZDG-UHFFFAOYSA-N 0.000 claims description 3
- AXRVTRDRHNAPRN-UHFFFAOYSA-N [2-[dimethylamino(phenyl)methyl]cyclohexyl] 4-methoxybenzoate;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C(=O)OC1C(C(N(C)C)C=2C=CC=CC=2)CCCC1 AXRVTRDRHNAPRN-UHFFFAOYSA-N 0.000 claims description 3
- 230000003288 anthiarrhythmic Effects 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 230000002276 neurotropic Effects 0.000 claims description 3
- 230000001777 nootropic Effects 0.000 claims description 3
- 239000003638 reducing agent Substances 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- MADUKBQNRNATLR-UHFFFAOYSA-N 1-(2-chlorophenyl)-N,N-dimethyl-1-[2-[(4-methylphenyl)methoxy]cyclohexyl]methanamine Chemical compound C=1C=CC=C(Cl)C=1C(N(C)C)C1CCCCC1OCC1=CC=C(C)C=C1 MADUKBQNRNATLR-UHFFFAOYSA-N 0.000 claims description 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical class [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminum hydride Chemical compound [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 claims description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims description 2
- 230000001131 transforming Effects 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 6
- 206010013663 Drug dependence Diseases 0.000 claims 2
- 208000008787 Cardiovascular Disease Diseases 0.000 claims 1
- 208000000094 Chronic Pain Diseases 0.000 claims 1
- 201000007930 alcohol dependence Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- HMONSXRREGWFKT-UHFFFAOYSA-N lithium;bis(2-methylpropyl)alumanylium;hydride Chemical compound [H-].[H-].[Li+].CC(C)C[Al+]CC(C)C HMONSXRREGWFKT-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
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- 238000006243 chemical reaction Methods 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 230000027455 binding Effects 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- WVSQYKDRGSOGRK-UHFFFAOYSA-N 2-[dimethylamino(phenyl)methyl]cyclohexan-1-ol Chemical compound C=1C=CC=CC=1C(N(C)C)C1CCCCC1O WVSQYKDRGSOGRK-UHFFFAOYSA-N 0.000 description 9
- IJOOHPMOJXWVHK-UHFFFAOYSA-N Trimethylsilyl chloride Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
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- 238000007792 addition Methods 0.000 description 6
- 150000002081 enamines Chemical class 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 5
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- 230000002401 inhibitory effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
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- 150000001298 alcohols Chemical class 0.000 description 4
- NNUFCPXGFRLSRB-UHFFFAOYSA-M benzylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CC1=CC=CC=C1 NNUFCPXGFRLSRB-UHFFFAOYSA-M 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 description 3
- KTZNVZJECQAMBV-UHFFFAOYSA-N 1-(cyclohexen-1-yl)pyrrolidine Chemical compound C1CCCN1C1=CCCCC1 KTZNVZJECQAMBV-UHFFFAOYSA-N 0.000 description 3
- HXGMBPVFIKAXKE-UHFFFAOYSA-N 2-[(2-chlorophenyl)-(dimethylamino)methyl]cyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1C(N(C)C)C1CCCCC1=O HXGMBPVFIKAXKE-UHFFFAOYSA-N 0.000 description 3
- RLAIUHMFJDHPGV-UHFFFAOYSA-N 2-[dimethylamino(phenyl)methyl]cyclohexan-1-one Chemical compound C=1C=CC=CC=1C(N(C)C)C1CCCCC1=O RLAIUHMFJDHPGV-UHFFFAOYSA-N 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 239000002111 antiemetic agent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
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- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
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- NQDXTGYNAHWRJB-UHFFFAOYSA-N 1-[2-[(3-fluorophenyl)methoxy]cyclohexyl]-N,N-dimethyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1C(N(C)C)C1CCCCC1OCC1=CC=CC(F)=C1 NQDXTGYNAHWRJB-UHFFFAOYSA-N 0.000 description 2
- CSNAWUIMSCOKDI-UHFFFAOYSA-N 2-[(2-chlorophenyl)-(dimethylamino)methyl]cyclohexan-1-ol;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C(N(C)C)C1CCCCC1O CSNAWUIMSCOKDI-UHFFFAOYSA-N 0.000 description 2
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- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
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- 125000004432 carbon atoms Chemical group C* 0.000 description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
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- 229940035676 ANALGESICS Drugs 0.000 description 1
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- HSUGRBWQSSZJOP-RTWAWAEBSA-N Diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
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Abstract
3-amino-3-arylpropan-1-ol compounds corresponding to the formula Iin which R1 to R5, A and X have the meanings according to claim 1, and their preparation and use as medicaments.
Description
DERIVATIVES OF 3-AMINO-3-ARILOPROPAN-1-OL, ITS PREPARATION AND ITS USE Description of the invention The invention relates to 3-amino-3-arylpropan-1-ol derivatives of the general formula I
wherein Rx, R2, each independently from each other, C? _6 alkyl, or R1 and R2 together form a ring (CH2) 2_6 which may also be benzocondensate or substituted by phenyl RH, methyl R4, R ° in each case independent of each other, C6-6-alkyl, C3-6-cycloalkyl, phenyl, benzyl, phenethyl, or R4 and R5 together form a ring (CH2) 3-6 or CH2CH2OCH2CH2, A an aryl radical that eventually has heteroatoms in the ring and / or X may be substituted a substituted benzyl of the formula XI XI or a substituted benzoyl of the formula XII
JU1,
wherein R12 to R14 in each case independent of each other, mean H, F, Cl, Br, CHF2, CF3, OR11, SR11, OCF3, S02CH3, S02CF3, Ci-e-alkyl, phenyl, CN, COOR11, N02 with R, 1 ± 1A Ci-e-alkyl, phenyl, benzyl, phenethyl and their diastereomers or enantiomers in the form of their bases or physiologically acceptable acid salts, as well as with their preparation and use as medicaments. The treatment of chronic and non-chronic allergic states is of great importance in medicine, since pain is among the basic symptoms of the clinic. Currently there is a need worldwide for additional therapy against pain, not exclusively opioid but very effective. The urgent need for actions to achieve a treatment of chronic and non-chronic algesia states specifically oriented and appropriate to the patient, so that it is meant to understand the successful treatment of pain, and satisfactory for the patient, is documented by the large amount of scientific works that have appeared lately in the field of applied analgesia or, where appropriate, the investigation of the foundations of nociception. Classic opioids, such as morphine, are very effective in the treatment of severe pain. However, its application is restricted due to its known side effects, for example respiratory depression, vomiting, sedation, constipation, addiction and to which a tolerance develops. Therefore they can only be administered over a longer period or at higher dosages subject to special precautionary measures such as, for example, facultative prescriptions (Goodman, Gilman, The Pharmacological Basis of Theraputics, Pergamon Press, New York 1990). They are also less effective in the case of some states of algesia, particularly in the case of neuropathic pain. The task on which the invention is based was to find a new structural class of analgesically active substances, suitable for pain therapy. Other tasks were to find active substances also suitable as local anesthetics and / or antiarrhythmics and / or antiemetics and / or nootropics. { neurotropic) and / or for the treatment / therapy of carcinovascular diseases and / or urinary incontinence and / or diarrhea and / or pruritus and / or alcohol addiction and / or drugs and / or medications, and / or of inflammations. It was found that the class of compounds of the general formula I is distinguished by a pronounced analgesic effect. Additionally, the compounds of the general formula I show a clear affinity to bonding point 2 of the sodium channel (BTX bond), to the point of binding of the benzothiazepine of the L-type calcium channel (diltiazem bond). Because of this, the class of the compounds of the general formula I is also suitable for preparing a local anesthetic and / or an antiarrhythmic and / or an antiemetic and / or a nostrópics (neurstrópics) and / or to prepare a medicament for the treatment / the therapy of caries and / or urinary incontinence and / or diarrhea and / or pruritus and / or dependence on alcohol and / or drugs and / or drugs and / or inflammations . Therefore, the invention relates to 3-amino-3-arylpropan-l-ol derivatives of the general formula I, and their diastereomers or enantiomers in the form of their bases or salts of physiologically acceptable acids. Preferred are compounds of the general formula I in which R1 and R2 together form a ring (CH2) 2-6, which may also be benzocondensate or substituted phenyl, R3 to R5, A and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which R1 and R2 together form a ring (CH2) 4 which may also be benzocondensate or substituted phenyl, R3 to R5, A and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which R3 represents hydrogen, R1, R2, R4, R5, A and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which A means a radical of the substituted phenyl group of formula XIII
XITI
where R6 to R1D mean, in each case independent of each other, H, F, Cl, Br, I, CF3, OH, OR11, OCF3, SR11, S02CH3, S02CF3, Ci-e-alkyl, phenyl, CN, COOR11 , N02, or R6 and R7 or R7 and R8 together form a ring 0CH20 or 0CH2CH20, R11C? -6-alkyl, phenyl, benzyl, phenethyl or A means a thiophene or furan radical, substituted or unsubstituted, and R1 to R5 and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which R1 and R2 together form a ring (CH2) 2_6, which may also be benzocondensate or substituted phenyl, R3 represents hydrogen, R4, R5, A and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which R1 and R2 together form a ring (CH2) 4 which may also be benzo-condensed or substituted for phenyl, A is a radical of the substituted phenyl group of formula XIII, or a thiophene or furan radical, substituted or unsubstituted, R3 rep hydrogen, R4, R5 and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which R1 and R2 together form a ring (CH2), A is a radical of the group of substituted phenyl of the formula XIII or a thiophene or furan radical, substituted or unsubstituted, R3 represents hydrogen, R4, R5 and X have the meaning according to the definition of the general formula I, or compounds of the general formula I in which R1 and R2 together form a ring (CH2), A is a substituted or unsubstituted thiophene radical, R3 represents hydrogen, R4, R5 and X have the meaning according to the definition of the general formula I, or compounds of the general formula I wherein R1 and R2 together form a ring (CH2) 4, A is a substituted or unsubstituted furan radical, R3 represents a radical of the group of hydrogen or methyl, R4, R5 and X have the meaning according to the definition of the general formula I, or compounds of the formula ula general I in which X represents a substituted benzyl radical of the formula XI, R1 to R5 and A have the meaning according to claim 1. Other preferred compounds are: Dimethyl-. { [2- (2-methylbenzyloxy) cyclohexyl] phenylmethyl} -amine, and the corresponding hydrochloride [2- (dimethylaminophenylmethyl) cyclohexyl] -4-trifluoromethyl-benzoate, and the corresponding hydrochloride [2- (dimethylaminophenylmethyl) cyclohexyl] -4-methoxybenzoate, and the corresponding hydrochloride. { [2- (2-chlorobenzyloxy) cydohexyl] - (2-chlorophenyl) -methyl} dimethylamine, and the corresponding hydrochloride. { (2-chlorophenyl) - [2- (4-methylbenzyloxy) cyclohexyl] -methyl} dimethylamine, and the corresponding hydrochloride. { [2- (4-Fluorobenzyloxy) cyclohexyl] phenylmethyl} -dimethylamine, and the corresponding hydrochloride In a particular embodiment of the invention, the enantiomers of a compound according to the invention are used in a non-equimolar proportion as an active substance in a medicament that may possibly contain other active substances, since the proportion of an enantiomer in the mixture of enantiomers preferably represents from 5 to 45 mass percent. Within the scope of the present invention, the expression "C? _6-alkyl" means straight or branched chain hydrocarbons with 1-6 carbon atoms. As an example, methyl, ethyl, propyl, isopropyl, n-butyl, sec. -butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl. Within the frame of the present invention the term "C3_7-cycloalkyl" means saturated cyclic hydrocarbons or straight or branched chain alkyl radicals containing saturated cyclic hydrocarbons, with a total of 3 to 7 carbon atoms. By way of example, cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclobutyl, 1-cyclopropylethyl, 2-cyclopropyl-ethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl or cycloheptyl are mentioned. Within the framework of the present invention the term "aryl" means carbocycles, preferably aromatic, unsubstituted or optionally mono- or polysubstituted with the radicals R6 to R10 according to general formula XIII, which may contain heteroatoms in the ring system. Preferably, a substituted phenyl of the formula XIII is substituted for the aryl. Preferably the aryl radicals with heteroatoms mean within the scope of the present invention 5- or 6-membered unsaturated heterocyclic compounds, optionally condensed with other rings, mono- or polysubstituted with radicals R6 to R10 according to general formula XIII, or unsubstituted, which they contain one or two heteroatoms such as nitrogen, oxygen and / or sulfur. As an example of the group of unsaturated heterocyclic compounds, furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline are listed. Another object of the present invention are the processes for the preparation of the compounds of the general formula I. In order to prepare the compounds of the general formula I, the Mannich bases of the formula II are reacted with a suitable nucleophile, such as, for example, a organometallic compound (H3C) Y, wherein Y means, for example, MgCl, MgBr, Mgl or Li, or with a reducing agent such as, for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydride aluminum diisobutyl or a complex analog of these compounds at temperatures between -70 ° C and + 110 ° C. The ethers or esters of the general formula I can be obtained according to normal methods from the corresponding alcohols by reacting the alcohols with the corresponding benzyl or benzoyl halides in the presence of inorganic or organic bases. The esters can also be obtained by condensation of the alcohols with carboxylic acids (R.C. Larock; Comprehensive Organic Transformations; VCH Publishers; New York, Weinheim, Cambridge 1989).
IX
The reaction of the Mannich base of formula II with a Grignard MeY compound in which Y means MgCl, MgBr or Mgl, or with an organolithium compound MeLi can be carried out in an aliphatic ether, for example diethyl ether and / or tetahydrofuran, in a hydrocarbon, for example hexane or toluene, or in mixtures of hydrocarbons and aliphatic ethers, at temperatures between -70 ° C and + 110 ° C. MeLi organolithium compounds can be obtained from organohalogen compounds MeZ, in which Z stands for Cl, Br or I, by reaction with, for example, a solution of n-butyllithium / hexane by the exchange of halogen-lithium. In the reaction of a Mannich base of formula II with a metal-organic compound MeY, depending on the reaction conditions, tertiary alcohols are preferably obtained with the relative configuration of formula la, in which the cis-aminoarylmethyl group is associates the hydroxyl group if R1 and R2 form a cyclic system. In the case of open-chain systems, the analogous stereochemistry that must be specified as anti is obtained. The compounds of the formula la can be obtained diastomerically pure by separation by column chromatography or by crystallization, also of their salts, for example the hydrochlorides.
The reaction of the Mannich base of formula II with a reducing agent can be carried out in alcohols, water, an ether, a hydrocarbon, a halogen hydrocarbon or mixtures of these solvents at temperatures between -70 ° C and +110. ° C. The conditions of the reduction can be selected in such a way that one of the two possible stereoisomers Ib and le is obtained preferentially or exclusively.
Ib Ia
The Mannich bases of the formula II can be obtained by the reaction of the enamines of the formula III with an inainium salt of the formula IV, in which Y means, for example, Cl ", A1C1", Br ~ or I -.
III IV
The enamines are prepared according to methods known from the literature from ketones of the formula V and secondary amines, for example dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53). The iminium salts are prepared according to methods known from the literature by reacting the amine of the formula VI with acid chlorides, for example acetyl chloride or thionyl chloride (Houben-Weyl-Methoden der Organischen Chemie, E21b ( 1995) 1925-1929).
VI VII
In this it is not necessary to isolate the iminium salts of the formula IV, but they can be prepared in situ and reacted with the enamines of the formula III to obtain Mannich bases of the formula II (Angew.Chem.106 (1994) 2531-2533). By virtue of the enamino-imine tautomerism analogous to the keto-enol tautomerism, it is also possible to use imines of the formula VII instead of the enamines of the formula III. Alternatively it is also possible to directly react ketones of the formula V with iminium salts of the formula IV. But it is also possible to prepare the Mannich bases of the formula II by reacting the enamines of the formula III with an aromatic aldehyde of the formula VIII and a secondary amine HNR4R5, also in the form of the corresponding hydrochloride HNR4R5, HCl, in the presence of triethylamine, chlorotrimethylsilane and sodium iodide (Synlett (1997) 974-976).
TO
VJI?
With the methods described above, depending on the reaction conditions, the Mannich bases of formula II are preferably obtained with the relative configuration of formula Ha in which the anti-amino group is associated with R1. The compounds of the formula Ha can be obtained in pure diastomeric form by crystallization, also their salts, for example the hydrochlorides, or by chromatographic separation.
However, the preparation of the Mannich bases of the formula II is less stereoselectively developed by the addition of 1,4 secondary amines HNRR5 to the enones of the formula IX which are obtained from the condensation of aldol of ketones of the formula V with aromatic aldehydes of the formula VIII (US 4,017,637). Accordingly, this procedure is suitable for the preparation of the other possible stereoisomers.
The meaning of the radicals R1 to R5 and A corresponds to the meaning according to the formula I If chiral amines are used to prepare enamines of the formula III or imines of the formula VII, then in the subsequent Mannich reaction it is possible to obtain bases of Mannich of formula II enriched from enantiomers to enantiomerically pure (Houben-Weyl-Methoden der Organischen Chemie, E21b (1995) 1925-1929). The 3-amino-3-arylpropan-1-ol derivatives of the general formula I which are substituted with a phenol can be prepared, for example, from the corresponding methyl ether derivatives with diisobutylaluminum hydride in an aromatic hydrocarbon, for example toluene, at a temperature between 60 ° C and 130 ° C (Synthesis (1975) 617-630).
The compounds of formula I can be converted into their salts with physiologically acceptable acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid , fumaric acid, lactic acid, citric acid, glutamic acid and / or asparginic acid, in a manner known per se. The formation of the salt is preferably carried out in a solvent such as diethyl ether, diisopropyl ether, alkyl acetate, acetone and / or 2-butanone. For the preparation of the hydrochlorides, trimethylchlorosilane in aqueous solution is also suitable. The substances analogous to formula I are toxicologically innocuous, so that they are suitable as a pharmaceutical active substance in medicaments. Accordingly, another object of the invention are medicaments which contain as active substance at least one compound of the formula I. The medicaments according to the invention are preferably suitable as analgesics. Biochemical investigations have shown that, in addition to their analgetic activity, the compounds of the general formula I also show a marked affinity to the bonding point of the sodium channel (BTX link), to the point of bonding the benzothiazepine of the channel of type L calcium (diltiazem bond). Because of this, in addition to the particularly preferred use of pain therapy, the compounds according to the invention are also suitable for use as a local anesthetic and / or to counteract arrhythmia and / or as antiemetic and / or nootropic (neurotropic) and / or for the treatment / therapy of carcinovascular diseases and / or urinary incontinence and / or diarrhea and / or pruritus and / or dependence on alcohol and / or drugs and / or drugs and / or inflammations. In addition to at least one 3-amino-3-arylpropan-1-ol derivative of the formula I, the pharmaceutical formulations contain vehicles, fillers, solvents, diluents, colorants and / or binders. The choice of these auxiliary substances as well as the amounts to be used thereof will depend on the form of administration of the medicament, whether oral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal or local, for example on infections of the skin, mucous membranes and eyes. For oral application, preparations in the form of tablets, dragees, capsules, granules, drops, juices or syrups are suitable for parenteral, topical and inhalation application solutions, suspensions, dry preparations of easy reconstitution, as well as sprays. The compounds of the general formula I according to the invention in a tank, in dissolved form or in a plaster, optionally with the addition of subcutaneous penetration promoting agents, are suitable examples of percutaneous application forms. The compounds of the general formula I according to the invention can be released in delayed form from oral or percutaneous application preparations. The amount of active substance that should be administered to patients varies depending on the weight of the patient, the form of application, the indications and the degree of severity of the disease. In general, 0.5 to 500 mg / kg of at least one 3-amino-3-arylpropan-l-ol derivative of formula I are applied.
Pharmacological investigations Examination of analgesia in the writhing test conducted in mice The investigation on analgesic activity was investigated according to writhing induced in mice by phenylquinone (modified according to IC Hendershot and J. Forsaith (1959), J. Pharmacol. Ther 125, 237-240). For this purpose, male NMRI mice weighing 25 to 30 g were used. 10 minutes after the intravenous administration of the test substances, groups of 10 animals per dose of substance were administered intraperitoneally 0.3 ml / mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Cia. Sigma, Deisenhofen; the solution by the addition of 5% ethanol and storage in a water bath at 45 ° C). The animals were placed in individual observation cages. The number of pain-induced extension movements (known as Writhing Reactions = stretching the body with extension of the hind limbs) was counted by a key counter 5 to 20 minutes after the administration of phenylquinone. As a control animals were taken that only receive a physiological solution of sodium chloride. All substances were examined in the normal dosage of 10 mg / kg. Percent inhibition (% inhibition) of the writhing reaction by a substance was calculated according to the following formula:
Writhing reactions of treated animals% inhibition = 100 - * 100 Writhing reactions of control animals
Based on the decrease in writhing reactions as a function of dose, in comparison with phenylquinone control groups examined in parallel, the values were calculated for some substances by regression analysis (Martens evaluation program, EDV-Service, Eckental) ED50 with a confidence range of 95% of the writhing reaction. All the compounds according to the invention investigated showed a pronounced analgesic activity. The results "are compiled in table 1. Table 1: Checking the analgesia in the writhing test in mice
Biochemical investigations Research on calcium L-channel bonding Benzothiazepine binding site (diltiazem binding) The biological membrane material was isolated from the cerebral cortex of the rat. As ligand, [3 H] -cis- (+) - diltiazem (5 nM in the preparation) was used. Incubation for 20 minutes at 25 ° C. The non-specific binding is defined as the radioactivity that is measured in the presence of (±) -diltiazem (10 ~ 6 M in the preparation). The unbound ratio of the radioactive ligand is separated after incubation with the aid of a filtration process through Whatman glass fiber GF / B membranes. The membranes are then measured in the ß counter after a washing process. The method was developed according to the publication of Schoemaker and Langer (H. Schoemaker and S.Z. Langer (1985) Eur. J. Pharmacol. 111, 273-277). The CD value for this high affinity binding point was determined at 4.10 ± 0.75 nM (N = 3, that is, average values ± SEM (standard deviation of the mean) of 3 independent test series, which are carried out in triple parallel tests).
Investigations on the link to the sodium channel Linkage point 2 (BTX link) Linkage point 2 of the sodium channel is what is known as the Batracotoxinin (BTX) linkage point.
As a ligand, [3 H] -batracotoxinin A20 a-benzoate (10 nM in the preparation) was used. These particles of the ion channel (synaptosomes) were concentrated in the cerebral cortex of rats according to Gray and Whittaker (E.G. Gray V.P. Whittaker (1962) J. Anat. 76, 79-88). A non-specific binding is defined as the radioactivity that is measured in the presence of veratridin (0.3 mM in the preparation). Incubation for 120 minutes at 37 ° C. The test conditions were carried out according to the publication by Pauwels, Leysen and Laduron (P.J. Pauwels, J.E. Leysen and P.M. Laduron (1986) Eur. J. Pharmacol., 124, 291-298). The CD value for this link point is 24.63 ± 1.56 nM (N = 3, that is, average values ± SEM (standard deviation of the mean) of 3 independent test series, which are carried out in triple parallel tests ).
Evaluation In addition to the percentage inhibition of the test systems in the case of fixed concentrations of the test substance (NA uptake: 1 μm in the preparation, analysis in the ion channel: 10 μm in the preparation) the dependencies were checked of the dose. In this, IC50 values were obtained that can be converted to inhibition constants (Ki) according to the "Cheng-Prusoff equation" (Y.C. Cheng and W.H. Prusoff (1973) Biochem. Pharmacol., 22, 3099-3108). The IC50 values were obtained with the help of the computer program "Figure F" (Version 6.0, Biosoft, Cambridge, England). The values
Km, 'dissociation constant) were calculated according to
Lineweaver and Burk (H. Lineweaver and D. Burk (1934) J. Am. Chem. Soc. 56. 658-666). In order to reproduce CD values, the computer program "Ligand" (Version 4, Biosoft, England) was used. The results of the biochemical investigations are summarized in table 2. Table 2: Biochemistry
EXAMPLES The following examples serve to explain in more detail the process according to the invention, but do not limit the general idea of the invention. The yields of the prepared compounds are not optimized. No temperature is corrected.
Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, Germany, was used as the stationary phase for column chromatography. Thin-layer chromatographic investigations were carried out with prefabricated HPTLC plates, silica gel 60 F 254, from the company E. Merck of Darmstadt, Germany. The separation of the racemates was carried out on a Chiracel OD 250 x 4.6 mm column with a guard column from the company Daicel. The mixing ratios of the eluents for all chromatographic tests are always indicated as volume / volume. RT means room temperature, Vol.% Percent by volume, m% percent by mass, and% excess enantiomers by percent.
Example 1 Dimethyl-. { [2- (2-methyl-benzyloxy) -cyclohexyl-phenyl-methyl} amine, hydrochloride 1. step Benzylidenedimethylammonium chloride 10 g (56 mmoles) of N, N, N ', N' -tetramethyl-C-phenylmethanediamine (J. Am. Chem. Soc. 77 (1955) 1114-1116) dissolved in 100 ml of ether and cooled to 0 ° C in an ice bath. 4.0 ml (56 mmol) of acetyl chloride were added dropwise under nitrogen atmosphere. After the first drops a white salt precipitated, the temperature rose slightly. After 15 hours at room temperature, it was decanted, the solid was washed three times in each case with 100 ml of ether, filtered on a protective gas frit under a nitrogen atmosphere and dried to constant vacuum weight. oil pump. In this way, 7.7 g of benzylidenedimethylammonium chloride were obtained (80.9% of theory). 2. Stage 2- (dimethylaminophenylmethyl) cyclohexanone 7.1 ml (44 mmol) of 1- (pyrrolidino) -1-cyclohexene were dissolved in 45 ml of dichloromethane and cooled to -70 ° C under nitrogen with a dry ice bath / isopropanol. Under stirring 7.5 g (44 mmol) of benzylidenedimethylammonium chloride from step 1 were added, the mixture was heated within two to three hours at -30 ° C, and allowed to stand for 15 hours thereto2- (dimethylaminophenylmethyl) cyclohexanone 7.1 ml (44 mmoles) of 1- (pyrrolidino) -1-cyclohexene were dissolved in 45 ml of dichloromethane and cooled to -70 ° C under nitrogen atmosphere with a dry ice / isopropanol bath. Under stirring 7.5 g (44 mmol) of benzylidene dimethyl ammonium chloride from step 1 were added, the mixture was heated within two to three hours at -30 ° C, and allowed to stand for 15 hours therein, filtered and concentrated in the water. rotary evaporator without heat input (500 to 10 mbar). In this way, 10.1 g of crude base (99.5% of the theory) were obtained. 9.81 g (42.4 mmol) of the crude base were dissolved in 83 ml of 2-butanone, and 0.76 ml (42.2 mmol) of water and 5.36 ml (42.4 mmol) of chlorotrimethylsilane were successively added. The preparation was allowed to stand for 15 hours at room temperature, the precipitated solid was separated by suction, washed with small portions of ether, and dried until the constancy of vacuum weight of an oil pump. In this way, 8.92 g of the 2- (dimethylaminophenylmethyl) cyclohexanone hydrochloride (78.6% of theory) were obtained. 3. Stage 2- (dimethylaminophenylmethyl) cyclohexanol To 26 ml (39 mmol) of diisobutylaluminum hydride (1.5 M in toluene) were added dropwise under nitrogen at room temperature 3.0 g
(13.0 mmol) of the 2- (dimethylaminophenylmethyl) cyclohexanone prepared according to example 1 (2. stage) dissolved in 26 ml of toluene. With stirring, the mixture was heated at reflux for 15 hours. For working up, 13 ml of ethanol and 13 ml of water were slowly added dropwise, the suspension was allowed to stand for several hours at 0 ° C, filtered through a glass frit and washed several times with a little toluene. . The filtrate was concentrated in the rotary evaporator (500 to 10 mbar), the solvent residues were removed in a high vacuum (approximately 0.1 mbar). 2.62 g (86.6% of theory) of 2- (dimethylaminophenylmethyl) cyclohexanol were obtained. 4. Stage Dimetil-. { [2- (2-methyl-benzyloxy) cyclohexyl] phenylmethyl} amine, the hydrochloride 1.00 g (4.29 mmol) of 2- (dimethylaminophenylmethyl) cyclohexanol were dissolved in 5.0 ml of dimethyl sulfoxide p.a. and under a nitrogen atmosphere 577 mg (5.14 mmol) of potassium terbutylate dissolved in 1.0 ml of dimethyl sulfoxide p.a. The reaction mixture was heated for 30 minutes at 50 ° C, 904 mg (6.43 mmol) of 2-methylbenzylchloride was added dropwise and the mixture was stirred at 50 ° C for a further 15 hours. For working up, 10 ml of water were added and extracted three times with 15 ml of ether respectively. The combined extracts were washed with respectively 10 ml of a solution of potassium hydroxide (2 M) and water and extracted three times with 25 ml of hydrochloric acid (5% by mass) respectively. The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 414 mg of crude base were obtained. The crude base was dissolved in 4 ml of 2-butanone and 11 μl (0.61 mmoles) of water and 155 μl (1.22 mmoles) of chlorotrimethylsilane were successively added. The preparation was allowed to stand for 15 hours at room temperature, the precipitated solid was removed by suction, washed with small portions of ether and dried under vacuum of the oil pump until weight constancy. In this way, 221 mg of the Dimetil- hydrochloride was obtained. { [2- (2-methyl-benzyloxy) -cyclohexyl-phenyl-methyl} -amine (13.8% of the theory) that under warming decomposes from 79 ° C. Example 2 [2- (dimethylaminophenylmethyl) cyclohexyl] -4-trifluoromethyl-benzoate 1. Step 2- (dimethylaminophenylmethyl) cyclohexanol A 80.0 g (299 mmol) of 2- (dimethylaminophenyl-methyl) cyclohexanone prepared according to Example 1 (2) Step), dissolved in 650 ml of methanol, a total of 28.3 g (747 mmol) of sodium borohydride were added in portions and stirred for one hour. For working up, 680 ml of dilute hydrochloric acid (1 N) were added and extracted with 500 ml of ether. The aqueous phase was made alkaline (pH = 10) with a solution of ammonia (25% by volume) and extracted three times with respectively 250 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotary evaporator (500 to 10 mbar). 62.5 g (94% of theory) of 2- (dimethylaminophenylmethyl) cyclohexanol were obtained. 2. Chlorhydrate stage of [2- (dimethylaminophenylmethyl) cyclohexyl] -4-trifluoromethyl-benzoate 1.34 g (6.43 mmol) of 4- (trifluoromethyl) benzoyl-chloride were dissolved in 4 ml of dichloromethane and at -10 ° C (cooling bath methanol / ice) were added 870 mg (8.57 mmol) of triethylamine. Then 1.0 g (4.29 mol) of 2- (dimethylaminophenylmethyl) cyclohexanol dissolved in 2 ml of dichloromethane were added dropwise and stirred for 15 hours at room temperature. For working up, 2 ml of a potassium hydroxide solution (0.5 N) were added, the organic phase was separated, dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 1.7 g of crude base were obtained. From the crude base, with chlorotrimethylsilane / water in 2-butanone according to the example
1 (4. stage) 877 mg of [2- (dimethylaminophenylmethyl) cyclohexyl] -4-trifluoromethyl-benzoate hydrochloride (34% of theory) with a melting point of 230 ° C were obtained.
Example 3 [2- (Dimethylaminophenylmethyl) cyclohexyl] -4-methoxybenzoate 1.06 g (6.43 mmol) of 4-methoxybenzoylchloride were dissolved in 4 ml of dichloromethane and at -10 ° C (methanol / ice cooling bath) were added 870 mg (8.57 mmol) of triethylamine. Then 1.0 g (4.29 mmoles) of the 2- (dimethylaminophenylmethyl) -cyclohexanol prepared according to Example 2 (1. stage) dissolved in 2 ml of dichloromethane were added dropwise and stirred for 15 hours at room temperature. For the elaboration, 2 ml of a potassium hydroxide solution were added
(0.5 N), the organic phase was separated, dried over sodium sulfate, filtered and concentrated in the rotary evaporator (500 to 10 robar). 1.78 g of crude base were obtained. From the crude base, with chlorotrimethylsilane / water in 2-butanone according to example 1 (4. stage), 1.00 g of [2- (dimethylaminophenylmethyl) cyclohexyl] -4-methoxybenzoate hydrochloride (58% of theory) were obtained. with a melting point of 230 ° C. Example 4 Chlorohydrate of. { [2- (2-chlorobenzyloxy) cydohexyl] - (2-chloro-phenyl) methyl} -dimethylamine 1. step 2- [(2-chlorophenyl) dimethylaminomethyl] cyclohexanone To 471 ml (469 mmoles) of a solution of sodium iodide (1 M in acetonitrile) cooled with an ice bath at 0 ° C, added to it under stirring 17.4 g (213 mmol) of freshly dried dimethylamine hydrochloride, 60 ml (427 mmol) of triethylamine and 60 ml (469 mmol) of chlorotrimethylsilane were added dropwise, and stirred for one hour at room temperature. Under cooling with ice, 24 ml (213 mmoles) of 2-chlorobenzaldehyde were added, and stirring was continued for a further hour at room temperature. The mixture was again cooled to 0 ° C with an ice bath, 34 ml (213 mmol) of 1- (pyrrolidino) -1-cyclohexene were added and stirring was continued for two hours at room temperature. For working up, the preparation was mixed under ice cooling with 300 ml of semi-concentrated hydrochloric acid, stirred for 10 minutes, washed twice with respectively 300 ml of ether and basified (pH about 9) with 770 ml of a dilute ammonia solution (5% by volume). It was extracted three times with respectively 300 ml of ether, the combined organic extracts were dried over sodium sulfate, filtered and concentrated in the rotary evaporator (500 to 10 mbar) without the addition of heat. In this manner, 38.3 g 2- [(2-chlorophenyl) dimethylamino-methyl] cyclohexanone was obtained (68% of the theory). 2. Stage 2- [(2-chlorophenyl) dimethylaminomethyl] -cyclohexanol hydrochloride 10.0 g (37.6 mmol) of 2- [(2-chlorophenyl) dimethylaminomethyl] cyclohexanone were dissolved in 190 ml of methanol and 2.85 g were added in portions ( 75.2 mmoles) of sodium borohydride. For working up, 170 ml of hydrochloric acid (1 M) were added with stirring and extracted with 100 ml of ether. It was basified (pH> 10) with 15 ml of an ammonia solution (25% by volume), and extracted three times with respectively 100 ml of ether. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 8.10 g of crude base were obtained (80.3% of the theory). From 1.98 g (7.39 mmol) of this base, with chlorotrimethylsilane / water in 2-butanone according to example 1 (4. stage), 1.74 g of 2- [(2-chlorophenyl) dimethylamino-methyl] -cyclohexanol hydrochloride were obtained ( 78% of theory), which decomposes from 131 ° C. 3. Stage Hydrochloride. { [2- (2-chlorobenzyloxy) cydohexyl] - (2-chloro-phenyl) methyl} dimethylamine 902 g (5.60 mmoles) of 2-chlorobenzylchloride and 1.0 g (3.73 mmoles) of 2- [(2-chlorophenyl) dimethylaminomethyl] -cyclohexanol were dissolved in 6.0 ml of dimethylsulphoxide, 503 mg were added under nitrogen atmosphere ( 4.48 mmoles) of solid potassium terbutylate, and heated for 15 hours at 100 ° C. For working up, 10 ml of water were added and extracted three times with 15 ml of ether respectively. The combined extracts were washed with respectively 10 ml of a solution of potassium hydroxide (2 M) and water and extracted three times with respectively 25 ml of hydrochloric acid (5% by mass). The combined acid extracts were alkalized (pH >; 11) with sodium hydroxide (32% by mass) and extracted three times with 25 ml of dichloromethane respectively. The combined extracts were dried over sodium sulfate, filtered and concentrated on the rotary evaporator (500 to 10 mbar). 277 mg of crude base were obtained. From this base, with chlorotrimethylsilane / water in 2-butanone according to example 1 (4. stage), 151 mg of the hydrochloride of. { [2- (2-chlorobenzyloxy) cydohexyl] - (2-chloro-phenyl) methyl} dimethyl-amine (9.4% of theory), with a melting range of 108 -100 ° C. Example 5 Hydrochloride of. { [2- (3-Fluorobenzyloxy) cyclohexyl] phenylmethyl} dimethylamine 1.00 g (4.29 mmol) of 2- (dimethylaminophenyl-methyl) -cyclohexanol prepared according to example 1 (3. stage) were dissolved in 5 ml of dimethyl sulfoxide, and at 50 ° C 503 mg (4.48 mmol) were added. potassium terbutylate. It was then heated to 100 ° C and 323 μl (2.61 mmol) of 3-fluorobenzylchloride were added. This addition was repeated two more times after in each case two hours, and the reaction mixture was then heated for another 15 hours at 100 ° C. The working up was carried out according to example 1 (4. step), whereby 166 mg of hydrochloride was obtained. { [2- (3-fluorobenzyloxy) cyclohexyl] phenylmethyl} -dimethylamine (11% of the theory), which under heating decomposes from 203 ° C. Example 6 Hydrochloride of. { [2- (4-Fluorobenzyloxy) cyclohexyl-phenylmethyl} dimethylamine To a suspension of 108 mg (4.48 mmol) of sodium hydride in 1 ml of dimethylformamide p.a. a solution of 1.00 g (4.29 mmol) of the 2- (dimethylaminophenylmethyl) cyclohexanol prepared according to example 2 (1. stage) in 5 ml of dimethylformamide p.a. The reaction mixture was heated to 100 ° C and added
323 μl (2.61 mmoles) of 3-fluorobenzylchloride. This addition was repeated two more times after in each case two
- hours, and the reaction mixture was then heated for another 15 hours at 100 ° C. The working-up was carried out according to example 1 (4. step), whereby 393 mg of hydrochloride was obtained. { [2- (4-Fluorobenzyloxy) cyclohexyl] phenylmethyl} -dimethylamine (24% of theory), which under decomposition decomposes from 210 ° C.
Claims (31)
1. Derivatives of 3-amino-3-arylpropan-1-ol of the general formula I where R1, R2 signify, in each case independent of each other, Ci-ß- to the quilo, or R1 and R2 together form a ring (CH2) 2_6 which may also be benzocondensate or substituted phenyl RJ H, methyl R4, R °, in each case independent of each other, Ci-β-acyl, C3_6-cycloalkyl, phenyl, benzyl, phenethyl, or R4 and R5 together form a ring (CH2) 3-e or CH2CH20CH2CH2, A an aryl radical which eventually has heteroatoms in the ring and / or a substituted benzyl of the formula XI Kl may be substituted or a substituted benzoyl of formula XII XL;, wherein R12 to R1, in each case independently of one another, mean H, F, Cl, Br, CHF2, CF3, OR11, SR11, 0CF3, S02CH3, S02CF3, C6-alkyl, phenyl, CN, COOR11 , N02 with R11 Ci-e-alkyl, phenyl, benzyl, phenethyl and their diastereomers or enantiomers in the form of their bases or physiologically acceptable acid salts
2. Compounds according to claim 1, characterized in that R1 and R2 together form a ring (CH2) 2-6r which can be benzocondensate or substituted of phenyl, 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 ring (CH2) which may be benzocondensate or substituted phenyl, R3 to R5, A and X have the meaning according to claim 1.
4. Compounds according to claim 1, characterized by the fact that R3 represents hydrogen, R1, R2, R4, R
5, A and X have the meaning according to the claim 1. The compounds according to claim 1, characterized in that A means a radical of the substituted phenyl group of the formula XIII XIIt where Rb a, R 10, in each case independent of each other, H, F, Cl, Rr, X, CF 3, OH, OR 11, 0CF 3, SR 11, S 0 2 CH 3, S 0 2 CF 3, d-β-alkyl, phenyl, CN , COOR11, N02, or R6 and R7 or R7 and R8 together form a ring 0CH20 or OCH2CH20, R11C? -6-alkyl, phenyl, benzyl, phenethyl or A means a thiophene or furan radical, substituted or unsubstituted, and R1 a R5 and X have the meaning according to claim 1.
6. Compounds according to claim 1 characterized in that R1 and R2 together form a ring (CH2) 2-e, which may be benzocondensate or substituted phenyl, R3 represents hydrogen, R4, R5, A and X have the meaning according to claim 1.
7. Compounds according to claim 1, characterized in that R1 and R2 together form a ring (CH2) which may be benzocondensate or substituted phenyl, A is a radical of the substituted phenyl group of Formula XIII according to claim 5, or a thiophene or furan radical, substituted or substituted, R3 represents hydrogen, R4, R5 and X have the meaning according to claim 1.
8. Compounds according to claim 1, characterized by the fact that R1 and R2 together form a ring (CH2), A is a radical of the substituted phenyl group of formula XIII according to claim 5, or a thiophene or furan radical, substituted or unsubstituted, R3 represents hydrogen, R4, R 5 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 ring (CH2) 4, A is a substituted or unsubstituted thiophene radical. , R3 represents hydrogen, R4, R5 and X have the meaning according to the definition of the claim
1.
10. Compounds according to claim 1, characterized in that R1 and R2 together form a ring (CH2) 4, A is a substituted or unsubstituted furan radical, R3 represents hydrogen, R4, R5 and X have the meaning in accordance to the definition of claim 1.
11. Compounds according to claim 1, characterized in that X represents a substituted benzyl radical of the formula XI, R1 to Rs and A have the meaning according to claim 1.
12. Compounds according to claim 1: Dimethyl-. { [2- (2-methylbenzyloxy) cyclohexyl] phenylmethyl} -amine, and the corresponding hydrochloride [2- (dimethylaminophenylmethyl) cyclohexyl] -4-trifluoromethyl-benzoate, and the corresponding hydrochloride [2- (dimethylaminophenylmethyl) cyclohexyl] -4-methoxybenzoate, and the corresponding hydrochloride. { [2- (2-chlorobenzyloxy) cydohexyl] - (2-chlorophenyl) -methyl} dimethylamine, and the corresponding hydrochloride. { (2-chlorophenyl) - [2- (4-methylbenzyloxy) cyclohexyl] -methyl} dimethylamine, and the corresponding hydrochloride. { [2- (4-Fluorobenzyloxy) cyclohexyl] phenylmethyl} -dimethylamine, and the corresponding hydrochloride
13. A medicament containing at least one compound according to claims 1 to 12 as an active substance.
14. A medicament containing as active substances a mixture of the enantiomers of a compound according to claims 1 to 12, that both enantiomers are not present in equimolar amounts, and possibly other active substances.
15. A medicament containing as active substances a mixture of the enantiomers of a compound according to claims 1 to 12, wherein one of the enantiomers has a relative proportion of between 5 and 45 percent by mass of the enantiomeric mixture, and optionally other active substances.
16. Process for the preparation of a compound according to claims 1 to 12, characterized in that a Mannich base of the general formula II is reacted II wherein R1, R2, R4, R5 and A have the meaning according to general formula I, with a Grignard compound of the general formula (Í13C) Y wherein Y means MgCl, MgBr or Mgl, or MeLi, or a reducing agent, preferably from the group of sodium borohydride, sodium sanoborohydride, aluminum-lithium hydride, diisobutylaluminum hydride or a complex analogue of these compounds, to obtain an alcohol of the general formula Id Id, in which R1 to R5 and A have the meaning according to general formula I, an alcohol of the general formula Id is reacted in a temperature range of 0 ° -150 ° C in the presence of inorganic bases or organic with HalX, where Hai has the meaning of halogens of the group of F, Cl, Br or I and X has the meaning according to the general formula I, or is condensed with XOH in a temperature range of 0 ° -150 ° C, thereby transforming it to a compound of the general formula I.
17. Use of a compound according to claims 1 to 12 for preparing a medicament for the control of pain.
18. Use according to claim 17 for preparing a medicament for combating neuropathic pains.
19. Use according to claim 17 for preparing a medicament for combating chronic pain.
20. Use of a compound according to claims 1 to 12 for preparing a medicament with local analgesic activity.
21. Use of a compound according to claims 1 to 12 for preparing a medicament with antiarrhythmic activity.
22. Use of a compound according to claims 1 to 12 for preparing a medicament with antiemetic activity.
23. Use of a compound according to claims 1 to 12 for preparing a medicament with nootropic (neurotropic) activity.
24. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of cardiovascular diseases.
25. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of urinary incontinence.
26. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of diarrhea.
27. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of pruritus.
28. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of alcohol dependence.
29. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of drug addiction.
30. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of drug dependence.
31. Use of a compound according to claims 1 to 12 for preparing a medicament for the treatment of inflammations.
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