EP1851191A1 - Sels de phosphate des composes 6-dimethylaminomethyl-l-(3-methoxyphenyle)-1,3-dihydroxy-cyclohexane - Google Patents

Sels de phosphate des composes 6-dimethylaminomethyl-l-(3-methoxyphenyle)-1,3-dihydroxy-cyclohexane

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Publication number
EP1851191A1
EP1851191A1 EP06707123A EP06707123A EP1851191A1 EP 1851191 A1 EP1851191 A1 EP 1851191A1 EP 06707123 A EP06707123 A EP 06707123A EP 06707123 A EP06707123 A EP 06707123A EP 1851191 A1 EP1851191 A1 EP 1851191A1
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EP
European Patent Office
Prior art keywords
polymorph
pain
dimethylaminomethyl
methoxyphenyl
cyclohexane
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.)
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Application number
EP06707123A
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German (de)
English (en)
Inventor
Michael Gruss
Andreas Fischer
Wolfgang Hell
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Gruenenthal GmbH
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Gruenenthal GmbH
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Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1851191A1 publication Critical patent/EP1851191A1/fr
Withdrawn legal-status Critical Current

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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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
    • C07C217/74—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 rings other than six-membered aromatic rings being part of the carbon skeleton
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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
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    • A61P25/36—Opioid-abuse
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to 6-dimethylaminomethyl-l- (3-methoxyphenyl) -1, 3-dihydroxy-cyclohexane compounds (I) in the form of phosphate salts, processes for their preparation and the use of these compounds in medicaments.
  • Tramadol hydrochloride - (IRS, 2RS) -2 [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, hydrochloride - occupies a special position among the centrally active analgesics, since this drug is a strong pain inhibitor without the side effects known for opioids (Pharmacol J. Exp. Ther., 267, 331 (1993)).
  • Tramadol is a racemate and consists of equal amounts of (+) and (-) enantiomers. In vivo, the drug forms the metabolite O-desmethyl-tramadol, which is also present as a mixture of enantiomers.
  • EP-B 0753506 has found analgesic substances which are suitable for the treatment of severe pain without producing the side effects typical of opioids.
  • the subject of EP-B 0753506 are 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the formula X.
  • R 1 is H, OH, Cl or F
  • R 2 and R 3 are identical or different and are H, Ci- 4 alkyl, benzyl zyl, CF 3, OH, OCH 2 -C 6 H 5, O-Ci 4 alkyl, Cl or F, with the proviso in that at least one of the radicals R 2 or R 3 denotes H,
  • R 4 is H, CH 3, PO (OCi-4-alkyl) 2, CO (OCi_ 5 alkyl), CO-NH-C 6 H 4 -C1-3- alkyl, CO-C 6 H 4 -R 5, C 1 -C 5 -alkyl, C 1 -C 6 -NHR 7 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group,
  • R 5 is OC (O) C ⁇ - 3 -alkyl in the ortho position or CH 2 -N (R 8 ) 2 in the meta-o-para position, where R 8 is Ci_ 4 -alkyl or both radicals R 8 together with N represent the 4-morpholino radical, and R 6 and R 7 are identical or different and are H or CI_ 6 alkyl,
  • EP-B 0753506 is a process for the preparation of 6-dimethylaminomethyl-l-phenyl-cyclohexane compounds of the formula X in which R 1 is OH and R 2 and R 3 are the same or different and H, Ci_ 4 alkyl , Benzyl, CF 3 , Cl or F, with the proviso that at least one of R 2 or R 3 is H and R 4 is H, CH 3 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, with the proviso that R 4 is neither CH 3 nor H when both R 2 and R 3 are H, the
  • EP-B 0753506 is a process for the preparation of 6-dimethylaminomethyl-l-phenyl-cyclohexane compounds of the formula X, in which R ⁇ is OH, one of the radicals R 2 or R 3 H and the other OH, OC ] __4 Alkyl or
  • OCH 2 C 5 H 5 and R 4 is H, CH 3 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, which is characterized in that a ß-dimethylaminoketone having spiro-cyclic acetal structure of the formula V
  • OCH2C5H5 means convicted.
  • the compounds of EP-B 0753506 have a pronounced analgesic effect and are toxicologically harmless. They are therefore suitable as pharmaceutical active ingredients. Accordingly, subject of the invention is also the use of a 6-dimethylaminomethyl-l-phenyl-l-cyclohexane compound of the formula X as an active ingredient in medicaments, preferably as an active ingredient in analgesics.
  • An object of the present invention was now to find a form of the highly effective compound 6-dimethylaminomethyl-l- (3-methoxyphenyl) -1, 3-dihydroxy-cyclohexane, which is physiologically compatible and does not have the disadvantages mentioned above, namely crystallizes in a dominant, polymorphic form and optimally exhibits low hygroscopicity and low tendency to release water under moderate environmental conditions, and therefore can be easily reproduced and stored without major changes.
  • R 2 is OH and R 3 is H or R 3 is OH and R 2 is H and
  • R 4 is CH 3 in the form of their salts of phosphoric acids.
  • the phosphate salts thus defined are referred to below as phosphate salts IP according to the invention.
  • the compounds of the above general formula (I) due to their stereocenters in the form of one of their pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, may be present in any desired mixing ratio in the salts according to the invention.
  • the phosphoric acids used according to the invention are understood to be the oxo acids of phosphorus.
  • the orthophosphoric acid relative molecular weight 98.0 g / mol
  • the di- also pyro-
  • the condensed meta- u Derive polyphosphoric acids, which are included in the invention.
  • stepwise replacement of the H atoms of orthophosphoric primary, secondary and tertiary phosphates can be formed, which are also included according to the invention.
  • the phosphate salts I-P according to the invention are salts of the reaction of I, in particular with condensed phosphoric acids, such as meta- and diphosphoric acid, and salts of orthophosphoric acid.
  • Salts of diphosphoric acid and orthophosphoric Phos ⁇ phoric acid are preferred. Very particular preference is given to salts of ortho-phosphoric acid.
  • Another object is phosphate salts I-P according to the invention, characterized in that the compounds in the salts of the configuration of the formula Ia
  • R 1 and R 2 are each OH, R 3 is H and R 4 is CH 3 .
  • orthophosphate salt of the racemic compound (IRS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol of the following structure:
  • the phosphates according to the invention in particular ortho-phosphates, can be one of the enantiomers (+) - (IR, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexane-1,3 -diol and (-) - (IS, 3S, 6S) -6-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexan-1, 3-diol or both of these enantiomers in a non-racemic mixing ratio.
  • a further subject matter is processes for the preparation of the phosphate salts IP according to the invention, in which the reaction of a compound of the general formula (I) is preferably carried out in a suitable reaction medium (reaction medium), preferably with phosphoric acid.
  • a suitable reaction medium preferably with phosphoric acid.
  • Another object is a process for preparing a phosphate salt according to the invention characterized in that another (ie different from phosphate) salt of a compound of general formula (I), in particular a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, Succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic and / or aspartic acid or the base, most preferably the hydrochloride or free base I is reacted with phosphoric acid, preferably in molar ratio I to phosphoric acid of 2: 1 to 1: 2 , more preferably 1
  • the particular compound of the general formula (I) can advantageously be liberated from the salt used beforehand in the usual manner known to the person skilled in the art in the form of the free base.
  • Another object is a process for preparing the phosphate salts of I according to the invention wherein base I at 10-40 0 C, preferably 20-30 0 C, very preferably 25 0 C in alcohol, preferably isopropanol, ethanol, very preferably ethanol and suspended with dilute phosphoric acid is added is stirred at 0 -10 0 C, preferably 5-7 ° C and optionally with Phoshatsalz of I at 0-10 0 C, preferably 5-7 0 C is seeded.
  • the product can then be filtered off and dried after 2-5 hours, preferably 3-4 hours.
  • an inventive method for the preparation of the phosphate salts of the invention come from I used can, wherein Base is added to I at 20-30 0 C in isopropanol and / or ethanolamine nol optionally in admixture with water with diluted phosphoric acid, at 0 -10 0 C is stirred and optionally inoculated with phosphate salt of I at 0-10 0 C. Afterwards, the product can be sucked off and dried after 2-5 hours (hrs.).
  • Another object of the present invention is a medicament containing at least one inventive phosphate salt IP, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or each in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients.
  • inventive phosphate salt IP in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or each in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients.
  • the medicament according to the invention is preferably suitable for the prophylaxis and / or treatment of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; of migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis; cognitive disorders, preferably cognitive Deficiency states, especially preferred Attention Deficit Disorder (ADD): panic attacks; Epilepsy; To cough; urinary incontinence; diarrhea; pruritus; Schizophrenia; cerebral ischemia; Muske1Spasmen; convulsions; Disorders of ingestion, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; alcohol and / or drug (especially nicotine and / or cocaine) and / or drug abuse; Alcohol and / or drug (in particular nicotine and / or cocaine) and / or drug dependence preferably for the prophylaxis and / or reduction of withdrawal symptoms in
  • the medicament according to the invention is particularly preferably suitable for the prophylaxis and / or treatment of pain, preferably of acute pain, chronic pain, neuropathic pain or visceral pain; Depressions; Epilepsy; Parkinson's disease; Alcohol and / or drug (especially nicotine and / or cocaine) and / or drug abuse; Alcohol and / or drug (in particular nicotine and / or cocaine) and / or drug dependence, preferably for the prophylaxis and / or reduction of Withdrawal symptoms in alcohol and / or drug (in particular nicotine and / or cocaine) and / or drug dependence; the development of tolerance to drugs, especially opioids, or anxiolysis.
  • the medicament according to the invention is suitable for the prophylaxis and / or treatment of pain, preferably of acute pain, chronic pain, neuropathic pain or visceral pain.
  • the medicament according to the invention is likewise suitable for the prophylaxis and / or treatment of inflammatory pain.
  • At least one phosphate salt according to the invention in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any desired Mixing ratio, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the prophylaxis and / or treatment of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain , from migraine, depression, neurodegenerative diseases, preferably selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis, cognitive disorders, preferably cognitive deficiencies, most preferably attention deficit syndrome (ADD), panic attacks, epilepsy, cough, urinary incontinence, diarrhea, pruritus, schizophrenia, cerebral I
  • ADD attention deficit syndrome
  • the medicament according to the invention can be used as a liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, Aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled in capsules or in a Suspended liquid, be present and administered as such.
  • composition according to the invention usually contains further physiologically acceptable pharmaceutical excipients, which can preferably be selected from the group consisting of carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, lubricants, lubricants, aromatics and binders.
  • physiologically acceptable excipients depend on whether the drug is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example , to infections on the skin which Mucous membranes and on the eyes, should be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, easily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • Suitable percutaneous administration preparations are also depot preparations in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents.
  • Orally or percutaneously applicable preparation forms can release the particular phosphate salts according to the invention with a delay.
  • the amount of the respective phosphate salt according to the invention to be administered to the patient can vary and depends, for example, on the weight or age of the patient and on the mode of administration, the indication and the severity of the disease. Usually, 0.005 to 5000 mg / kg, preferably 0.05 to 500 mg / kg, more preferably 0.1-50 mg / kg body weight of the patient of at least one such compound is applied.
  • experimental evidence is given, which prove the advantageousness of the phosphate salt IP according to the invention over the HCl salt disclosed in EP-B 0753506, hereinafter referred to as IH.
  • the HCl salt IH prepared according to EP-B 0753506 and the phosphate salt IP produced according to the invention are compared with one another.
  • thermogravimetric investigations (sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C), the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • thermogravimetric investigations (sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C), the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • thermogravimetric investigations (sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C), the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • thermogravimetric investigations sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C
  • the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • Table 5 (according to the invention) The storage of the samples was carried out at about 75 ( ⁇ 5)% relative humidity for about 8.5 days. Subsequently, the samples were stored for a further approx. 6 h at a relative humidity of approx. 4 ( ⁇ 5)%.
  • thermogravimetric investigations (sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C), the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • the storage of the samples was carried out at about 75 ( ⁇ 5)% relative humidity for about 7 days. Subsequently, the samples were stored for about 20 h at a relative humidity of about 4 (+5)%.
  • thermogravimetric investigations (sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C), the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • the storage of the samples was carried out at about 95 ( ⁇ 5)% relative humidity for about 7 days. Subsequently, the samples were stored for a further approx. 20 h at a relative humidity of approx. 4 ( ⁇ 5)%.
  • thermogravimetric investigations (sample amount about 5-20 mg, heating rate about 10 K / min, heating range from about 25 0 C to about 240 0 C), the samples were examined for their mass loss out. Indicated is the approximate difference of the moisture content (in
  • Sample P3 was stored in the laboratory for approximately 55 minutes under ambient conditions before the second storage step.
  • first storage step 95% humidity
  • second storage step 4% humidity
  • Shape middle determined by X-ray powder diffraction certain polymorphic form of the material after the storage step at high humidity
  • the phosphate salt I-P according to the invention as defined in contrast to the HCl adduct I-H, can be used stoichiometrically and storable. Furthermore, the stable form polymorph A, which is obtained in a wide range of environmental conditions (potentially the amorphous form or in suspension in acetonitrile another solvate can be obtained in a wide range of environmental conditions) no longer forms in others regularly preferred under conditions of the preparation process according to the invention Polymorphs, in contrast to the non-inventive case of the HCl adduct of 6-dimethylaminomethyl-1- (3-methoxyphenyl) -1, 3-dihydroxy-cyclohexane.
  • the HCl-salt mixtures prepared according to EP-B 0753506, which do not vary reproducibly, are e.g. Forms A and C converts to Form B or Forms A, C and D converts to Form B, or Forms A, C and D, respectively, to Forms B and A or even Form B; take non-reproducible amounts of water under conditions with increased air humidity (from a lower limit of approx. 60% RH up to an upper limit of approx. 100% RH, especially in the range approx. 70 - approx. 100% RH, especially in the range approx 75 - approx. 100% RH).
  • Example 10 By targeted special manipulations of the reaction conditions deviating from the reaction conditions according to the invention can be further z.T. producing unstable polymorphs: Example 10, 11, 12 (Form B, acetonitrile solvate), Example 16 (Form C, metastable), Example 15, 18, 19 (amorphous form).
  • Example 21 X-ray diffractograms of the shapes A, B, C, and amorphous are shown for characterization, and in Examples 22 and 23, respectively, the result of a comparative IR or RAMAN study.
  • Form A Preparation from a solution or suspension of the base of I in organic solvents or water or mixtures thereof.
  • the solvents may preferably be selected from water; methanol; ethanol; 1-propanol; 2-propanol; Acetone; Ethyl acetate; hexane; 2-butanone; Toluene; Tetrahydrofuran, - isopropyl ether; 1,4-dioxane; 1-propanol; 1-butanol; 2-methyl-1-propanol; 1-pentanol; 3-methyl-1-butanol; diethyl ether; (tert ButyDmethylether; tetrahydrofuran; methoxybenzene; 4-methyl-2-pentanone, iso-butyl methyl ketone; formic acid; Acetic acid; Ethyl formate, - methyl acetate; Ethyl acetate, - n-propyl acetate; N-butyl a
  • Form B Preference is given to acetonitrile or mixtures of acetonitrile and organic solvents or water.
  • Polymorphic "amorphous" preferred: water; methanol; ethanol; 1-propanol; 2-propanol; acetone; ethyl acetate; hexane, - 2-butanone; toluene; tetrahydrofuran; isopropyl ether; 1,4-dioxane; 1-propanol; 1-butanol; 2-methyl-1-propanol; 1-pentanol; 3-methyl-1-butanol; diethyl ether; (tert-butyl) methyl ether; tetrahydrofuran; methoxybenzene; 4-methyl-2-pentanone; formic acid Acetic acid, ethyl acetate, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, dichloromethane, dimethyl sulfoxide or mixtures thereof, most preferably acetonitrile, water, most
  • the application furthermore relates to all polymorphs of I-P, in particular polymorphs A, B, C, "amorphous" and mixtures thereof, particular preference being given to polymorph A. Further subject matter are processes for preparing the polymorphs of I-P.
  • the invention also relates to pharmaceutical compositions comprising one or more polymorphs from the group A, B, C, "amorphous", preferably A.
  • a further object is the use of one or more polymorphs of IP for the manufacture of a medicament for the treatment of pain, incontinence, degeneration. pressure, anxiety, preferably pain, especially preferred acute and chronic pain.
  • the application further polymorph A of orthophosphate I-P is characterized by a powder diagram as shown in Fig.l, measured with CuKalpha radiation.
  • the application further polymorph A of orthophosphate I-P characterized by measured peaks corresponding to Table 1 in the powder diffractogram, measured with CuKalpha radiation.
  • the application further polymorph A of the orthophosphate I-P characterized by a measured RAMAN spectrum at 1064 ran as shown in Fig.9.
  • the application further polymorph A of the orthophosphate salt of (IRS, 3RS, 6RS) -6-dimethylaminomethyl-l- (3-methoxyphenyl) cyclohexane-1, 3-diol characterized by a powder diffractogram comprising one or both of following reflections: 30.0 and 33.7 (each ⁇ 0.2 2 ⁇ ).
  • a powder diffractogram comprising one or both of following reflections: 30.0 and 33.7 (each ⁇ 0.2 2 ⁇ ).
  • the powder diffractogram additionally one or more of
  • the application further polymorph A of the orthophosphate salt of (IRS, 3RS, 6RS) -6-dimethylaminomethyl-l- (3-methoxyphenyl) cyclohexane-1, 3-diol characterized by a Raman spectrum comprising one or more of following signals: 2912, 3020 and 3060 (each in cm '1 ⁇ 4 cm "1 )
  • the Raman spectrum can still one or more of following signals: 2843, 2922, 2966 and 3089 (each in cm '1 +
  • the application further relates to a process for the preparation of polymorph A, according to which (lRS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1, 3-diol reacted with orthophosphoric acid in a reaction medium and the resulting polymorph A is optionally purified and isolated.
  • the reaction may be at a temperature of 10-40 0 C, preferably 20-30 0 C, very preferably carried out at about 25 0 C.
  • an alcohol optionally in admixture with water, preferably isopropanol and / or ethanol optionally in admixture with water, very preferably ethanol optionally in admixture with water.
  • the mixture of (IRS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexane-1,3-diol and orthophosphoric acid may be included 0 -10 0 C, preferably 5-7 ° C, stirred and optionally inoculated with polymorph A at 0-10 0 C, preferably 5-7 ° C.
  • the application further polymorph A obtainable by one of the methods described above.
  • the application further polymorph B of orthophosphate I-P is characterized by a powder diagram as shown in Fig.2, measured with CuKalpha radiation.
  • the application further polymorph B of orthophosphate I-P is characterized by measured peaks according to Table 2 in the powder diffractogram, measured with CuKalpha radiation.
  • the application further polymorph B of orthophosphate I-P characterized by a measured RAMAN spectrum at 1064 nm as shown in Fig.9.
  • the application further polymorph B of the orthophosphate salt of (IRS, 3RS, 6RS) -6-dimethylaminomethyl-l- (3-methoxyphenyl) cyclohexane-1, 3-diol characterized by a powder diffractogram comprising one or more of following reflections: 17.0, 17.4 and 20.2 (each ⁇ 0.2 2 ⁇ ). Vorzugs ⁇
  • the powder diffractogram additionally one or more
  • the Raman spectrum additionally has one or more of the following signals: 2839, 2926, 2964 and 3084 (each in cm -1 +
  • the application further relates to a process for the preparation of polymorph B, according to the polymorph A in acetonitrile or a medium based on acetonitrile, optionally at elevated temperature, stirred and the resulting polymorph B is isolated.
  • the medium can contain, in addition to acetonitrile, an alcohol, preferably ethanol.
  • the application further polymorph B is obtainable according to one of the preceding methods.
  • polymorph C of orthophosphate I-P is characterized by a powder diagram as shown in Figure 3, measured with CuKalpha radiation.
  • the application further polymorph C of orthophosphate I-P is characterized by measured peaks according to Table 3 in the powder diffractogram, measured with CuKalpha radiation.
  • the powder diffractogram additionally one or both of fol ⁇
  • the application further relates to a process for the preparation of polymorph C, according to which less than 10 milligrams of the orthophosphate salt of (IRS, 3RS, 6RS) -6- Dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol are suspended in acetonitrile at 50 ° C. for 2 days, the supernatant solution is filtered off, the acetonitrile is slowly evaporated off and the resulting solid is vacuum-dried for one day at room temperature ,
  • the application further polymorph "amorphous" of the orthophosphate I-P characterized by a powder diagram as shown in Fig.4, measured with CuKalpha radiation.
  • the application further relates to a process for the preparation of polymorph "amorphous", according to the polymorph B at a temperature of> 50 0 C, preferably dried under reduced pressure.
  • Hours more preferably> 72 hours, at a temperature of> 60 0 C, preferably dried at about 68 0 C in a vacuum.
  • RT means room temperature, m.p. melting point.
  • Approximately 30-50 mg of the phosphate salt of I are treated with about 100 ⁇ L of the solvent. For faster dissolution of the samples, the sample was treated between the addition steps in the ultrasonic bath.
  • the sample was stored in a sample vial at room temperature without a cover to achieve rapid evaporation of the solvent.
  • the sample was covered in a sample vial at room temperature with a foil into which a few holes were made by means of a needle.
  • the evaporation of the solvent could be slower compared to the open sample.
  • the vacuum below is to be understood as meaning a vacuum in the range of approximately 10 to 150 mbar. apparative
  • the powder diffractograms were recorded using STOE Stadi P, Shimad to XRD-6000 or Inel XRG-3000.
  • the samples were weighed into an aluminum crucible which was closed with a perforated lid.
  • the samples were usually examined in the range of 25 ° C to 25O 0 C 'and 350 0 C in a nitrogen flow.
  • the heating rate was 10 ° C / min.
  • Modulated DSC data was recorded on a TA Instruments 2920 equipped with a cooling system. The samples were weighed into an aluminum crucible which was capped but not crimped. The modulation amplitude was +/- 0.8 0 C and a 60 s period with a reduced heating rate of 1 ° C / min from 0-150 0 C.
  • TGA assays were performed using TA Instruments 2950 thermogravimetric analyzer or Mettler-Toledo TGA / SDTA851
  • FT-Raman spectra were recorded on a FT-Raman 960 spectrometer (Thermo Nicolet).
  • the excitation wavelength of the laser was 1064 nm.
  • the power of the Nd: YVO 4 laser Radiation of the samples was about 0.5 W.
  • the detector used was a germanium (Ge) detector.
  • the samples were placed in a glass tube or in a 0.8 mm glass capillary in a gold-coated holder. 128 or 256 scans were summed, the wavelength range was 98-3600 cm -1 at a spectral resolution of 4 cm -1 , using Happ-Genzel apodization.
  • Infrared spectra were recorded with a Magna-IR 860 Fourier-Transform Infrared (FT-IR) spectrometer (Thermo Nicolet).
  • the device contains an Ever-Glo mid / far IR IR radiation source, an 'extended rank' potassium bromide beam splitter and a DTGS (deuterated triglycine sulfate) detector. Further, a Thermo Spectra Tech Collector was used. For a spectrum, 128 or 256 scans were summed, the resolution was about 1 - 4 cm "1 .
  • the samples were mixed with dry KBr in a mass ratio of 99: 1 to 97: 3 (KBr to sample).
  • the sample was placed in a 1.3 cm sample carrier.
  • the background spectrum was measured on a KBr sample to produce a log I / R spectrum.
  • hydrochloride salts I-H were prepared according to the procedure in EP-B 0753506 in Example 18:
  • Base I was prepared as described in patent EP0753506 under example 18. 13.83 kg of a solution of base I in acetone, corresponding to 6.09 kg of pure base I, 25 l of acetone and 3.18 l of water were added to a 100 l double-jacket reaction system with electric anchor stirrer, PT100 temperature measuring device and oil-based cooling / heating system 25 + 5 ° C un ⁇
  • the differential thermal analysis shows three endotherms, Peaktempe- temperatures at about HO 0 C, about 133 0 C, about 200 0 C and 207 0 C.
  • Thermogravimetric analysis shows no weight loss until ' decomposition.
  • hydrochloride salt H2 1.3 g of the hydrochloride salt H2 are dried in a Petri dish in a vacuum drying oven at 140 ° C. for 46 hours.
  • the evaluation of the X-ray powder diffractogram shows the presence of forms A and D of the hydrochloride salt.
  • the differential thermal analysis shows three endotherms, Peaktempe- temperatures at about 133 ° C, about 200 0 C and 206 0 C.
  • Thermogravimetric analysis shows no weight loss until decomposition.
  • H2 501.3 mg H2 are weighed into a Petri dish and stored at approximately 95% ( ⁇ 5) relative humidity at room temperature for 180 hours. Subsequently, the sample for another approx. Stored for 6 hours in the presence of dry beads at about 5% ( ⁇ 5) relative humidity.
  • the water content of the sample is about 5% by thermogravimetric analysis.
  • the base I is extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. The half-concentrated solution is allowed to stand at room temperature for about 5 days.
  • the X-ray powder diffractogram shows the shape A.
  • the precipitated solid was filtered off with suction through a glass filter funnel and placed in a vacuum pot cabinet dried at about 6O 0 C and a vacuum of about 70-120 mbar for about 2 hours to constant mass.
  • the material was crystalline. In the sample up to about 0.2 mm long rod-shaped crystals were seen.
  • the purity is determined to be about 95.1% by HPLC.
  • the X-ray powder diffractogram shows the presence of the mold
  • the precipitated white solid is filtered through a G4 glass filter funnel and sucked dry. The solid is then dried in a vacuum oven at 25 0 C overnight.
  • PI PI
  • 3 ml of ethanol / water 9: 1 by volume / v / v
  • the solution is cooled to room temperature while stirring with a magnetic stir bar. After about 5 minutes, fine white solid precipitates out. 1 mL of solvent is added to stir the suspension. This is then stirred at about 4 0 C overnight.
  • the precipitated white crystalline solid is filtered off by means of a G4 glass filter, once with 2 mL cold ethanol-water mixture washed and sucked dry. After complete drying in air, the yield is determined.
  • the sample contains 100% of the phosphate salt of I.
  • the analysis by differential thermal analysis showed endothermy at about 125 0 C, endothermia at about 139 0 C and then decomposition from about 200 0 C.
  • the X-ray powder diffractogram shows form A.
  • the robustness of the synthesis is shown by a possible variation of the stoichiometric ratios of base to acid.
  • the ratio Base: Acid about 1: 1.
  • 1.4 g of the base I are placed in a 25 ml two-necked flask in 7 ml of ethanol.
  • the suspension cleared. After 1.4 mL (pH 7.3), the solution was stirred for about 40 minutes without further addition. There is a white solid precipitated and the suspension has a pH of about 8.7. The acid is added again in 2OO ⁇ L increments. After completion of the addition, the mixture is stirred for about 1 hour, the solid is then filtered through a tared G4 glass filter, washed once with about 4 mL of ethanol and dried by means of an applied vacuum. After about 30 minutes, the solid is filled into a sample jar.
  • thermoanalysis showed endothermicity at approx. 134 ° C.
  • the X-ray powder diffractogram shows the form A.
  • the loss of mass has been determined by thermogravimetry to 4.21% in the range 30-150 0 C.
  • the robustness of the synthesis is shown by a possible variation of the stoichiometric ratios of base to acid.
  • the ratio Base: Acid about 1: 2.
  • 1.4 g of the base I are placed in a 25 ml two-necked flask in 7 ml of ethanol.
  • the pH at the beginning of the titration was around pH 9.1.
  • Example 8 The robustness of the synthesis is shown by a possible variation of the stoichiometric ratios of base to acid and the use of different solvents.
  • the ratio Base: Acid about 2: 1.
  • the robustness of the synthesis is shown by a possible variation of the stoichiometric ratios of base to acid and the use of different solvents.
  • the ratio Base: Acid about 2: 1.
  • 603.9 mg of Base I were weighed into a 50 ml round bottom flask. To this was added 50 ml of ethyl ether and the suspension was then stirred with a magnetic stir bar.
  • the polymorph Form B about 30-50 mg of the phosphate salt of I were treated with about 100 ⁇ L of the solvent. For faster dissolution of the samples, the sample was treated between the addition steps in the ultrasonic bath. Solvent was added until the samples were completely dissolved by visual inspection. Thereafter, the solution was filtered through a 0.2 ⁇ m filter attached to a hypodermic syringe and stored in a sample vial at room temperature without capping to achieve rapid evaporation of the solvent.
  • the formed solid was collected after complete evaporation of the solvent.
  • the sample may optionally be additionally dried at room temperature in vacuo.
  • the X-ray powder shows the shape as differential thermal analysis shows endotherm at approximately 117 0 C, endotherm at about 145 0 C and endotherm at about 150 0 C
  • Form B of the phosphate salt of I is different from Form A due to the thermal data, X-ray powder diffraction pattern, 1 H NMR spectrum and Raman spectrum.
  • the thermal analysis of the form B shows at about 117 0 C and about 145 ° C, two major endothermies, at about 150 0 C, a smaller endothermicity.
  • Thermogravimetry showed a weight loss of 7.75% to about 132 0 C.
  • Karl Fischer titration was found for the form B, a water content of 5.9 wt.%. From the Diffrenz between these two values was then closed on the acetonitrile content.
  • the Raman spectrum of Form B shows the presence of acetonitrile through a peak at approximately 2249 cm -1 .
  • the infrared spectrum of Form B indicates the presence of acetonitrile through a peak at approximately -2247 cm -1 .
  • the infrared spectrum of Form B has some 'other peaks that do not occur in the form of A.
  • Form B was contained exclusively from samples which were produced only with the solvent acetonitrile or in which this had the greater proportion in the solvent mixture.
  • Example 11 Form B could be prepared reproducibly by suspending Form A in acetonitrile at room temperature for 6 days.
  • Form B could be prepared reproducibly by suspending Form A in acetonitrile at 50 ° C. for two days.
  • Form B was dried in vacuo at 40 ° C. for 13 hours. Based on X-ray powder diffractometry, thermal analysis and 1 H NMR spectroscopy, no changes in the physical form were observed.
  • the acetonitrile content after treatment was about 2.5% as an evaluation of the 1 H NMR spectrum showed.
  • Form B was dried in vacuo at 40 ° C. for 24 hours.
  • the acetonitrile content after treatment was about 2.5% as an evaluation of the 1 H NMR spectrum showed.
  • Form B was dried for 3 days at 68 ° C. in a drying oven in vacuo. The sample turned to amorphous material. After this treatment, no acetonitrile remained in the sample.
  • Example 16
  • the resulting solid was vacuum dried for one day at room temperature prior to analysis.
  • the X-ray powder diffractogram Form C is shown in Figure 3 in the Appendix.
  • the supernatant solution is filtered off and the solvent is evaporated slowly.
  • the resulting solid sample was dried in vacuo at room temperature for 1 day.
  • the amorphous form of the phosphate salt of I could be prepared by drying the form B for about 3 days at 68 0 C in vacuo.
  • the amorphous phosphate salt crystallized on storage at a relative humidity of 75% RH after 8 days and formed Form A.
  • the glass transition temperature was rence thermal analysis using modulated differential found in about 86.7 0 C.
  • the crystalline forms and the amorphous form can be distinguished by powder diffractograms.
  • the forms A and B can be distinguished by the infrared spectra. See Figs. 7 and 8 in the appendix.
  • the forms A and B can be distinguished on the basis of the Raman spectra. See Figs. 9 and 10 in the appendix.

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Abstract

L'invention concerne des composés 6-diméthylaminométhyl-l-(3-méthoxyphényle)-1,3-dihydroxy-cyclohexane sous forme de sels de phosphate, des procédés permettant de les produire et l'utilisation de ces composés dans des médicaments.
EP06707123A 2005-02-25 2006-02-21 Sels de phosphate des composes 6-dimethylaminomethyl-l-(3-methoxyphenyle)-1,3-dihydroxy-cyclohexane Withdrawn EP1851191A1 (fr)

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DE102005009217A DE102005009217A1 (de) 2005-02-25 2005-02-25 Phosphatsalze der 6-Dimethylaminomethyl-1-(3-methoxyphenyl)-1,3-dihydroxy-cyclohexanverbindungen
PCT/EP2006/001547 WO2006089707A1 (fr) 2005-02-25 2006-02-21 Sels de phosphate des composes 6-dimethylaminomethyl-l-(3-methoxyphenyle)-1,3-dihydroxy-cyclohexane

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AR053145A1 (es) 2007-04-25
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IL185468A0 (en) 2008-01-06
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