DE19802327A1 - Synergistic analgesic composition containing 1-phenyl-cyclohexene and aminobutyric acid derivatives - Google Patents
Synergistic analgesic composition containing 1-phenyl-cyclohexene and aminobutyric acid derivativesInfo
- Publication number
- DE19802327A1 DE19802327A1 DE1998102327 DE19802327A DE19802327A1 DE 19802327 A1 DE19802327 A1 DE 19802327A1 DE 1998102327 DE1998102327 DE 1998102327 DE 19802327 A DE19802327 A DE 19802327A DE 19802327 A1 DE19802327 A1 DE 19802327A1
- Authority
- DE
- Germany
- Prior art keywords
- hydrogen
- general formula
- compounds
- methyl
- carbon atoms
- 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.)
- Ceased
Links
- 230000000202 analgesic effect Effects 0.000 title claims abstract description 9
- 239000000203 mixture Substances 0.000 title abstract description 3
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical class CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 title abstract 2
- 230000002195 synergetic effect Effects 0.000 title description 3
- WCMSFBRREKZZFL-UHFFFAOYSA-N 3-cyclohexen-1-yl-Benzene Chemical compound C1CCCC(C=2C=CC=CC=2)=C1 WCMSFBRREKZZFL-UHFFFAOYSA-N 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 claims description 4
- 229960002870 gabapentin Drugs 0.000 claims description 4
- 229960001402 tilidine Drugs 0.000 claims description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical class NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 3
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 3
- 229960001233 pregabalin Drugs 0.000 claims description 3
- PDJZPNKVLDWEKI-GOEBONIOSA-N (1R,2S)-nortilidine Chemical compound C=1C=CC=CC=1[C@]1(C(=O)OCC)CCC=C[C@@H]1NC PDJZPNKVLDWEKI-GOEBONIOSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 claims description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- PSFSEGZJZZWLBJ-UHFFFAOYSA-N 2-amino-1-phenylcyclohex-3-ene-1-carboxylic acid Chemical class C1(=CC=CC=C1)C1(C(C=CCC1)N)C(=O)O PSFSEGZJZZWLBJ-UHFFFAOYSA-N 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 5
- 229940035676 analgesics Drugs 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- -1 (S) -3-aminomethyl-5-hexanecarboxylic acid Chemical compound 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- XZJCLSJTTJPNPE-UHFFFAOYSA-N 4-(aminomethyl)-6-methylheptanoic acid Chemical compound NCC(CCC(=O)O)CC(C)C XZJCLSJTTJPNPE-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002743 euphoric effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000000404 glutamine group Chemical class N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
Landscapes
- Health & Medical Sciences (AREA)
- Emergency Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die Erfindung betrifft synergistische Arzneimittelzubereitungen
mit analgetischer Wirkung, enthaltend eine Wirkstoffkombination
bestehend aus
The invention relates to synergistic pharmaceutical preparations with an analgesic effect, comprising an active ingredient combination consisting of
-
a) einem basisch substituierten Cyclohexen der allgemeinen
Formel I
worin
R1 und R2, die gleich oder verschieden sein können, einen Alkylrest mit 1 bis 6 C-Atomen oder zwei miteinander verknüpfte Alkylenreste und
R3 einen Alkylrest mit 1 bis 6 C-Atomen bedeuten unda) a basic substituted cyclohexene of the general formula I.
wherein
R 1 and R 2 , which may be the same or different, are an alkyl radical having 1 to 6 carbon atoms or two alkylene radicals linked to one another and
R 3 is an alkyl radical having 1 to 6 carbon atoms and -
b) einem Glutaminsäure- bzw. Gammaaminobuttersäureanalogen der
allgemeinen Formel II
worin
R1 ein geradkettiger oder verzweigter Alkylrest mit 1 bis 6 C-Atomen, Phenyl oder Cycloalkyl mit 3 bis 6 C-Atomen,
R2 Wasserstoff oder Methyl, oder
R1 und R2 zusammen mit dem C-Atom Cycloalkyl mit 4 bis 6 C-Atomen bedeuten,
R3 Wasserstoff, Methyl oder Carboxyl ist, und
R4 Wasserstoff oder eine Alkylgruppe mit 1 bis 6 C-Atomen ist sowie pharmakologisch verträgliche und pharmazeutisch akzeptable Salze der Verbindungen der allgemeinen Formel I und II.b) a glutamic acid or gamma aminobutyric acid analog of the general formula II
wherein
R 1 is a straight-chain or branched alkyl radical with 1 to 6 C atoms, phenyl or cycloalkyl with 3 to 6 C atoms,
R 2 is hydrogen or methyl, or
R 1 and R 2 together with the carbon atom represent cycloalkyl having 4 to 6 carbon atoms,
R 3 is hydrogen, methyl or carboxyl, and
R 4 is hydrogen or an alkyl group with 1 to 6 carbon atoms and pharmacologically acceptable and pharmaceutically acceptable salts of the compounds of the general formula I and II.
Bevorzugt sind Verbindungen der allgemeinen Formel I, in welcher R1 und R2 gleich oder verschieden sind und Wasserstoff oder eine Methylgruppe und R3 eine Ethylgruppe bedeuten. Besonders bevorzugt sind (±)-Ethyl-(trans-2-dimethylamino-1- phenyl-3-cyclohexen-trans-1-carboxylat (Tilidin) und (±)-Ethyl- (trans-2-(methylamino)-1-phenyl-3-cyclohexen-trans-1-carboxylat (Nortilidin) bzw. deren Enantiomere sowie deren Salze, bevorzugt das Hydrochlorid oder das Dihydrogenorthophosphat.Preferred compounds of the general formula I are those in which R 1 and R 2 are identical or different and are hydrogen or a methyl group and R 3 is an ethyl group. (±) -Ethyl- (trans-2-dimethylamino-1-phenyl-3-cyclohexene-trans-1-carboxylate (tilidine) and (±) -ethyl-(trans-2- (methylamino) -1- phenyl-3-cyclohexene-trans-1-carboxylate (nortilidine) or their enantiomers and their salts, preferably the hydrochloride or the dihydrogen orthophosphate.
Bevorzugte Verbindungen der allgemeinen Formel II sind solche, in denen R1 Wasserstoff, R2 eine Isobutylgruppe oder R1 und R2 zusammen mit dem C-Atom eine Cyclohexylgruppe und R3 und R4 Wasserstoff ist. Besonders bevorzugt sind Aminomethyl-1- cyclohexanessigsäure (Gabapentin), 3-Aminomethyl-5-methyl hexancarbonsäure und dessen Enantiomer (S)-3-Aminomethyl-5- hexancarbonsäure (Pregabalin).Preferred compounds of the general formula II are those in which R 1 is hydrogen, R 2 is an isobutyl group or R 1 and R 2 together with the carbon atom are a cyclohexyl group and R 3 and R 4 is hydrogen. Aminomethyl-1-cyclohexanoacetic acid (gabapentin), 3-aminomethyl-5-methyl hexanecarboxylic acid and its enantiomer (S) -3-aminomethyl-5-hexanecarboxylic acid (pregabalin) are particularly preferred.
Verbindungen der allgemeinen Formel I sind bekannt aus DE 15 18 959, Verbindungen der allgemeinen Formel II sind beispielsweise in der WO 93/23383 zur Behandlung epileptische Anfälle beschrieben.Compounds of the general formula I are known from DE 15 18 959, Compounds of the general formula II are for example in WO 93/23383 for the treatment of epileptic seizures described.
Wegen der basischen Natur der Verbindungen der allgemeinen Formel I auch direkt Salze mit den sauren Verbindungen der allgemeinen Formel II gebildet werden.Because of the basic nature of the compounds of the general Formula I also directly salts with the acidic compounds of general formula II are formed.
Die Verbindungen der allgemeinen Formeln I und II sowie deren Salze bzw. Additionsalze beider können in üblichen Zubereitungen und in Mischungen mit üblichen pharmazeutisch annehmbaren Trägern oder Verdünnungsmitteln angewendet werden.The compounds of general formulas I and II and their Salts or addition salts of both can be used in conventional Preparations and in mixtures with usual pharmaceutical acceptable carriers or diluents.
Die erfindungsgemäßen Zubereitungen können in flüssiger oder fester Form oral, topisch oder parenteral appliziert werden. Als Injektionslösung kommt vor allem Wasser zur Anwendung, welche die bei Injektionslösungen üblichen Zusätze wie Stabilisierungsmittel, Lösungsvermittler oder Puffer enthält.The preparations according to the invention can be in liquid or solid form can be administered orally, topically or parenterally. Water is mainly used as the solution for injection, which are the usual additives for injection solutions such as Contains stabilizers, solubilizers or buffers.
Die Zubereitungen können als übliche galenische Formulierungen, wie z. B. Tabletten, Kapseln, Dragees, Pflaster, Emulsionen oder Salben vorliegen. Sie werden hergestellt, indem man die Verbindungen oder deren Salze in an sich bekannter Weise in einen pharmakologisch unbedenklichen Trägerstoff und gegebenenfalls geeigneten Zusätzen einarbeitet.The preparations can be used as conventional pharmaceutical formulations, such as B. tablets, capsules, coated tablets, plasters, emulsions or Ointments are present. They are made by using the Compounds or their salts in a manner known per se in a pharmacologically acceptable carrier and where appropriate, incorporates suitable additives.
Derartige Zusätze sind z. B. Tartrat- oder Citrat-Puffer, Ethanol, Komplexbildner (wie Äthylendiamintetraessigsäure und deren nichttoxische Salze) sowie hochmolekulare Polymere (wie flüssiges Polyäthylenoxid) zur Viskositätsregulierung. Feste Trägerstoffe sind z. B. Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, höhermolekulare Fettsäuren (wie Stearinsäure), Gelatine, Agar- Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette, feste hochmolekulare Polymere (wie Polyäthylenglykol); für orale Applikation geeignete Zubereitungen können gewünschtenfalls noch zusätzliche Geschmacks- und/oder Süßstoffe enthalten.Such additives are e.g. B. tartrate or citrate buffers, Ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Celebrations Carriers are e.g. B. starch, lactose, mannitol, Methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, agar Agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as Polyethylene glycol); suitable for oral application Preparations can, if desired, additional Contain flavor and / or sweeteners.
Verbindungen der allgemeinen Formel I, insbesondere Tilidin, besitzen eine mittlere analgetische Potenz. Die Wirkung von Tilidin läßt sich in limitierter Weise durch eine Steigerung der Dosis zwar erhöhen, jedoch muß bei stärksten Schmerzen auf höher potente Wirkstoffe, wie z. B. Morphin, gewechselt werden.Compounds of the general formula I, in particular tilidine, have a medium analgesic potency. The effect of Tilidine can be increased in a limited way increase the dose, but must be in severe pain higher potent active ingredients, such as B. morphine.
Die strukturellen Analogen der Glutamin- bzw. Gamma aminobutersäure gemäß der allgemeinen Formel II, insbesondere Gabapentin und Pregabalin, sind bekannt für ihre Wirksamkeit bei cerebralen Krampfanfällen. Bei der klinischen Anwendung von Gabapentin stellte sich heraus, daß dieses zusätzlich eine analgetische Wirksamkeit besitzt, insbesondere bei neuropathischen Schmerzen, wobei der Wirkungsmechanismus allerdings noch ungeklärt ist.The structural analogues of glutamine or gamma aminobuteric acid according to general formula II, in particular Gabapentin and Pregabalin are known for their effectiveness for cerebral seizures. In the clinical application of Gabapentin turned out to be an additional one has analgesic efficacy, especially in neuropathic pain, the mechanism of action however, is still unclear.
Überraschenderweise wurde gefunden, daß die Kombination beider Wirkstoffe eine deutlich niedrigere Dosierung als die Einzelanwendung erlaubt, wobei eine analgetische Wirkung entfaltet wird, die die Maximalwirkung der einzelnen Komponenten bei weitem übertrifft und damit überadditiv ist. Zudem wurde gefunden, daß auch eine erfindungsgemäße Wirkstoffkombination intrathekal applizierbar ist und im Gegensatz zu den Verbindungen der allgemeinen Formel I, die derart verabreicht unwirksam sind, eine unerwartet hohe analgetische Wirkung entfalten, die gegenüber der normalen enteralen bzw. parenteralen Verabreichung eine weitere erhebliche Reduzierung der eingesetzten Wirkstoffmenge ermöglicht.Surprisingly, it was found that the combination of both Active ingredients have a significantly lower dosage than that Single use allowed, with an analgesic effect is unfolded, which is the maximum effect of each Components far outperformed and therefore superadditive. It was also found that an inventive Active ingredient combination can be applied intrathecally and in Contrary to the compounds of general formula I, the administered ineffective are unexpectedly high develop analgesic effect compared to normal enteral or parenteral administration another considerable reduction in the amount of active ingredient used enables.
Mit der erfindungsgemäßen Wirkstoffkombination werden äußerst potente analgetische Arzneimittelzubereitungen mit minimalen Nebenwirkungen zur Verfügung gestellt, deren analgetische Potenz im Bereich von starken Opioiden wie Morphin oder Fentanyl liegt. Durch die synergistische Wirkung der Kombination, die sich vor allem auf die Verbindungen der Formel I auswirkt, kann die Dosierung dieser Komponente sehr niedrig gehalten werden. Dieses hat den zusätzlichen Vorteil, daß das Mißbrauchsrisiko erheblich reduziert wird und einer Toleranzentwicklung sowie dem möglichen euphorisierenden Effekt starker Analgetika entgegengewirkt wird. Durch die erfindungsgemäße Kombination wird deshalb ein gegenüber allen bisherigen starken Analgetika überlegenes Arzneimittel zur Verfügung gestellt, da Verbindungen der Formel II nicht diese unerwünschten Eigenschaften üblicher starker Analgetika zeigen.With the active ingredient combination according to the invention, extreme potent analgesic drug preparations with minimal Side effects provided, their analgesic Potency in the range of strong opioids such as morphine or Fentanyl lies. Due to the synergistic effect of Combination, mainly related to the compounds of the formula I affects, the dosage of this component can be very low being held. This has the additional advantage that Risk of abuse is significantly reduced and one Tolerance development and the possible euphoric effect strong analgesics is counteracted. Through the The combination according to the invention will therefore be one against all previously strong analgesics drug superior Provided because compounds of formula II do not have this show undesirable properties of usual strong analgesics.
Claims (5)
- a) einem substituierten Cyclohexen der allgemeinen Formel I
worin
R1 und R2, die gleich oder verschieden sein können, einen Alkylrest mit 1 bis 6 C-Atomen oder zwei miteinander verknüpfte Alkylenreste und
R3 einen Alkylrest mit 1 bis 6 C-Atomen bedeuten und - b) einem Glutaminsäure- bzw. Gammaaminobuttersäureanalogen
der allgemeinen Formel II
worin
R1 ein geradkettiger oder verzweigter Alkylrest mit 1 bis 6 C-Atomen, Phenyl oder Cycloalkyl mit 3 bis 6 C-Atomen,
R2 Wasserstoff oder Methyl, oder
R1 und R2 zusammen mit dem C-Atom Cycloalkyl mit 4 bis 6 C-Atomen bedeuten,
R3 Wasserstoff, Methyl oder Carboxyl ist, und
R4 Wasserstoff oder eine Alkylgruppe mit 1 bis 6 C-Atomen ist
sowie pharmakologisch verträgliche und pharmazeutisch akzeptable Salze der Verbindungen der allgemeinen Formel I und II.
- a) a substituted cyclohexene of the general formula I.
wherein
R 1 and R 2 , which may be the same or different, are an alkyl radical having 1 to 6 carbon atoms or two alkylene radicals linked to one another and
R 3 is an alkyl radical having 1 to 6 carbon atoms and - b) a glutamic acid or gamma aminobutyric acid analog of the general formula II
wherein
R 1 is a straight-chain or branched alkyl radical with 1 to 6 C atoms, phenyl or cycloalkyl with 3 to 6 C atoms,
R 2 is hydrogen or methyl, or
R 1 and R 2 together with the carbon atom represent cycloalkyl having 4 to 6 carbon atoms,
R 3 is hydrogen, methyl or carboxyl, and
R 4 is hydrogen or an alkyl group with 1 to 6 carbon atoms
as well as pharmacologically acceptable and pharmaceutically acceptable salts of the compounds of the general formula I and II.
- a) Tilidin und/oder Nortilidin und
- b) Gabapentin und/oder Pregabalin.
- a) tilidine and / or nortilidine and
- b) gabapentin and / or pregabalin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998102327 DE19802327A1 (en) | 1998-01-23 | 1998-01-23 | Synergistic analgesic composition containing 1-phenyl-cyclohexene and aminobutyric acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998102327 DE19802327A1 (en) | 1998-01-23 | 1998-01-23 | Synergistic analgesic composition containing 1-phenyl-cyclohexene and aminobutyric acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19802327A1 true DE19802327A1 (en) | 1999-07-29 |
Family
ID=7855355
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1998102327 Ceased DE19802327A1 (en) | 1998-01-23 | 1998-01-23 | Synergistic analgesic composition containing 1-phenyl-cyclohexene and aminobutyric acid derivatives |
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| DE (1) | DE19802327A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001001983A1 (en) * | 1999-07-02 | 2001-01-11 | Warner-Lambert Company | A synergistic combination: gabapentin and pregabalin |
| US7164034B2 (en) | 1999-06-10 | 2007-01-16 | Pfizer Inc. | Alpha2delta ligands for fibromyalgia and other disorders |
| US7393872B2 (en) | 1999-04-09 | 2008-07-01 | Euro-Celtique S.A. | Sodium channel blocker compositions and the use thereof |
-
1998
- 1998-01-23 DE DE1998102327 patent/DE19802327A1/en not_active Ceased
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7393872B2 (en) | 1999-04-09 | 2008-07-01 | Euro-Celtique S.A. | Sodium channel blocker compositions and the use thereof |
| US7164034B2 (en) | 1999-06-10 | 2007-01-16 | Pfizer Inc. | Alpha2delta ligands for fibromyalgia and other disorders |
| US7381747B2 (en) | 1999-06-10 | 2008-06-03 | Warner-Lambert Company Llc | Alpha 2 delta ligands for post-traumatic stress disorder |
| WO2001001983A1 (en) * | 1999-07-02 | 2001-01-11 | Warner-Lambert Company | A synergistic combination: gabapentin and pregabalin |
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