CA2439269A1 - Pharmaceutical salts of 1-phenyl-3-dimethylaminopropane compounds - Google Patents

Pharmaceutical salts of 1-phenyl-3-dimethylaminopropane compounds Download PDF

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CA2439269A1
CA2439269A1 CA002439269A CA2439269A CA2439269A1 CA 2439269 A1 CA2439269 A1 CA 2439269A1 CA 002439269 A CA002439269 A CA 002439269A CA 2439269 A CA2439269 A CA 2439269A CA 2439269 A1 CA2439269 A1 CA 2439269A1
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alkyl
salt
pharmaceutical salt
forming
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CA2439269C (en
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Johannes Bartholomaeus
Heinrich Kugelmann
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Gruenenthal GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • 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
    • C07C215/48—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • 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
    • C07C215/64—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 rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C217/64—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
    • C07C217/68—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 with singly-bound oxygen atoms, six-membered aromatic rings and amino groups bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C217/74—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C07D489/04—Salts; Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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  • Urology & Nephrology (AREA)
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  • Biomedical Technology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Saccharide Compounds (AREA)

Abstract

The invention relates to pharmaceutical salts comprised of a pharmaceutical active substance and of at least one sugar substitute, to medicaments containing these salts, and to the use of these salts for producing medicaments.

Claims (39)

1. A pharmaceutical salt of a pharmaceutical active compound and at least one sugar substitute with the exception of the respective pharmaceutical salt of a sugar substitute and tramadol, (+)-tramadol, (-)-tramadol, (+)-demethyltramadol and (-)-demethyltramadol.
2. The pharmaceutical salt as claimed in claim 1, characterized in that the solubility of the salt in water is <= 250 mg/ml of water, preferably <= 200 mg/ml, particularly preferably <= 150 mg/ml, very particularly preferably <= 100 mg/ml.
3. The pharmaceutical salt as claimed in claim 1 or 2, characterized in that the salt-forming sugar substitute is saccharin, cyclamate or acesulfam, preferably saccharin.
4. The pharmaceutical salt as claimed in one of claims 1 to 3, characterized in that the salt-forming active compound is selected from the group consisting of the salt-forming analgesics, antiobesity agents, analeptics, antihypoxemics, antirheumatics, opioid antagonists, anthelmintics, antiallergics, antiarrhythmics, antibiotics, anti-dementives (nootropics), antidiabetics, anti-emetics, antivertiginous agents, antiepileptics, antihypertensives, antihypotensives, antimycotics, antiinflammatories, antitussives, expectorants, arteriosclerosis agents, .beta.-receptor blockers, calcium channel blockers, broncholytics, anti-asthmatics, cholinergics, diuretics, circulation-promoting agents, weaning agents, geriatrics, hypnotics, sedatives, immunomodulators, oral therapeutics, pharyngeal therapeutics, coronary agents, hypolipidemics, local anesthetics, neural therapeutics, gastric agents, intestinal agents, migraine agents, muscle relaxants, anesthetics, neuropathy preparations, ophthalmologicals, otologicals, Parkinson agents, psychopharmaceuticals, rhinologicals, sinusitis agents, spasmolytics, platelet aggregation inhibitors, tuberculosis agents, urologicals and cytostatics.
5. The pharmaceutical salt as claimed in claim 4, characterized in that the active compound is selected from the group consisting of the salt-forming analgesics, analeptics, antihypoxemics, antiallergics, antiarrhythmics, antiemetics, anti-vertiginous agents, antihypertensives, anti-hypotensives, antitussives, expectorants, a-receptor blockers, calcium channel blockers, ophthalmologicals, otologicals, spasmolytics and urologicals, preferably from the group consisting of the salt-forming analgesics.
6. The pharmaceutical salt as claimed in claim 4 or 5, characterized in that the salt-forming analgesic is selected from the group consisting of the salt-forming opioids, the salt-forming opioid analogs, ephedrine, chloroquine, lidocaine, ethaverine, preglumetacin and triflupromazine.
7. The pharmaceutical salt as claimed in claim 6, characterized in that the salt-forming opioid or opioid analog is selected from the group consisting of morphine, codeine, ethylmorphine, diacetylmorphine, dihydrocodeine, etorphine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone, pethidine, ketobemidone, fentanyl, alfentanil, remifentanil, sufentanil, levomethadone, levomethadyl, dextromoramide, dextropropoxyphene, diphenoxylate, piritramide, tilidine, buprenorphine, butorphanol, dezozine, nalbuphine, nalorphine, pentazocine, nefopam, flupirtin and meptazinol.
8. The pharmaceutical salt as claimed in claim 7, characterized in that the salt-forming opioid is selected from the group consisting of morphine, codeine, hydrocodone, hydromorphone, oxycodone, tilidine, fentanyl and buprenorphine.
9. The pharmaceutical salt as claimed in one of claims 1 to 3, characterized in that the salt-forming active compound is a salt-forming compound of 1-phenyl-3-dimethylaminopropane compounds of the general formula I
in which X is OH, F, Cl, H or an OCOR6 group, R1 is a C1-9-alkyl group, R2 is H or a C1-4-alkyl group and R3 is H or a straight-chain C1-4-alkyl group or the radicals R2 and R3 together form a C4-7-cycloalkyl radical, and if R5 is H, R4 is meta-O-Z where Z is H, C1-3-alkyl, PO (O-C1-4-alkyl)2, CO(OC1-5-alkyl) , CONH-C6H4-(C1-3-alkyl), CO-C6H4-R7, where R7 is ortho-OCOC1-3-alkyl or meta- or para-CH2N (R8)2 where R8 is C1-4-alkyl or 4-morpholino, or R4 is meta-S-C1-3-alkyl, meta-Cl, meta-F, meta-CR9R10R11 where R9, R10, R11 are H or F, ortho-OH, ortho-O-C2-3-alkyl, para-F or para-CR9R10R11 where R9, R10, R11 are H or F , or if R5 is para-Cl, -F, -OH or -O-C1-3-alkyl, R4 is meta-Cl, -F, -OH or -O-C1-3-alkyl, or R4 and R5 together are 3,4-OCH=CH- or 3,4-OCH=CHO-, R6 is C1-3-alkyl, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
10. The pharmaceutical salt as claimed in claim 9, characterized in that X is OH, F, Cl or H, R1 is a C1-4-alkyl group, R2 is H or CH3 and R3 is H or CH3 and if R5 is H, R4 is meta-O-C1-3-alkyl, meta-OH, meta-S-C1-3-alkyl, meta-F, meta-Cl, meta-CH3, meta-CF2H, meta-CF3 or para-CF3 or if R5 is a para-Cl or -F, R4 is meta-C1 or -F, or R4 and R5 together are 3,4-OCH=CH-.
11. The pharmaceutical salt as claimed in claim 9 or 10, characterized in that the radicals R2 and R3 have different meanings and the compounds of the general formula I as claimed in claim 9 are present in the form of their diastereomers having the configuration Ia
12. The pharmaceutical salt as claimed in one of claims 9 to 11, characterized in that the salt-forming 1-phenyl-3-dimethylaminopropane compound is selected from the group consisting of (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-di-methylpropyl)phenol, (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, (-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)phenol, (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)pheno1, (+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and (-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
13. The pharmaceutical salt as claimed in one of claims 1 to 3, characterized in that the salt-forming active compound is a salt-forming compound of 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula II, in which R1' is H, OH, Cl or F, R2' and R3' are identical or different and are H, C1-4-alkyl, benzyl, CF3, OH, OCH2-C6H5, O-C1-4-alkyl, Cl or F with the proviso that at least one of the radicals R2' or R3' is H, R4' is H, CH3, PO(O-C1-4-alkyl)2, CO(O-C1-5-alkyl), CO-NH-C6H4-C1-3-alkyl, CO-C6H4-R5', CO-C1-5-alkyl, CO-CHR6'-NHR7' or an unsubstituted or substituted pyridyl, thienyl, thiazoyl [sic] or phenyl group, R5' is OC(O)C1-3-alkyl in the ortho-position or CH2-N(R8')2 in the meta- or para-position, where R8' is C1-4-alkyl or both radicals R8' together with N are the 4-morpholino radical, and R6' and R7' are identical or different and are H or C1-6-alkyl, with the proviso that if both radicals R2' and R3' are H, R4' is not CH3 if R1' is H, OH or Cl or R4' is not H if R1' is OH, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
14. The pharmaceutical salt as claimed in claim 13, characterized in that R1' is H, OH or F.
15. The pharmaceutical salt as claimed in claim 13 or 14, characterized in that the compounds of the general formula II have a configuration in which the phenyl ring and the dimethylaminomethyl group are in each case arranged in an equatorial position to one another.
16. The pharmaceutical salt as claimed in one of claims 13 to 15, characterized in that the salt-forming 6-dimethylaminomethyl-1-phenylcyclohexane compound is selected from the group consisting of (-)-(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)-phenol, (1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexane-1,3-diol and (1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxyphenyl)cyclohexane-1,3-diol.
17. The pharmaceutical salt as claimed in one of claims 1 to 3, characterized in that the salt-forming active compound is a salt-forming compound of 1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general formula III, in which in each case A is O or S, R1'' is H, C1-6-alkyl, C2-6-alkenyl, C5-7-cycloalkyl or halogenated C1-6-alkyl, the group is R2'' is C1-6-alkyl, C2-6-alkenyl, C5-7-cycloalkyl-methyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
18. The pharmaceutical salt as claimed in claim 17, characterized in that R1'' is H, C1-4-alkyl, 2'-methyl-2'-propenyl, cyclopentyl or fluoroethyl, with the proviso that R1'' is C1-4-alkyl if A is S, R2'' is C1-4-alkyl, C2-4-alkenyl, cyclopentylmethyl, phenyl, C1-4-alkoxyphenyl, benzyl, C1-4-alkylbenzyl, mono- or dihalogenated phenyl or mono- or dihalogenated benzyl.
19. The pharmaceutical salt as claimed in claim 17 or 18, characterized in that R1'' is H, methyl, ethyl, isopropyl, 2'-methyl-2'-propenyl, cyclopentyl or fluoroethyl, with the proviso that R1'' is methyl if A is S, R2'' is methyl, propyl, 2'-methylpropyl, allyl, 2'-methyl-2'-propenyl, cyclopentylmethyl, phenyl, 3-methoxyphenyl, benzyl, 4-tert-butylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl or 3,4-dichloro-benzyl.
20. The pharmaceutical salt as claimed in one of claims 17 to 19, characterized in that the compounds of the general formula III have a configuration in which the phenyl ring and the dimethylaminomethyl group are in each case arranged in an equatorial position to one another.
21. The pharmaceutical salt as claimed in one of claims 17 to 20, characterized in that the salt-forming 1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compound of the general formula III is selected from the group consisting of (+)-(1R,2R,4S)-2-(dimethylaminomethyl)-4-(4-fluorobenzyloxy)-1-(3-methoxyphenyl)cyclohexanol, (+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-chloro-benzyloxy)-1-(3-methoxyphenyl)cyclohexanol and (+)-(1R,2R,4S)-3-[2-dimethylaminomethyl-4-(4-fluorobenzyloxy)-1-hydroxycyclohexyl]phenol.
22. The pharmaceutical salt as claimed in one of claims 1 to 3, characterized in that the salt-forming active compound is a salt-forming dimethyl-(3-arylbut-3-enyl)amine compound of the general formula IV, in which [sic]
the radical R1''' is C1-5-alkyl and R2''' is H or C1-5-alkyl or R1''' and R2''' together are - (CH2)2-4-, -(CH2)2-CHR7''' or -CH2-CHR7'''-CH2-, R3''' is H or C1-5-alkyl, R4''' is H, OH, C1-4-alkyl, O-C1-4-alkyl, O-benzyl, CF3, O-CF3, Cl, F or OR8''', R5''' is H, OH, C1-4-alkyl, O-C1-4-alkyl, O-benzyl, CHF2, CF3, O-CF3, Cl, F or OR8''' and R6''' is H, OH, C1-4-alkyl, O-C1-4-alkyl, O-benzyl, CF3, O-CF3, Cl, F or OR8''', with the proviso that two of the radicals R4''', R5''' or R6''' are H, or R4''' and R5''' together are -CH=C (R9''')-O- or -CH=C(R9''')-S-, with the proviso that R6''' is H, or R5''' and R6''' together are -CH=CH-C(OR10''')=CH-, with the proviso that R4''' is H, R7''' is C1-8-alkyl, C3-8-cycloalkyl, O-C1-4-alkyl, O-benzyl, CF3, Cl or F, R8''' is CO-C1-5-alkyl, PO(O-C1-4-alkyl)2, CO-C6H4-R11''', CO(O-C1-5-alkyl), CO-CHR12'''-NHR13''', CO-NH-C6H3-(R14''')2 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl [sic] or phenyl group, R9''' is H or C1-4-alkyl, R10''' is H or C1-3-alkyl, R11''' is OC(O)-C1-3-alkyl in the ortho-position or CH2-N-(R15''')2 in the meta- or para-position, where R15''' is C1-4-alkyl or both radicals R15''' together with N form the 4-morpholino radical, R12''' and R13''' are identical or different and are H, C1-6-alkyl or C3-8-cycloalkyl or R12''' and R13''' together are -(CH2)3-8-, R14''' is H, OH, C1-7-alkyl, O-C1-7-alkyl, phenyl, O-aryl, CF3, Cl or F, with the proviso that the two radicals R14''' are identical or different, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
23. The pharmaceutical salt as claimed in claim 22, characterized in that R1''' is C1-3-alkyl and R2''' is H or C1-3-alkyl, or R1''' and R2''' together are -(CH2)2-4- or -(CH2)2-CHR7''', R3''' is H or C1-3-alkyl, R4''' is H, OH, CF3, Cl, F or OR8''', R5''' is H, OH, C1-4-alkyl, O-C1-4-alkyl, O-benzyl, CHF2, CF3, Cl, F or OR8''' and R6''' is H, OH, O-C1-4-alkyl, O-benzyl, CF3, Cl, F or OR8''', with the proviso that two of the radicals R4''', R5''' or R6''' are H, or R4''' and R5''' together are -CH=C(R9''')-O- or -CH=C(R9''')-S-, with the proviso that R6''' is H, or R5''' and R6''' together are -CH=CH-C (OR10''')=CH-, with the proviso that R4''' is H, and R7''' is C1-4-alkyl, CF3, Cl or F.
24. The pharmaceutical salt as claimed in claim 22 or 23, characterized in that R1''' is CH3 or C3H7 and R2''' is H, CH3 or CH2CH3, or R1''' and R2''' together are - (CH2)2-3- or - (CH2)2-CHR7''', R3''' is H, CH3 or CH2CH3, R4''' is H or OH, R5''' is H, OH, OCH3, CHF2 or OR B''' and R6''' is H, OH or CF3, with the proviso that two of the radicals R4''' , R5''' or R6''' are H, or R4''' and R5''' together are -CH=C(CH3)-S-, with the proviso that R6''' is H, or R5''' and R6''' together are -CH=CH-C(OH)=CH-, with the proviso that R4''' is H, and R8''' is CO-C6H4-R11''' where R11''' is OC(O)-C1-3-alkyl in the ortho-position.
25. The pharmaceutical salt as claimed in one of claims 22 to 24, characterized in that R1''' is CH3 and R2''' is H or CH3 or R1''' and R2''' together are -(CH2)2-3- or -(CH2)2-CH(CH3)-, R3'''is H or CH3, R4''' is H, R5''' is OH or OR8''', R6''' is H, and R8''' is CO-C6H4-R11''' where R11''' is OC(O)-CH3 in the ortho-position.
26. The pharmaceutical salt as claimed in one of claims 22 to 25, characterized in that the salt-forming dimethyl-(3-arylbut-3-enyl)amine compound present is trans-(-)-(1R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl]phenol.
27. A medicament comprising at least one pharmaceutical salt as claimed in one of claims 1 to 26 and, if appropriate, physiologically tolerable excipients.
28. A medicament comprising at least one pharmaceutical salt as claimed in one of claims 6 to 26 for the control of pain.
29. A medicament comprising at least one pharmaceutical salt as claimed in one of claims 9 to 26 for the control of urinary incontinence.
30. The medicament as claimed in one of claims 27 to 29, characterized in that it are [sic] present formulated in the form of gels, chewing gums, juices, sprays, tablets, chewable tablets, coated tablets, powders, if appropriate filled into capsules, easily reconstitutable dry preparations, preferably in the form of gels, aqueous or oily juices, sublingual sprays, tablets or chewable tablets.
31. The medicament as claimed in one of claims 27 to 29, characterized in that it is present formulated in multiparticulate form, preferably in the form of microtablets, microcapsules, granules, active compound crystals or pellets, particularly preferably in the form of microtablets, granules or pellets, optionally filled into capsules or compressed to give tablets.
32. The medicament as claimed in one of claims 27 to 31, characterized in that the salt is present at least partially in delayed-release form.
33. The medicament as claimed in claim 32, characterized in that delaying of the release is carried out by applying a release-delaying coating, embedding in a release-delaying matrix, binding to an ion-exchange resin or by a combination of at least two of these methods.
34. The medicament as claimed in claim 33, characterized in that the release-delaying coating is based on a water-insoluble, optionally modified natural or synthetic polymer, optionally in combination with a customary plasticizer, or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these components.
35. The medicament as claimed in claim 33, characterized in that the matrix is based on a hydrophilic matrix material, preferably hydrophilic polymers, particularly preferably on cellulose ethers, cellulose esters and/or acrylic resins, very particularly preferably on ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or their their salts, amides and/or esters.
36. The medicament as claimed in claim 33, characterized in that the matrix is based on a hydrophobic matrix material, preferably hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or appropriate esters or ethers or their mixtures, particularly preferably on mono- or diglycerides of C12-C30 fatty acids and/or C12-C30-fatty alcohols and/or waxes or their mixtures.
37. The medicament as claimed in one of claims 27 to 36, characterized in that it has a protective coating, preferably an enteric protective coating.
38. The use of at least one pharmaceutical salt as claimed in one of claims 6 to 26 for the production of a medicament for the control of pain.
39. The use of at least one pharmaceutical salt as claimed in one of claims 9 to 26 for the production of a medicament for the treatment of urinary incontinence.
CA2439269A 2001-02-28 2002-02-28 Pharmaceutical salts of 1-phenyl-3-dimethylaminopropane compounds Expired - Lifetime CA2439269C (en)

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