EP1196373A1 - 3-amino-2-benzyl-1-phenyl-propanderivate - Google Patents

3-amino-2-benzyl-1-phenyl-propanderivate

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Publication number
EP1196373A1
EP1196373A1 EP00943873A EP00943873A EP1196373A1 EP 1196373 A1 EP1196373 A1 EP 1196373A1 EP 00943873 A EP00943873 A EP 00943873A EP 00943873 A EP00943873 A EP 00943873A EP 1196373 A1 EP1196373 A1 EP 1196373A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
benzyl
corresponding hydrochloride
radicals
dimethylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00943873A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael Sattlegger
Helmut Buschmann
Babette-Yvonne Koegel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
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Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1196373A1 publication Critical patent/EP1196373A1/de
Withdrawn legal-status Critical Current

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    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
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    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/62—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
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    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
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    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the invention relates to substituted 3-amino-2-benzyl-1-phenyl-propane derivatives, processes for their preparation, medicaments containing these compounds and the use of these substances for the production of medicaments.
  • Classic opioids such as the morphine
  • morphine are effective in the treatment of severe to very severe pain.
  • undesirable side effects include respiratory depression, vomiting, sedation, constipation and a development of tolerance. They are also less effective in neuropathic or incidental pain, as is often the case in tumor patients.
  • the object on which the invention is based was to provide analgesically active substances which are suitable for the treatment of severe pain, in particular for the treatment of chronic and neuropathic pain.
  • these drugs should have as few side effects of the opioid analgesics as e.g. Nausea, vomiting, addiction, respiratory depression, constipation.
  • the invention therefore relates to substituted 3-amino-2-benzyl-1-phenyl-propande ⁇ ' vate of the general formula I,
  • R ° H, OH or a single bond
  • R 2 H, a C
  • . 10 alkyl, an aryl or an aryl radical bonded via a C 6 alkylene group, preferably H, a d-3 alkyl or an aryl radical bonded via a C 3 alkylene group
  • R 8 a C 10 alkyl, an aryl or an aryl radical bonded via a C 6 alkylene group, preferably a C 3 alkyl group or one bonded via a d 3 alkylene group aryl radical
  • R 10 a Ci.io-alkyl or a C 4 . 8 -cycloalkyl radical, preferably ad. 3 alkyl radical
  • R 11 a C 10 alkyl radical, preferably a C 3 alkyl radical
  • R 12 radicals H, a C 10 alkyl, a C 4 . 8 - cycloalkyl, an aryl or one via a C ⁇ . 6 -alkylene group-bonded aryl radical, preferably a -C 3 alkyl radical
  • R ° OH
  • R 3 H, CH 3 , unbranched C 3 H 7 , unbranched C 5 Hn, cyclohexyl, phenyl or benzyl
  • R ° OH
  • R ° OH
  • R 3 phenyl
  • R 6 Cl
  • R 1 , R 2 , R 4 , R 5 and R 4 'to R 6 ' H
  • R ° OH
  • R 3 phenyl
  • R 6 ' Cl
  • R 1 , R 2 , R 4 to R 6 , R 4 ' and R 5 ' H
  • R ° OH
  • R 3 phenyl
  • R 5 ', R 6 ' each the group OCH 3
  • R 1 , R 2 , R 4 to R 6 and R 4 ' H
  • R ° OH
  • R 3 phenyl
  • R 1 , R 2 , R 4 , R 5 , R 4 ' and R 5 ' H
  • R ° OH
  • R G ' OCH 3
  • R 1 to R 6 , R 4 ' and R 5 ' H
  • Alkyl radicals are also understood to mean hydrocarbons which are substituted at least once, preferably with halogen, particularly preferably with fluorine. If these contain more than one substituent, they can be the same or different.
  • the alkyl radicals are preferably methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2- Dimethylpropyl, hexyl, 1-methylpentyl, heptyl, nonyl or decanyl.
  • Alkenyl radicals are also taken to mean hydrocarbons which are substituted at least once, preferably with halogen, particularly preferably with fluorine, and which have at least one double bond. If the alkenyl radical contains more than one substituent, these can be the same or different.
  • the alkenyl radicals are preferably 2-propenyl, 2-butenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl.
  • An aryl radical is also at least one with an OH, a halogen, preferably F and / or Cl, a CF 3 , a C 6 alkyl, a Ci-e alkoxy, a C 1 - 7- Cycloalkoxy-, a C 3 . 7- cycloalkyl, a C 2 -alkylene or phenyl radical substituted phenyls or naphthyl radicals understood.
  • the phenyl radicals can also be condensed with further rings.
  • a heterocyclyl radical is understood to mean both saturated and unsaturated heterocyclic compounds, preferably 5-7-membered heterocyclic compounds, which contain at least one heteroatom, preferably nitrogen, oxygen and / or sulfur, particularly preferably nitrogen and / or oxygen.
  • the saturated heterocycles are preferably 1,4-dioxane, tetrahydrofuran or 1,4-thioxane.
  • the unsaturated heterocycles are preferably furan, thiophene, pyridine, pyrimidine, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine or quinazoline.
  • the following substituted 2-benzyl-3-dimethylamino-1-phenyl-propane derivatives are particularly preferred:
  • the invention further relates to processes for the preparation of substituted 3-amino-2-benzyl-1-phenyl-propane derivatives of the general
  • the compounds of the general formula IV are oxidized in solution, preferably in aqueous or ethereal solution, with an oxidizing agent, preferably with inorganic salts, particularly preferably with potassium dichromate or sodium hypochlorite, to give compounds of the general formula V.
  • tertiary alcohols of the general formula VII are preferably obtained with a configuration in which the amino group ice, threo (or Z, E) is arranged to the hydroxyl group is:
  • the resulting tertiary alcohols of the general formula VII can be obtained by diastereomerically pure separation by column chromatography or by crystallization of their salts, preferably the hydrochlorides.
  • the invention further relates to processes for the preparation of compounds of the general formula I in which R 4 and / or R 5 and / or R 6 represent an OH group and R ° to R 3 and R 12 are those given in the general formula I.
  • the compounds of general formula I can be used with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, Conversion of succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and / or aspartic acid into their salts in a manner known per se. Salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetate, acetone and / or 2-butanone. Trimethylchlorosilane in methyl ethyl ketone is also suitable for the preparation of the hydrochlorides.
  • physiologically compatible acids for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, Conversion of succinic acid, tartaric acid,
  • substituted 3-amino-2-benzyl-1-phenylpropane derivatives according to the invention of the general formula I are toxicologically harmless and are therefore suitable pharmaceutical active ingredients.
  • the invention therefore furthermore relates to medicaments which have at least one substituted 3-amino-2-benzyl-1-phenylpropane derivative of the general formula I and / or their enantiomers, diastereomers, bases or salts of physiologically tolerated acids and, if appropriate, others as active ingredient Contain active substances and / or auxiliary substances.
  • R ° OH
  • R 3 H, CH 3 , unbranched C 3 H 7 , unbranched C 5 Hn, cyclohexyl, phenyl or benzyl
  • R ° OH
  • R ° OH
  • R 3 phenyl
  • R 6 Cl
  • R 1 , R 2 , R 4 , R 5 and R 4 'to R 6 ' H
  • R ° OH
  • R 3 phenyl
  • R 6 ' Cl
  • R 1 , R 2 , R 4 to R G , R 4 ' and R 5 ' H
  • R ° OH
  • R 3 phenyl
  • R 5 ', R 6 ' each the group OCH 3
  • R 1 , R 2 , R 4 to R 6 and R 4 ' H
  • R ° OH
  • R 3 H, CH 3 , unbranched C 3 H 7 , unbranched C 5 Hn, cyclohexyl, phenyl or benzyl
  • R ° OH
  • R 3 phenyl
  • R 6 ' Cl
  • R 1 , R 2 , R 4 to R 6 , R 4 ' and R 5 ' H
  • R ° OH
  • R 3 phenyl
  • R 5 ', R 6 ' each the group OCH 3
  • R 1 , R 2 , R 4 to R 6 and R 4 ' H
  • R ° OH
  • R 3 phenyl
  • R 6 is the group OCH 3
  • R 1 , R 2 , R 4 , R 5 and R 4 'to R 6 ' H
  • R ° OH
  • R 3 phenyl
  • R 6 ' are the group OCH 3
  • R 1 , R 2 , R 4 to R 6 , R 4 ' and R 5 ' H
  • R ° OH
  • R 3 phenyl
  • Another object of the invention is also the use of at least one substituted 3-amino-2-benzyl-1-phenyl-propanedivate of the general formula I and / or its enantiomers, diastereomers, bases or salts of physiologically acceptable acids for the production of a medicament
  • carrier materials In addition to at least one substituted 3-amino-2-benzyl-1-phenylpropane ⁇ vate of the general formula I, carrier materials, fillers, solvents, diluents, dyes and / or binders are used to prepare corresponding pharmaceutical formulations.
  • auxiliaries The selection of auxiliaries and the amounts to be used the same depends on whether the medicinal product is to be administered orally, intravenously, intrape ⁇ toneal, intradermally, intramuscularly, intranasally, buccally or locally, for example on infections on the skin, mucous membranes and eyes.
  • Preparations in are suitable for oral administration Forms of tablets, dragees, capsules, granules, drops, juices and syrups, for parenteral, topical and inhalative application solutions, suspensions, easily reconstitutable dry preparations and sprays
  • Compounds of the general formula I according to the invention in a depot in dissolved form or in a plaster, if necessary under Appropriate percutaneous agents are added to promote skin penetration Application preparations.
  • Formulations which can be used orally or percutaneously can release the compounds of the general formula I according to the invention with a delay.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. 50 to 500 mg / kg of at least one 3-amino-2-benzyl-1-phenyl-propane derivative of the general formula I are usually applied.
  • racemate separations were carried out on a Chiracel OD column.
  • reaction solution was extracted three times with 200 ml of ether each time and the combined ether extracts were dried over sodium sulfate. The solvent was removed in vacuo. After drying, 28 5 g (98%) of 1- (3-methoxyphenyl) -3-phenyl- propan-1-ol as a gray oil
  • the ether extracts were combined, dried over sodium sulfate and the ether was distilled off.
  • the (2RS) -2-benzyl-3-dimethylamino-1 - (3-methoxyphenyl) propan-1-one was dissolved in 100 ml of methyl ethyl ketone and mixed with ethereal HCl solution to pH 1.
  • the precipitate obtained in this way was filtered off with suction, washed with ether and dried in vacuo, and 2-benzyl-3-dimethylamino-1- (3-methoxyphenyl) propan-1-one hydrochloride was obtained in a yield of 33.0 g (83 %) with a melting point of 130 ° C.
  • (2RS)-2-benzyl-3-dimethylamino-1- (3-trifluoromethylphenyl) propane-1-one hydrochloride The synthesis was carried out according to the instructions for Example 1. Instead of the 3-methoxybenzaldehyde, 25 0 g (0 14 mol) of 3-trifluoromethylbenzaldehyde were used. The G ⁇ gnard reaction, oxidation and Mannich reaction steps resulted in a total yield of 21 1 g (41 %) to (2RS) -2-benzyl-3-dimethylamino-1- (3-t ⁇ fluoromethylphenyl) propane-1-one hydrochloride with a melting point of 104 ° C.
  • the synthesis of the compound was carried out in four stages. The first three stages were carried out according to the instructions for Example 1 with an identical molar ratio.
  • the fourth reaction step was the cleavage of the methyl ether to give the compound (2RS) -2-benzyl-3-dimethylamino-1 - (3- hydroxy-phenyl) propan-1-one-hydrochloride with methionine and methanesulfonic acid
  • 10 0 g (0 03 mol) of the methyl ether were dissolved in 3 2 ml (0 033 mol) methanesulfonic acid and with 4 5 g (0 6 mol) methionine heated to 75 ° C for 2 hours.
  • Example 2 The synthesis was carried out according to the instructions for Example 1 with an identical molar ratio.
  • the racemate thus obtained was then separated into the enantiomers by chromatography on a Chiracel OD column with ethanol, ethyl acetate and saturated aqueous ammonia solution in a ratio of 1/1 / 0.05 and (+) - (R) -2-benzyl-3-dimethylamino Obtained 1 - (3-methoxy-phenyl) propan-1-one hydrochloride.
  • Example 2 The synthesis was carried out according to the instructions for Example 1 with an identical molar ratio.
  • the racemate thus obtained was then separated into the enantiomers by chromatography on a Chiracel OD column with ethanol, ethyl acetate and saturated aqueous ammonia solution in a ratio of 1/1 / 0.05 and (-) - (S) -2-benzyl-3-dimethylamino Obtained 1 - (3-methoxy-phenyl) propan-1-one hydrochloride.
  • (2RS)-2-Benzyl-3-dimethylamino-1 - (3,4,5-trimethoxyphenyl) propane-1-one hydrochloride The synthesis was carried out according to the instructions for Example 1. Instead of the 3-methoxybenzaldehyde, 10.0 g (0.05 mol) of 3,4,5-trimethoxybenzaldehyde were used. The reaction steps of the Grignard reaction, oxidation and Mannich reaction led to (2RS) -2-benzyl-3-dimethylamino-1 - (3,4,5-trimethoxyphenyl) propane in a total yield of 14.5 g (60%) -1 -one hydrochloride with a melting point of 125 ° C.
  • Example 2 The synthesis was carried out in accordance with the instructions for Example 1. This was followed by ether cleavage as in Example 6 and a column chromatographic resolution using ethanol as the eluent. she resulted in (-) - (S) -2-benzyl-3-dimethylamino-1 - (3-hydroxyphenyl) propane-1-one hydrochloride in a total yield of 20 mg (0.5%).
  • This compound is first reacted with an equimolar amount of the cuprate of ethyl bromide in a 1,4 addition to the corresponding enolate.
  • the organic copper compound is generated in situ from the Grignard compound from ethyl bromide and magnesium by transmetallation with copper l-iodide.
  • This enolate is further implemented in situ. It is reacted with an equimolar amount of the Eschenmoser salt, stirred at 20 ° C. overnight and then worked up in an aqueous medium. The aqueous phase is made alkaline and the product extracted with ether. Z- (2RS) - (3RS) -2-dimethylaminomethyl-1,3-diphenyl-pentan-1-one hydrochloride was then precipitated into methyl ethyl ketone by adding trimethylsilyl chloride to the free base.
  • Example 42 The synthesis was carried out according to the instructions for Example 38. 3-methoxy-acetophenone and 3-methoxy-benzaldehyde were used in equimolar amounts in the aldol condensation. The corresponding chalcone derivative was reacted with bromobenzene in the cuprate addition. Then the conversion takes place with the Eschenmoser salt. The synthesis leads in a total yield of 4.5 g (17%) over the three stages to the compound (2RS) - (3RS) -2-dimethylaminomethyl-1, 3-bis- (3-methoxyphenyl) -3-phenyl- propan-1-one hydrochloride with a melting point of 139.1 ° C.
  • Example 42 Example 42:
  • Example 38 The synthesis is carried out according to the instructions for Example 38. 1-Naphthalen-2-yl-ethanone and 3-methoxybenzaldehyde were used in equimolar amounts in the aldol condensation. The chalcon derivative was implemented with m-bromoanisole in the cuprate addition. The reaction was then carried out with an equimolar amount of Eschenmoser salt. The synthesis resulted in a total yield of 10.3 g (65%) over the three steps to (2RS) - (3RS) -2-dimethylaminomethyl-3,3-bis- (3-methoxy-phenyl) -1-naphthalene-2- yl-propan-1-one hydrochloride with a melting point of 192.8 ° C.
  • the G ⁇ gnard reagent was reacted in this Example generated from 1, 2 g (11 mmol) of ethyl bromide in 50 ml of ether with 0 27 g (11 mmol) of magnesium and with 2.5 g (7 5 mmol) of 2-benzyl-3-dimethylamino-1- (3-methoxy -phenyl) -propan-1-one at 0 ° C implemented
  • the yield of E- (2RS) - (3RS) -2-benzyl-1-dimethylamino-3- (3-methoxyphenyl) pentan-3-ol-hydrochloride was 1 87 g (71%), the melting point 186 0 ° C
  • the synthesis was carried out up to the third step in accordance with the instructions for Example 1.
  • the compound 2-benzyl-3-dimethylamino-1 - (3-methoxyphenyl) propan-1-one was then reacted with benzyl magnesium bromide.
  • the G ⁇ gnard reagent was prepared from 1 5 g (8 75 mmol) of benzyl bromide in 50 ml of ether with 0 21 g (8 75 mmol) of magnesium and generated with 2.5 g (7 5 mmol) of 2-benzyl-3-dimethylamino-1 - (3-methoxy-phenyl ) -propan-1 -one implemented at 0 ° C.
  • Reagent was generated from 3 7 g (20 mmol) of m-bromoanisole in 5 ml of tetrahydrofuran (THF) with 0 5 g (20 mmol) of magnesium and with 5 g (15 mmol) of 2-benzyl-3-dimethylamino-1 - (3rd -methoxy-phenyl) -propan-1 -one reacted in 10 ml (THF) at 0 ° C
  • the yield of Z- (1 RS) - (2RS) -2-benzyl-1- (4- chlorophenyl) -3-dimethylamino-1 - (3-methoxyphenyl) propan-1-ol hydrochloride was 2.5 g (41%) with a melting point of 145 ° C.
  • the synthesis was carried out up to the third step in accordance with the instructions for Example 3.
  • the compound (3RS) -2-benzyl-1- (4-chlorophenyl) ⁇ 3-dimethylamino-propan-1-one was then reacted with ethyl magnesium bromide.
  • the Grignard reagent is generated from 1.5 g (20 mmol) of ethyl bromide in 10 ml of ether with 0.5 g (20 mmol) of magnesium and with 5 g (15 mmol) of (3RS) -2-benzyl-1 - (4-chlorophenyl) -3-dimethylamino- propan-1-one reacted in 10 ml ether at 0 ° C.
  • the synthesis was carried out up to the third step according to the instructions for Example 2. Then the compound 1- (3-benzyloxy-phenyl) -2-dimethylaminomethyl-3-phenyl-propan-1-one was reacted with ethyl magnesium bromide.
  • the Grignard reagent was generated from 1.5 g (14.0 mmol) of ethyl bromide in 50 ml of ether with 0.27 g (1 1.0 mmol) of magnesium and with 2.5 g (7.5 mmol) of 1 - (3-benzyloxy-phenyl) -2-dimethylaminomethyl-3 -phenyl-propan-1 -one reacted in 100 ml of ether at 0 ° C.
  • the synthesis was carried out according to the instructions for Example 47.
  • the Grignard reagent was generated from 2.3 g (19.0 mmol) of allyl bromide in 50 ml of ether with 0.41 g (18.0 mmol) of magnesium and with 5 g (15.0 mmol) of 2-benzyl-3- dimethylamino-1 - (3-methoxy-phenyl) -propan-1 -one implemented at 0 ° C.
  • the yield of E- (2RS) - (3RS) -2-dimethylaminomethyl-3- (3-methoxyphenyl) -1 - phenyl-hex-5-en-3-ol hydrochloride was 0.6 g (9%) with a melting point of 140-145 ° C.
  • the synthesis was carried out up to the fourth step in accordance with the instructions for Example 64.
  • the Z isomer was fractionally precipitated after the E isomer.
  • the yield of Z- (2RS) - [2-benzyl-3- (3-methoxyphenyl) pent-3-enyl] dimethylamine hydrochloride was 0.4 g (1.1 mmol, 4%) with a melting point of 165 ° C.
  • Example 64 The synthesis was carried out according to the instructions for Example 64 for the starting product of the hydrogenation. 10 g (24 mmol) of Z- (2RS) - [2-benzyl-3- (3-methoxy-phenyl) -pent-3-enyl] dimethylamine hydrochloride resulted in 10 after the hydrogenation in the presence of 1.0 g % Pd / C and a hydrogen pressure of 2 bar 3.3 g of the isomer mixture. The yield was 36% with a melting point of 141.8 ° C.
  • Example 67 Example 67:
  • Example 66 The methyl ether was then cleaved with dibutylaluminum hydride (DIBAIH). 2.8 g (8.0 mmol) of the compound (2RS) - (3RS) - [2-benzyl-3- (3-methoxyphenyl) pentyl] dimethylamine hydrochloride were first converted into the free base and then in 20 ml Toluene mixed with 25 ml of DIBAIH, heated to 110 ° C. for 3 hours and stirred at 20 ° C. overnight.
  • DIBAIH dibutylaluminum hydride
  • (2RS)-2-benzyl-3-dimethylamino-1- (4-methoxy-2,3-dimethylphenyl) propane-1-one hydrochloride The synthesis was carried out according to the instructions for Example 1. Instead of the 3-methoxybenzaldehyde, 4-methoxy-2,3-dimethyl-benzaldehyde was used. The reaction steps Grignard reaction, oxidation and Mannich reaction led to the compound (2RS) -2-benzyl-3-dimethylamino-1 - (4-methoxy-2,3-dimethylphenyl) propane-1-one hydrochloride in a total yield of 6.0 g. The melting point is 154.9 ° C.
  • the synthesis is carried out according to regulation 73. Instead of dimethylamine hydrochloride, methylamine hydrochloride is used in the third stage.
  • the yield of (RS) -1 - (3-methoxyphenyl) -2-methylaminomethyl-3-m-tolyl-propan-1-one hydrochloride is 0.2 g with a melting range of 18-120 ° C.
EP00943873A 1999-07-16 2000-06-23 3-amino-2-benzyl-1-phenyl-propanderivate Withdrawn EP1196373A1 (de)

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DE19933421A DE19933421A1 (de) 1999-07-16 1999-07-16 2-Benzyl-3-dimethylamino-1-phenyl-propanderi- vate
PCT/EP2000/005820 WO2001005743A1 (de) 1999-07-16 2000-06-23 3-amino-2-benzyl-1-phenyl-propanderivate

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DE10059412A1 (de) * 2000-11-30 2002-06-13 Gruenenthal Gmbh Verwendung von 1-Phenyl-3-dimethylamino-propanverbindungen zur Therapie der Harninkontinenz
DE10161644A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh N,N'-disubstituierte Piperazin-Verbindungen
DE10326097A1 (de) * 2003-06-06 2005-01-05 Grünenthal GmbH Verfahren zur Herstellung von Dimethyl-(3-aryl-butyl)-aminverbindungen
DE10328316A1 (de) * 2003-06-23 2005-01-20 Grünenthal GmbH Verfahren zur Herstellung von Dimethyl-(3-aryl-buthyl)-aminverbindungen als pharmazeutische Wirkstoffe
US7435229B2 (en) * 2004-02-25 2008-10-14 Wolf Erich W System for transcutaneous monitoring of intracranial pressure (ICP) using near infrared (NIR) telemetry
FR2902789A1 (fr) * 2006-06-21 2007-12-28 Genfit Sa Derives de 1,3-diphenylpropane substitues, preparations et utilisations
JP5382801B2 (ja) * 2006-10-25 2014-01-08 ヘンケル アイルランド リミテッド 新規のイミニウム塩およびこれを用いる電子欠損オレフィンの製造方法
WO2015075678A1 (en) 2013-11-21 2015-05-28 Unimark Remedies Ltd. A novel process for the preparation of 1-phenyl-3-aminopropane derivatives
AU2018210393A1 (en) 2017-01-20 2019-07-25 The Regents Of The University Of California Inhibitors of the N-terminal domain of the androgen receptor

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US3277165A (en) * 1962-02-08 1966-10-04 Merck & Co Inc Fumaramic acid derivatives
US3342829A (en) * 1963-06-15 1967-09-19 Hoechst Ag Bis-quaternary salts of triamines and process for preparing them
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