EP1746986A1 - Combinaison de substances actives comprenant du carbinol combine a au moins un ains - Google Patents

Combinaison de substances actives comprenant du carbinol combine a au moins un ains

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Publication number
EP1746986A1
EP1746986A1 EP05730128A EP05730128A EP1746986A1 EP 1746986 A1 EP1746986 A1 EP 1746986A1 EP 05730128 A EP05730128 A EP 05730128A EP 05730128 A EP05730128 A EP 05730128A EP 1746986 A1 EP1746986 A1 EP 1746986A1
Authority
EP
European Patent Office
Prior art keywords
methyl
imidazole
dimethylamino
radical
pyrazole
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Withdrawn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
EP05730128A
Other languages
German (de)
English (en)
Inventor
Helmut Heinrich Buschmann
Bonifacio Gutierrez Silva
Jörg Holenz
Antonio Farre Gomis
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.)
Esteve Pharmaceuticals SA
Original Assignee
Laboratorios del Dr Esteve SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from ES200400844A external-priority patent/ES2244326B1/es
Application filed by Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Publication of EP1746986A1 publication Critical patent/EP1746986A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to an active substance combination comprising at least one substituted carbinol compound and at least one non-steroidal anti-inflammatory drug (NSAID), a medicament comprising said active substance combination, a pharmaceutical formulation comprising said active substance combination and the use of said active substance combination for the manufacture of a medicament.
  • NSAID non-steroidal anti-inflammatory drug
  • Non-steroidal anti-inflammatory drugs such as acetylsalicylic acid or diclofenac are regularly used for the treatment of mild to moderate pain and fever.
  • the analgesic action of this class of compounds results from their inhibition of the enzymatic production of prostaglandins.
  • Cyclooxygenase is the key enzyme in the conversion of the of arachidonic acid derived from lipids of the cell membrane to prostaglandins and other eicosanoids. Cyclooxygenase exists in two different isoforms characterized by different expression patterns. Cyclooxygenase-1 is constitutively expressed in many cells of the body and responsible mainly for the production of eicosanoids serving normal physiological functions. Cyclooxygenase-2 expression is induced during inflammation and is considered to be responsible for the production of eicosanoids serving normal physiological functions in a healthy organism.
  • Typical side effects associated with the administration of compounds showing Cyclooxygenase-1 specifity or balanced Cyclooxygenase-1 and Cyclooxygenase-2 inhibition are gastrointestinal side effects such as damage of the gastric mucosa.
  • Cyclooxygenase-2 inhibitors of the first generation i.e. compounds which show a stronger inhibition of Cyclooxygenase-2 compared to Cyclooxygenase-1.
  • undesired gastrointestinal side effects are further reduced if inhibitors with even higher selectivity for Cyclooxygenase-2 are used in the therapy such so-called Cyclooxygenase-2 in hibitors of the second or higher generation are accompanied by other undesired side effects, particularly an increased risk of cardiovascular diseases such as edema, hypertonia or tachycardia.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • said medicament should not show the undesired side effects of such medicaments known from the prior art, or at least less frequent and/or to a I esser extent.
  • the present invention relates to an active substance combination comprising
  • R 1 represents a hydrogen atom, a linear or branched alkyl radical, a linear or branched alkenyl radical, an optionally at least mono-substituted cycloaliphatic radical, which may contain at least one nitrogen atom as ring member, or a phenyl radical,
  • R 2 represents a hydrogen atom, an option lly at least one nitrogen atom as ring member containing cycloaliphatic radical, which may be at least mono-substituted by a linear or branched alkyl radical and/or which may be bound via a linear or branched alkylene group, a NR 3 R 4 -moiety, which is bound via a linear or branched alkylene group, or a NR 5 R 6 -moiety, which is bound via a linear or branched alkylene group,
  • R 3 and R 4 identical or different, represent a linear or branched alkyl radical or an unsubstituted benzyl radical
  • R 5 and R 6 together with the bridging nitrogen atom represent a saturated, unsubstituted, optionally at least one further heteroatom as ring member containing heterocyclic radical,
  • X represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, wherein in each case the substituents are selected from the group consisting of a linear or branched alkyl radical, a linear or branched alkoxy group, a linear or branched alkyl radical, which is at least partially halogenated or a halogen atom,
  • Y represents a heteroaryl radical, which contains one or more nitrogen atoms as ring members and which is unsubstituted or at least mono-substituted by one or more substitutents independently from one another selected from the group consisting of a halogen atom, a linear or branched alkyl radical, an unsubstituted benzyl radical, a ciano group bound via a linear or branched d- 4 -alkylene group, a carboxy group bound via a linear or branched C ⁇ - 4 -alkyle ne group, a methoxy carbonyl group bound via a linear or branched C ⁇ .
  • 4 -alkylene group a hydroxy group bound via a linear or branched C ⁇ . 4 -alkylene group, an amino group bound via a linear or branched C ⁇ - - alkylene group, a (C-t- 4 ) dialkylamino grou bound via a linear or branched C 1 - 4 - alkylene group and a cycloaliphatic radical, which contains one or more nitrogen atoms as ring members and which is bound via a linear or branched C- ⁇ _ 4 -alkylene group, or Y represents an unsubstituted heteroaryl radical, which contains two nitrogen atoms as ring members and which is condensed with (annellated to) a saturated, one methyl-substituted nitrogen atom as ring member containing cycloaliphatic group,
  • NSAID non-steroidal anti-inflammatory drug
  • the active substance combination according to the present invention comprises one or more substituted carbinol compounds of general formula I given above, wherein R 1 represents a hydrogen atom, a linear or branched C 1 - 4 alkyl radical, a linear or branched C 2 .
  • alkenyl radical a 5-or 6-membered cycloaliphatic radical, which may contain at least one nitrogen atom as ring member and/or which may be at least mono-substituted by a linear or branched C- ⁇ - 4 alkyl radical, or a phenyl radical, preferably a hydrogen atom, a linear or branched C 1 - 4 alkyl radical, a vinyl group, a cyclohexyl radical, an N-Methyl-piperidyl radical or a phenyl radical, and the other substituents R 2 -R 6 , X and Y have the meaning given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate.
  • the active substance combination according to the present invention comprises one or more substituted carbinol compounds of general formula I given above, wherein R 2 represents a hydrogen atom, an optionally at least one nitrogen atom as ring member containing, 5- or 6-membered cycloaliphatic radical, which may be at least mono-substituted by a linear or branched C- ⁇ - -alkyl radical and/or which may be bound via a linear or branched C ⁇ - 4 -alkyl radical, a NR 3 R 4 -moiety, which is bound via a linear or branched C ⁇ - 4 alkylene group, or a NR 5 R 6 -moiety, which is bound via a linear or branched C ⁇ - 4 alkylene group, preferably a hydrogen atom, an optionally at least one nitrogen atom as ring member containing, 5- or 6-membered cycloaliphatic radical, which may be at least mono-substituted by a linear or branched Ci- 4
  • the inventive active substance combination comprises one or more substituted carbinol compounds of general formula I given above, wherein R 3 and R 4 , identical or different, independently from one another represent a linear or branched C 1 - 4 alkyl radical or an unsubstituted benzyl radical, preferably a linear or branched C1 . .
  • R 1 , R 2 , R 5 , R 6 , X and Y have the meaning given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate.
  • the active substance combination according to the present invention comprises one or more substituted carbinol compounds of general formula I given above, wherein R 5 and R 6 together with the bridging nitrogen atom represent a saturated, unsubstituted, optionally at least one oxygen atom as ring member containing, 5- or 6-membered heterocyclic radical, and the remaining substituents R 1 - R 4 , X and Y have the meaning given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate.
  • the active substance combination according to the present invention comprises one or more substituted carbinol compounds of general formula I given above, wherein X represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, wherein in each case the substituents are independently selected from the group consisting of a linear or branched C 1 - 4 alkyl radical, a linear or branched C 1 .
  • the active substance combination according to the present invention comprises one or more substituted carbinol compounds of general formula I, wherein Y represents an azole radical selected from the group consisting of
  • R 7 represents a linear or branched Cr 12 alkyl radical, a benzyl radical or a radical of the type:
  • n 1 or 2
  • R 8 represents a hydrogen atom, a methyl radical or a rialogen atom, preferably a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
  • R 9 represents a hydrogen atom, a Cr ⁇ 2 alkyl radical, a benzyl radical or a radical of the general formula (b1 ):
  • R 10 represents a piperidinyl radical, a phenyl radical, a cyano group, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group or a methyl ester group,
  • R 1 -R 6 and X have the meaning given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate.
  • inventive active substance combination comprises one or more substituted carbinol compounds of general formula I given above, wherein
  • R 1 represents a hydrogen atom; a linear or branched C 1 - 4 alkyl radical; a linear or branched C 2 . 4 alkenyl radical; a 5-or 6-membered cycloaliphatic radical, which may contain 1 or 2 nitrogen atoms as ring member(s) and/or which may be substituted by 1 , 2, 3 or 4 linear or branched C- 1 - 4 alkyl radicals that may be identical or different; or a phenyl radical;
  • R 2 represents a hydrogen atom; an optionally 1 , 2 or 3 nitrogen atom(s) as ring member(s) containing, 5- or 6-membered cycloaliphatic radical, which may be substituted by 1 , 2, 3 or 4 linear or branched C ⁇ . 4 -alkyl radical that may be identical or different and/or which may be bound via a linear or branched C ⁇ _ ⁇ -alkyl radical; a NR 3 R 4 -moiety, which is bound via a linear or branched C1-4 alkylene group; or a NR 5 R 6 -moiety, which is bound via a linear or branched C 1 -4 alkylene group;
  • R 3 and R 4 identical or different, independently from one another represent a linear or branched C 1 - 4 alkyl radical; or an unsubstituted benzyl radical;
  • R 5 and R 6 together with the bridging nitrogen atom represent a saturated, unsubstituted, optionally one oxygen atom as ring member containing, 5- or 6- membered heterocyclic radical;
  • X represents a phenyl radical, which may be substituted with 1 , 2, 3, 4 or 5 substituents or a thienyl radical, which may be substituted with 1 , 2 or 3 substituents, wherein in each case the substituents may be independently selected from the group consisting of a linear or branched C 1 - 4 alkyl radical, a linear or branched C 1 - 4 alkoxy radical, a linear or branched C 1 - 4 alkyl radical, which is at least partially fluorinated, a fluorine atom, a chlorine atom and a bromine atom; and
  • Y represents an azole radical selected from the group consisting of
  • R 7 represents a linear or branched C 1 - 12 alkyl radical, a benzyl radical or a radical of the type:
  • R 8 represents a hydrogen atom, a methyl radical or a halogen atom, preferably a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
  • R 9 represents a hydrogen atom, a C ⁇ 2 alkyl radical, a benzyl radical or a radical of the general formula (b1 ):
  • R 10 represents a piperidinyl radical, a phenyl radical, a cyano group, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group or a methyl ester group,
  • inventive active substance combination comprises one or more substituted carbinol compounds of general formula I given above, wherein
  • R 1 represents a hydrogen atom; a linear or branched C- 1 - 4 alkyl radical; a vinyl group; a cyclohexyl radical; an N-Methyl-piperidyl radical; or a phenyl radical;
  • R 2 represents a hydrogen atom; an optionally 1 , 2 or 3 nitrogen atom(s) as ring member(s) containing, 5- or 6-membered cycloaliphatic radical, which may be substituted by 1 , 2, 3 or 4 linear or branched Ci- 4 -alkyl radicals that may be identical or different and/or which may be bound via a linear or branched C ⁇ - 4 -alkyl radical; a NR 3 R 4 -moiety, which is bound via a linear or branched C 1 - 4 alkylene group; or a NR 5 R 6 -moiety, which is bound via a linear or branched C 1 - 4 alkylene group;
  • R 3 and R 4 identical or different, independently from one another represent a linear or branched C 1 - 4 alkyl radical
  • R 5 and R 6 together with the bridging nitrogen atom represent a saturated, unsubstituted, optionally one oxygen atom as ring member containing, 5- or 6- membered heterocyclic radical;
  • X represents a phenyl radical that may be substituted with 1 , 2, 3, 4 or 5 substituents or a thienyl radical that may be substituted with 1 , 2 or 3 substituents, wherein in each case the substituents may be independently selected from the group consisting of a methyl radical, a methoxy radical, a trifluoromethyl radical, a fluorine atom, a chlorine atom and a bromine atom;
  • Y represents an azole radical selected from the group consisting of a) a pyrazole of the general formula (a):
  • R 7 represents a linear or branched C 1 -12 alkyl radical, a benzyl radical or a radica of the type: ⁇ ⁇
  • n 1 or 2
  • R 8 represents a hydrogen atom, a methyl radical or a halogen atom, preferably a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
  • R 9 represents a hydrogen atom, a C 1 - 12 alkyl radical, a benzyl radical or a radical of the general formula (b1 ): R lu -(CH 2 ) n -
  • R 10 represents a piperidinyl radical, a phenyl radical, a cyano group, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group or a methyl ester group,
  • R 1 represents a hydrogen atom, a methyl radical, an ethyl radical, an n-propyl radical, an iso-propyl radical, a sec-butyl radical, a tert-butyl radical, an n-butyl radical, a vinyl radical, a cyclohexyl radical, an N-methyl-piperidinyl group, or a phenyl group,
  • R 2 represents a hydrogen atom, a dimethylaminoethyl group, a pyrrolidinylethyl group, a piperidinylethyl group, a methyl-benzyl-aminoethyl group, a morpholinylethyl group, a diisopropylaminoethyl group, a dimethylaminopropyl group, a piperidinylpropyl group, a pyrrolidinylpropyl group, a morpholinylpropyl group, an N- methyl-2-piperidyl group, an N-ethyl-2-piperidyl group, an N-propyl-2-piperidyl group, an N-rnethyl-2-pyrroiidinyl group, an N-ethyI-2-pyrrolidinyl group, an N-propyl-2- pyrrolidinyl group, or a 2-dimethylaminoethyl
  • X represents a phenyl radical, a 2-methyl-phenyl radical, a 3-methyl-phenyI radical, a 4-methyl phenyl radical, a 2-chloro-phenyl radical, a 3-chloro-phenyl radical, a 4- chloro-phenyl radical, a 2-fluoro-phenyl radical, a 3-fluoro-phenyl radical, a 4-fluoro- phenyl radical, a 2-trifluoromethyl-phenyl radical, a 3-trifluoromethyl-phenyl radical, a 4-trifluoromethyl-phenyl radical, a 2-methoxy-phenyl radical, a 3-methoxy-phenyl radical, a 4-methoxy-phenyl radical, a 3,4,5-tris-methoxy-phenyl radical, a 3,4- dichloro-phenyl radical, a 2,4-dichloro-phenylradical, a thien-2-yl radical, a thien
  • Y represents an azole radical selected from the group consisting of
  • R 7 represents a methyl radical, an ethyl radical, an n-propyl radical, an iso-propyl radical, an n-butyl radical, a sec-butyl radical or a tert-butyl radical,
  • R 8 represents a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom
  • R 9 represents a hydrogen atom, a methyl radical, an ethyl radical, an n- propyl radical, an iso-butyl radical, an n-butyl radical, a sec-butyl radical a tert-butyl radical, an n-pentyl radical, an n-hexyl radical, an n-heptyl radical, an n-octyl radical, an n-nonyl radical, an n-decyl radical, an n-undecyl radical an n-dodecyl radical, a benzyl radical, or a radical of the general formula (b1 ):
  • R 10 represents a piperidinyl radical, a phenyl radical, a cyano group, a hydroxyl radical, a carboxy radical, an amino group, a dimethylamino group, or a methyl ester group,
  • component (A) The preparation of the substituted carbinol compounds of general formula I, their stereoisomers, corresponding salts and corresponding solvates may be accomplished by the reagents and methods described, for example, in EP 0 289 380, US 5,017,596, W099/52525 (US 6,410,582) and WO99/07684 (US 6,118,009) . Methods for the optical resolution of said compounds, i.e. the preparation or separation of the respective stereoisomers are described, for example, in WO99/02500 (US 6,187,930) and WO97/20817 (US 5,849,931 ). The corresponding parts of these publications are hereby incorporated by reference and form part of the present disclosure.
  • Physiologically acceptable salts of the substituted carbinol compounds of general formula I given above may be obtained by conventional methods known to those skilled in the art.
  • Preferred pharmaceutically acceptable salts of these substituted carbinol compounds of general formula I given above are the citrate salts or the ditoluyltartrate salts.
  • Generally included are also addition salts of mineral acids or of organic acids such as oxalate, tartrate, citrate and hydroquinonesulfate.
  • the term “salt” herein is to be understood as including any form of an active compound of the inventive active substance combination in which this is present in ionic or charged form and is coupled with a corresponding counter-ion (a cation or anion) or is in solution.
  • the term “salt” further comprises complexes of an active compound of the inventive active substance combination with other ions or molecules, in particular complexes, which are complexed via ionic interactions.
  • physiologically acceptable salt is understood in particular as including a salt that is formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals - or with at least one, preferably inorganic, ion, preferably cation, which are physiologically tolerated, especially if used on humans and/or mammals.
  • physiologically tolerated salts of particular acids are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1 ,1-dioxo-1 ,2-dihydro-6-benzo[d]isothiazol-3-one (saccharin acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, alpha-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
  • physiologically tolerated salts of particular bases are salts of alkali and alkaline earth metals and/or with ⁇ NH x R 4 -x] + -ions, wherein x is 0, 1 , 2, 3 or 4 and R represents a linear or branched C1 . - 4 alkyl radical.
  • salts that are preferred are salts of physiologically tolerated acids.
  • the salt which is particularly preferred for the particular compound of component A is the citrate.
  • Non-steroidal anti-inflammatory drugs according to component (B) of the present invention include corresponding salts and corresponding solvates of these drugs as well.
  • Physiologically acceptable salts and solvates of these compounds of component (B) may be obtained by conventional methods known to those skilled in the art
  • Suitable non-steroidal anti-inflammatory drugs (NSAIDS) according to component (B) of the inventive active substance combination, suitable doses for the administration to patients as well as methods for their preparation are well known to those skilled in the art, e.g. from E. Friderichs, T. Christoph and H. Buschmann, "Analgesics and Antipyretics", Ullmann s Encyclopedia of Industrial Chemistry, Sixth Edition, Wiley- VCH Verlag GmbH, Weinheim, Germany 2000, pages 3-24 and H. Buschmann, T. Christoph, E. Friderichs, C. Maul, B. Sundermann (Editiors), "Analgesics - From Chemistry and Pharmacology to Clinical Application", 1. Edition 2002-Part ll-pages 13-126 Wiley- VCH Verlag, Weinheim, Germany. The respective parts of the description are hereby incorporated by reference and form part of the present disclosure.
  • the active substance combination of the present invention comprises compounds with Cyclooxygenase-1 and/or Cyclooxygenase-2 inhibiting activity selected from the group consisting of Acemetacin, Acetylsalicylic acid, Bufexamac, Diclofenac, Diflunisal, Ethenzamide, Etofenamate, Fenbufen, Fenoprofen, Feprazone, Flobufen, Flufenamic acid, Flurbiprofen, Ibuprofen, Indomethacin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac, Lonazolac, Lornoxicam, Meclofenamic acid, Mefenamic acid, Metamizol, Mofebutazone, Nabumetone, Naproxen, Niflumic acid, Oxaprozin, Oxyphenbutazone, Paracetamol, Phenidine, Phenylbutazone, Piroxicam, Propacetamol, Propyphenazone, Salicy,
  • the pharmacologically active substance combination of the present invention comprises as component (B) one or more non-steroidal anti-inflammatory drugs selected from the group of compounds showing Cyclooxygenase-1 specific inhibition or balanced Cyclooxygenase-1 and Cyclooxygenase-2 inhibition - typically referred to as Cyclooxygenase-1 inhibitors by those skilled in the art - and Cyclooxygenase-2 Inhibitors of the first generation.
  • Cyclooxygenase-1 -inhibitors may be selected from the group consisting of Acemetacin, Acetylsalicylic acid, Bufexamac, Diclofenac, Diflunisal, Ethenzamide, Etofenamate, Fenbufen, Fenoprofen, Feprazone, Flobufen, Flufenamic acid, Flurbiprofen, Ibuprofen, Indomethacin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac, Lonazolac, Lornoxicam, Meclofenamic acid, Mefenamic acid, Metamizol, Mofebutazone, Nabumetone, Naproxen, Niflumic acid, Oxaprozin, Oxyphenbutazone, Paracetamol, Phenidine, Phenylbutazone, Piroxicam, Propacetamol, Propyphenazone, Salicylamide, Sulindac, Tenoxicam, Tiaprofen
  • Cyclooxygenase-2 Inhibitors of the first generation are compounds having a less or equal to 100-fold selectivity for Cyclooxygenase-2 compared to Cyclooxygenase-1 , whereby said selectivity is determined according to the method described in L. Cullen et al., JPET, Vol. 287, 578-582, 1998 and A. Hiermann et al., Inflamm. Res., Vol. 47, 421-427, 1998. The respective descriptions are hereby incorporated by reference and form part of the present disclosure.
  • Suitable Cyclooxygenase-2 inhibitors of the first generation may preferably be selected from the group consisting of Etodolac, Meloxicam, Nimesulide and physiologically acceptable salts thereof.
  • the active substance combination of the present invention comprises as component (B) one or more nonsteroidal anti-inflammatory drugs selected from the group of Cyclooxygenase-1 inhibitors, whereby those Cyclooxygenase-1 inhibitors mentioned above may preferably be present.
  • the active substance combinaton comprises as component (b) one or more Cyclooxygenase-1 inhibitors selected from the group consisting of Acetylsalicylic acid, Diclofenac, Ibuprofen, Naproxen and physiologically acceptable salts thereof.
  • the molar ratio between the components of the active substance combination may vary over a broad range.
  • the molar ratio of component (A) to component (B) in the active substance combination of the present invention is in the range of 1 :10 to 10:1 , more preferably from 1 :4 to 4:1.
  • non-steroidal antiinflammatory drugs according to component (B) of the inventive active substance combination are known to exist in the form of physiologically acceptable salts, particularly those having one or more acid groups.
  • physiologically acceptable salts of these compounds may be selected from the group consisting of alkali metal salts, preferably potassium or sodium salts, and earth metal salts.
  • the compounds of component (B) as well as the compounds of component (A) may each be present in form of mixture of two or more different salts.
  • carbinol compounds of component (A) as well as many NSAIDs of component (B) may occur in form of a corresponding ether, ester or other derivative thereof. All of these compounds are also included by the present invention. Such suitable ethers, esters and other derivatives of the compounds of components (A) and (B) as well as methods for their preparation are well known to those skilled in the art. If the active compound of component (A) comprises at least one basic group and the active compound of component (B) comprises at least one acidic group or vice versa, both components may at least partially form a salt with one another.
  • the salts may be prepared, optionally purified and/or optionally isolated according to conventional methods well known to those skilled in the art, e.g.
  • the respective salt may also be formed in-situ, i.e. during the process of formulating the active substance combination into a particular dosage form.
  • component (A) and component (B) are at least partially present in form of a salt formed between these two components.
  • component (A) and component (B) are present in the inventive active substance combination in form of a 1 :1 salt, whereby said 1 :1 salts may preferably be selected from the group consisting of
  • the inventive active substance combination is suitable for the administration to humans, including infants, children and grown-ups, as well as for the administration to animals.
  • the total amount of the compound(s) according to component (A), referred to as the free compound, to be administered to the patient in a 24 hours period does not exceed 800 mg.
  • Suitable dosis for the respective NSAIDS are well-known to those skilled in the art, e.g. from the respective publications given above.
  • the inventive active substance combination comprises components (A) and (B) in the above defined molar ratios and within the afore given limits for the maximum dosis to be administered per day.
  • compositions are sometimes the subject of abuse.
  • an overdose of such an analgesic may be used in an attempt to commit suicide.
  • the active substance combination further comprises as component (C) one or more agents that are suitable to reduce, preferably prevent abuse of the active substances of component (A) and/or component (B).
  • anti-abuse agents are present in the inventive active substance combination, they are included in such a form that they are either not liberated at all or in such a way that they do not exert their anti-abuse effect if the active substance combination is administered to the patient according to its intended route of administration.
  • inventive active substance combination or - after separation - one of its components alone is administered via a route other than the intended route of administration, said anti-abuse agent will exert its effect and therefore reduce, preferably prevent abuse.
  • Suitable agents for reduction, preferably prevention of the abuse of these pharmacologically active components include aversive agents such as bittering agents, irritants, emetics, nauseants, and gelling agents, whereby two representatives of one class of these anti-abuse agents or two or more representatives of different classes of anti-abuse agents may be included in the active substance combination of the present invention to prevent, preferably to at least reduce different kinds of abuse.
  • Abuse of the inventive active substance combination may, for example, be reduced, preferably be prevented by the inclusion of an emetic.
  • the amount of said emetic is chosen in such a way thay it will not exert its emetic effect if the active substance combination is taken in a dose intended for the prophylaxis and/or treatment of the respective disorder. However, if said dose will exceed a certain limit, which is considered harmful for the patient, the accumulated dose of the emetic will exert its emetic effect.
  • Suitable anti-abuse agents according to component (C) of the inventive substance combination suitable amounts as well as methods for their incorporation into pharmceutical formulations are well-known to those skilled in the art, e.g. from WO03/013476 and WO 99/32120. The respective parts of the descriptions are hereby incorporated by references and form part of the present disclosure.
  • the present invention relates to a medicament comprising an inventive active substance combination and optionally at least one further active substance and/or optionally at least one auxiliary.
  • the inventive medicament is suitable for the treatment of pain
  • said pain is preferably selected from the group consisting of neuropathic pain, acute pain, chronic pain, post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, pain resulting from sunburns, post partum pains, migraine, angina pain, genitourinary tract-related pain, pain from cystitis and nociceptive pain, for the prophylaxis and/or treatment of neurogenic inflammation, for the prophylaxis and/or treatment of urinary incontinence, for the prophylaxis and/or treatment of depression, for the prophylaxis and/or treatment of inflammation and/or for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoi
  • the inventive medicament is suitable for the treatment of pain
  • said pain is preferably selected from the group consisting of neuropathic pain, acute pain, chronic pain, post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, pain resulting from sunburns, post partum pains, migraine, angina pain, genitourinary tract-related pain, pain from cystitis and nociceptive pain, for the prophylaxis and/or treatment of inflammation and/or for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, rheumatic fever,
  • components (A) and (B) of the active substance combination according to the present invention may be administered simultaneously or sequentially to one another, whereby in each case components (A) and (B) may be administerd via the same or different administration pathways, e.g. orally or parenterally. preferably both components (A) and (B) are administered simultaneously in one and the same administration form.
  • Another aspect of the present invention relates to the use of an inventive active substance combination for the manufacture of a medicament for the treatment of pain, whereby said pain is preferably selected from the group consisting of neuropathic pain, acute pain, chronic pain, post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, pain resulting from sunburns, post partum pains, migraine, angina pain, genitourinary tract-related pain, pain from cystitis and nociceptive pain, for the prophylaxis and/or treatment of urinary incontinence, for the prophylaxis and/or treatment of neurogenic inflammation for the prophylaxis and/or treatment of depression, for the prophylaxis and/or treatment of inflammation and/or for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be
  • an inventive active substance combination for the preparation of a medicament for the treatment of pain
  • said pain is preferably selected from the group consisting of neuropathic pain, acute pain, chronic pain, post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, pain resulting from sunburns, post partum pains, migraine, angina pain, genitourinary tract-related pain, pain from cystitis and nociceptive pain, for the prophylaxis and/or treatment of inflammation and/or for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis,
  • Yet another aspect of the present invention related to pharmaceutical formulations in different pharmaceutical forms comprising an inventive active substance combination and optionally at least one further active substance and/or optionally at least one auxiliary substance.
  • inventive pharmaceutical formulation is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.
  • Inventive pharmaceutical formulation for oral administration are preferably selected from the group consisting of tablets, dragees, capsules, drops, gels, juices, sirups, solutions and suspensions.
  • the pharmaceutical formulation of the present invention for oral administration may also be in the form of multiparticulates, preferably pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.
  • inventive pharmaceutical formulations may - depending on their route of administration - also contain one or more auxiliary substances known to those skilled in the art.
  • the pharmaceutical formulations according to the present invention may be produced according to standard procedures known to those skilled in the art, e.g. from the tables of contents from ..Pharmaceutics: the Science of Dosage Forms", Second Edition, Aulton, M.E. (Ed.) Churchill Livingstone, Edinburgh (2002); Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); ..Modern Pharmaceutics", Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc.
  • the pharmaceutical formulation comprises one or both of the components (A) and (B) at least partially in a sustained- release form.
  • sustained-release form By incorporating one or both of these components at least partially or completely in a sustained-release form it is possible to extend the duration of their effect, allowing for the beneficial effects of such a sustained release form, e.g. the maintenance of even concentrations in the blood.
  • Suitable sustained-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from legitimateModified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); dominantHandbook of Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000);”Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, S.D. (Ed.), CRC Press Inc., Boca Raton (1983) and from Takada, K.
  • the pharmaceutical formulation according to the present invention comprises at least one of the components (A.) and (B) at least partially in a sustained-release form
  • said sustained release may preferably be achieved by the application of at least one coating or provision of a matrix comprising at least one sustained-release material.
  • the sustained-release material is preferably based on an optionally modified , water- insoluble, natural, semisynthetic or synthetic polymer, or a natural, semisynthetic or synthetic wax or fat or fatty alcohol or fatty acid, or on a mixture of at least two of these afore mentioned components.
  • the water-insoluble polymers used to produce a sustained-release material are preferably based on an acrylic resin, which is preferably selected from the group of poly(meth)acrylates, particularly preferably poly(C ⁇ - 4 )alkyl (meth)acrylates, poly(C 1 - 4 )dialkylamino(C ⁇ - 4 )alkyl (meth)acrylates and/or copolymers or mixtures thereof, and very particularly preferably copolymers of ethyl acrylate and methyl methacrylate with a monomer molar ratio of 2:1 (Eudragit NE30D ® ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate- chloride with a monomer molar ratio of 1 :2:0.1 (Eudragit RS ® ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacryl
  • coating materials are commercially available as 30 wt.% aqueous latex dispersions, i.e. as Eudragit RS30D ® , Eudragit NE30D ® or Eudragit RL30D ® , and may also be used as such for coating purposes.
  • the sustained-release material is based on water-insoluble cellulose derivatives, preferably alkyl celluloses, particularly preferably ethyl cellulose, or cellulose esters, e.g. cellulose acetate.
  • alkyl celluloses particularly preferably ethyl cellulose, or cellulose esters, e.g. cellulose acetate.
  • Aqueous ethyl cellulose dispersions are commercially available, for example, under the trademarks Aquacoat ® or Surelease ® .
  • the sustained- release material may be based on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of these components.
  • the afore mentioned polymers of the sustained-release material may also comprise a conventional, physiologically acceptable plasticizer in amounts known to those skilled in the art.
  • plasticizers are lipophilic diesters of a C6-C40 aliphatic or aromatic dicarboxylic acid and a C- ⁇ -C 8 aliphatic alcohol, e.g. dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic citric acid esters, e.g. triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyltriethyl citrate, polyethylene glycols, propylene glycol, glycerol esters, e.g.
  • Aqueous dispersions of Eudragit RS ® and optionally Eudragit RL ® preferably contain triethyl citrate.
  • the sustained-release material may comprise one or more plasticisers in amounts of, for example, 5 to 50 wt.% based on the amount of polymer(s) used.
  • the sustained-release material may also contain other conventional auxiliary substances known to those skilled in the art, e .g. lubricants, coloured pigments or surfactants.
  • the pharmaceutical formulation of the present invention may also comprise at least one of the components (A) and (B) covered by an enteric coating form which dissolves as a function of pH. Because of this coating, part or all of the pharmaceutical formulation can pass through the stomach undissolved and the components (A) and/or (B) are only released in the intestinal tract.
  • the enteric coating preferably dissolves at a pH of between 5 and 7.5.
  • the enteric coating may be based on any enteric material known to those skilled in the art, e.g. on methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1 :1 (Eudragit L ® ), methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1 :2 (Eudragit S ® ), methacrylic acid/ethyl acrylate copolymers with a monomer molar ratio of 1 :1 (Eudragit L30D-55 ® ), methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a monomer molar ratio of 7:3:1 (Eudragit FS ® ), shellac, hydroxypropyl methyl cellulose acetate-succinates, cellulose acetate-phthalates or a mixture of at least two of these components, which can optionally also be used in combination with the above-mentione
  • the coatings of the pharmaceutical formulations of the present invention may be applied by the conventional processes known to those skilled in the art, e.g. from Johnson, J.L., absolutelyPharmaceutical tablet coating” , Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A.A. (Eds), Marcel Dekker, Inc. New York, (2001 ), 863-866; Carstensen, T., possiblyCoating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (Ed.), Marcel Dekker, Inc.
  • the pharmaceutical formulation of the present invention contains one or both of components (A) and (B) not only in sustained-release form, but also in non-retarded form.
  • a high initial dose can be achieved for the rapid onset of the beneficial effect.
  • the slow release from the sustained release form then prevents the beneficial effect from diminishing.
  • Such a pharmaceutical formulation is particularly useful for the treatment of acute health problems.
  • a pharmaceutical formulation having at least one immediate-release coating comprising at least one of the components (A) and (B) to provide for rapid onset of the beneficial effect after administration to the patient.
  • an inventive pharmaceutical formulation suitable for the treatment of pain may preferably comprise component (B) in immediate-relase form in addition to components (A) and (B) in sustained release form.
  • An inventive pharmaceutical formulation suitable for the treatment of inflammation and inflammation-related disorders may preferably comprise both components (A) and (B) each in immediate release form and in sustained release form.
  • the pharmacolog ical efficacy, particularly the analgesic efficacy, of the inventive substance combination is maintained or even improved with respect to the administration of the MSAID component alone for comparable amounts to be administered, whereas the undesired side effects typically associated with the NSAIDs component, particularly with Cyclooxygenase-1 inhibitors and Cyclooxygenase-2 inhibitors of the first generartion are significantly reduced.
  • the inventive active substance combination a Hows to make use of the many remedial effects associated with NSAIDs but without or at least to a significantly reduced extent having to cope with the disadvantages typically associated with their use.
  • the Writhing test for the determination of the analgesic activity of the inventive active substance combination is carried out according to the method described in the publication of E. Siegmund et al., Proc. Soc. Exp. Biol. Med. 1 957, 95, 729-731 using male Swiss albino mice (20-25 g body weight, obtained from Harlan, S. Feliu de Codinas, Spain).
  • the respective part of the description is hereby incorporated by reference and forms part of the respective disclosure.
  • the Writhing reactions are induced by intraperitoneal injection of phenylbenzoquinone (25 ml/kg in a 0.02 % (volume/volume) ethanolic solution in a 5 % (volume/volume) solution in destillated water with Evan ' s blue in an amount of 0.1 % weight/volume) and the writhing reactions are counted duri ng a 15 minute period following the injection.
  • the substances to be tested are orally administered 60 minutes prior to the injection of the phenylbenzoquinone solution.
  • the percentage of the inhibition of the writhing reactions is calculated on the basis of the control group as basis for 0 % inhibition.
  • the Formaline test for the determination of the analgesic activity of the inventive active substance combination is carried out according to the ethod described in the publication of T. Ohkubo et al., J. Pharmacol. Exp. Ther. 1990, 252, 1261-1268 using male Swiss albino mice (20-25 g body weight, obtained from Harlan, S. Feliu de Codinas, Spain).
  • the respective part of the description is hereby incorporated by reference and forms part of the respective disclosure.
  • the substances to be tested are intraperitoneally administered to the mice in 5 % by weight solution of arable gum in destilled water as vehicle. 15 minutes later 20 ⁇ l of a 5 % by weight solution of formaline in saline solution is injected into the back of the right paw of the animals. The total time in seconds of licking and/or biting t e injected paw is registered in the acute phase, i.e. 0-5 minutes (phase I), and in the chronic phase, i.e. 15-30 (phase II), minutes after injection of the formaline. The percentage of inhibition is calculated based on the medium values of trie acute and chronic phases of the control group as 0 % inhibition of the primary and secondary response.
  • the ulcerogenic effect of the inventive active substance combination is determined in male Wistar albino rats (body weight 160-200 g, obtained from Harlan, S. F eliu de
  • the rats Prior to the tests the rats are kept in cages for 24 hours with free access to drinking water. Afterwards the substances to be tested are orally administered to the rats in form of a 5 % by weight suspension in arabic gum. Three hours after the administration of the respective substances to be tested the rats are sacrificed by inhalation of carbon dioxide, the stomachs are removed, opened along the great curvature, washed with saline solution and extended over a suitable frame. By the use of a Projectt 1.2 image analyzer (Projectt, Barcelona, Spain) the ulcerated areas of the stomachs are determined and their size expressed in mm 2 .
  • a Projectt 1.2 image analyzer Projectt, Barcelona, Spain
  • Cizolirtine in form of its free base (259 g/mol), Naproxen (252 g/mol), Diclofenac (273 g/mol) and Ibuprofen (206 g/mol) are comparable.
  • the pharmacological tests according to the present examples have been carried out using identical dosages, such as 40 mg/kg, 80 mg/kg or 160 mg/kg.
  • Example 1
  • the active substance combination salt (c) as well as its respective components, i.e. diclofenac in form of its sodium salt and R-(+)-5-[ ⁇ -[2-(Dimethylamino)ethoxy]benzyl]- 1 -methyl-1 H-pyrazole (hereinafter referred to as R-(+)-cizolirtine) were tested for their analgesic activity and their ulcerogenic effects.
  • the respective results are given in the following tables D and E.
  • the active substance combination salt (e) as well as its respective components, i.e. ibuprofen or ibuprofen-sodium and R-(+)-5-[ ⁇ -[2-(Dimethylamino)ethoxy]benzyl]-1- methyl-1 H-pyrazole (hereinafter referred to as R-(+)-cizolirtine) were tested for their analgesic activity and their ulcerogenic effects.
  • the respective results are given in the following tables F and G.
  • inventive active substance combination salts show similar or even improved analgesic activity compared to the respective non-steroidal anti-inflammatory drug component alone, whereas the ulcerogenic effect usually associated with the administration of such an NSAID component is significantly reduced.

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Abstract

L'invention concerne une combinaison de substances actives comprenant au moins un composé de carbinol substitué et au moins un anti-inflammatoire non stéroïdien (AINS), un médicament comprenant ladite combinaison de substances actives, et une formulation pharmaceutique comprenant ladite combinaison de substances actives destinées à fabriquer un médicament.
EP05730128A 2004-04-05 2005-04-05 Combinaison de substances actives comprenant du carbinol combine a au moins un ains Withdrawn EP1746986A1 (fr)

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ES200400844A ES2244326B1 (es) 2004-04-05 2004-04-05 Combinacion de substancias activas.
US10/987,803 US20050222136A1 (en) 2004-04-05 2004-11-12 Active substance combination
PCT/EP2005/003641 WO2005097099A1 (fr) 2004-04-05 2005-04-05 Combinaison de substances actives comprenant du carbinol combine a au moins un ains

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EP1784178A1 (fr) * 2004-07-30 2007-05-16 Laboratorios Del Dr. Esteve, S.A. Aryl (ou heteroaryl) azolylcarbinols
ES2334548B1 (es) * 2005-07-29 2010-10-27 Laboratorios Del Dr. Esteve, S.A Forma de dosificacion de liberacion controlada de compuestos de pirazol para el tratamiento de la incontinencia urinaria.
US20090238763A1 (en) 2006-07-09 2009-09-24 Chongxi Yu High penetration compositions and uses thereof
US20090221703A1 (en) 2006-07-09 2009-09-03 Chongxi Yu High penetration composition and uses thereof
EP2746251A3 (fr) * 2006-09-03 2014-07-02 Techfields Biochem Co. Ltd Promédicaments hydrosolubles positivement chargés d'acétaminophène et composés associés à vitesse de pénétration cutanée très rapide
KR101853971B1 (ko) 2007-06-04 2018-05-02 테크필즈 인크 매우 높은 피부 및 막 침투율을 가지는 비스테로이드성 소염제(ｎｓａｉａ) 약물전구체 및 이들의 새로운 의약적 용도
RU2765463C2 (ru) 2008-12-04 2022-01-31 Чунси ЮЙ Композиции интенсивного проникновения и их применение
WO2013170655A1 (fr) 2012-05-16 2013-11-21 Techfields Pharma Co., Ltd. Compositions de promédicament à forte pénétration et composition pharmaceutique associée pour le traitement d'affections pulmonaires
JP6165816B2 (ja) * 2015-10-01 2017-07-19 テックフィールズ バイオケム カンパニー リミテッド 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ

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