WO1999065485A1 - Utilisation de derives de benzomorphane comme analgesique - Google Patents

Utilisation de derives de benzomorphane comme analgesique Download PDF

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Publication number
WO1999065485A1
WO1999065485A1 PCT/EP1999/004020 EP9904020W WO9965485A1 WO 1999065485 A1 WO1999065485 A1 WO 1999065485A1 EP 9904020 W EP9904020 W EP 9904020W WO 9965485 A1 WO9965485 A1 WO 9965485A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
hydrogen
ethyl
acyl
Prior art date
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PCT/EP1999/004020
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German (de)
English (en)
Inventor
Michael Sattlegger
Michael Przewosny
Werner Günter ENGLBERGER
Original Assignee
Grünenthal GmbH
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
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to AU47712/99A priority Critical patent/AU4771299A/en
Priority to EP99931054A priority patent/EP1085866A1/fr
Publication of WO1999065485A1 publication Critical patent/WO1999065485A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the invention relates to the use of benzomorphan derivatives of the general formula I,
  • R 1 Ci-Cg-alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, aryl;
  • R 2 is hydrogen, Ci-Cg-alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl;
  • R 3 is hydrogen, Ci-Cg-alkyl
  • R ⁇ and R ⁇ independently of one another hydrogen, C ⁇ -Cg-alkyl, halogen, OH, Ci-Cg-alkoxy, -O-acyl, -CN, -N0 2 , -NH 2 , -NH (Ci-Cg-alkyl ), - (Ci-Cg-alkyl) 2 , where the alkyl radicals can be the same, can mean -NH-acyl or -N-acyl- (Ci ⁇ Cg-alkyl), in the form of their diastereomers, enantiomers, bases or Salts of physiologically acceptable acids, as an analgesic.
  • Pain is a subjective sensory experience that consists of a sensory and an affective component.
  • the physiological aspects of pain development include the reception of every physico-chemical stimulus in potentially tissue-threatening intensity with activation of the so-called nociceptors, special uni- or polymodal nocis sensors of high-threshold primary ascending nerve pathways.
  • all parts of the nociceptive system can be changed in general: the reception by the nocis sensors, the transmission at the spinal level, the perception, awareness and processing at the supraspinal level. Plastic changes and chronifications can occur due to disorders in the afferent system, but also due to impaired perception and processing as well as disorders in the descending, controlling, endogenous pain-relieving system.
  • Chronic or neuropathic pain causes sensitization of the Nocis sensors by endogenous or exogenous substances. If stimulus persists or if the integrity of the nociceptor is disturbed, secondary and central sensitization may occur at the spinal level.
  • the inflammation-demanding tissue hormones and transmitters honeycam, serotonin, prostaglandins, interleukin 1
  • the inflammation-demanding tissue hormones and transmitters can lead to sensitization of the nociceptors with a lowered threshold of stimulation and increased spontaneous activity, with persistent inflammation processes also resulting in permanent processes of adaptive stimulation with adaptive stimulation processes spinal and supraspinal planes.
  • Classic opioids such as morphine are effective in treating severe to severe pain. Their use is, however, due to the known side effects such. B. Ate depression, vomiting, sedation, constipation and tolerance development are limited. In addition, they are less effective in neuropathic or incidental pain, from which tumor patients in particular suffer.
  • Opioids develop their analgesic effect by binding to membrane-bound receptors, which belong to the family of so-called G-protein-coupled receptors.
  • the biochemical and pharmacological characterization of subtypes of these receptors has now raised hope that subtype-specific opioids have a different activity / side effect profile than z.
  • B. Groom morphine Further pharmacological studies have meanwhile made the existence of several subtypes of these opioid receptors ( ⁇ i, ⁇ 2 , K ⁇ , ⁇ 2 , ⁇ 3 , ⁇ i and ⁇ 2 ) probable.
  • NMDA ion channel is particularly important here: a significant part of the communication of synapses takes place via it. This channel controls the calcium ion exchange between the neuronal cell and its surroundings. Knowledge of the physiological importance of ion channel-selective substances has been gained through the development of the patch-cla p technique. The effect of NMDA antagonists on the influence of treatum ions in the cell interior can be clearly demonstrated. It also turned out that these substances have an independent antinociceptive potential (eg ketamine).
  • ketamine independent antinociceptive potential
  • NMDA antagonists intervene directly in the crucial calcium balance of the cells in the transmission of pain. It is therefore the first time that the treatment of neuropathic forms of pain can be successfully carried out.
  • the side effect profile of the combined NMDA agonists and ⁇ -agonists could differ from that of the pure ⁇ -agonists (eg reduced respiratory depression, reduced constipation).
  • the substance class shows a clear affinity for the ⁇ - and NMDA binding site.
  • the weighting of the affinity of both components can be very different. There is no specific area. It ranges from the high ⁇ M to the sub nM range for both receptors, as described in J. Med. Che, 1997, 40, 2922-2930.
  • EP-A-0 004 960 describes analgesic effects for a number of 5,9-dimethyl-6,7-benzomorphan derivatives. These compounds are described as morphine antagonists. Bezomorphande ⁇ vate are known from EP-0 521 422 B. These compounds are used as drugs for the treatment of neurodegenerative diseases from the group of brain ischemia of various origins, e.g. B. Status epi leptikus, hypoglycemia, hypoxia, anoxia, brain trauma, brain trauma, brain edema, amyotrophic lateral sclerosis, Huntington's Disease, Alzheimer's disease, hypotension, Herzin ⁇ infarction, stroke or brain enrolled pe ⁇ natale asphyxia be ⁇ .
  • the invention relates to the use of benzomorphan derivatives of the general formula I:
  • Ci-Cg-alkyl C 3 -C 6 alkenyl, C -C 6 alkyl, aryl;
  • R2 is hydrogen, Ci-Cg-alkyl, C 3 -C 6 alkenyl, C 3 -C 6 -
  • R3 is hydrogen, Ci-Cg-alkyl
  • R 7 and R 8 independently of one another hydrogen, C ⁇ -Cg-alkyl, halogen, OH, Ci-C -alkoxy, -O-acyl, -CN, -N0 2 , -NH 2 , -NH ( Ci-Cg-alkyl ) , -N ( Ci-Cg-alkyl) 2 , where the alkyl radicals can be the same, -NH-acyl or -N-acyl- (Ci-Cg-alkyl), or in the form of their diastereomers, enantiomers, bases or salts of physiologically compatible acids, as an analgesic.
  • Preferred compounds of the general formula I are those in which X is oxygen, sulfur; R 1 is methyl, ethyl, propyl, isopropyl, phenyl; R 2 is methyl, ethyl, propyl, isopropyl, allyl, propargyl; R 3 is hydrogen, C1-C - alkyl; R 4 and R 5 are methyl, ethyl, propyl, isopropyl; R 6 methyl, ethyl, propyl / isopropyl, R 7 fluorine, chlorine, hydroxy, lower alkyl, lower alkoxy, acyloxy; R 8 can be hydrogen, lower alkyl, hydroxy or alkoxy.
  • Ci-Cg-alkyl means saturated branched or unbranched hydrocarbons having 1 to 8 carbon atoms.
  • the alkyl radical can optionally be substituted by one or more halogen atoms, which are preferably fluorine which can be the same or different from one another. Examples include the following hydrocarbon radicals such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, hexyl or 1-methylpentyl mentioned.
  • “Lower alkyl” denotes branched or unbranched hydrocarbons with 1 to 4 carbon atoms.
  • alkenyl means straight-chain or branched hydrocarbon radicals having 3 to 6 carbon atoms, having one or more Ren double bonds, which may optionally be substituted by a halogen atom, this is preferably fluorine, which may be the same or different from one another.
  • Examples include 2-propenyl, 2-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl -2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1, l-dimethyl-2-propenyl, 1, 2 -Diemthyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-2-pentenyl or 1, 3-dimethyl-3-butenyl mentioned.
  • alkynyl is understood to mean straight-chain or branched hydrocarbon radicals with 3 to 6 carbon atoms and with one or more triple bonds.
  • acyl means alkylcarbonyl radicals with straight-chain or branched lower alkyl radicals with 1 to 6 carbon atoms which are bonded via a carbonyl group.
  • the alkyl radicals can be substituted with one or more halogen atoms, which can be identical or different from one another Alkyl radicals having up to 4 carbon atoms are preferred, for example acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl or isobutylcarbonyl.
  • acyloxy is understood to mean an acyl group bound by an oxygen, where acyl has the meaning given above.
  • aryl means aromatic radical having 6 to 10 carbon atoms, it being possible for the aromatic to be substituted with one or more lower alkyl groups, alkoxy groups, nitro groups and / or one or more halogen atoms which are identical or different from one another can.
  • alkoxy is understood to mean a straight-chain or branched hydrocarbon radical having 1 to 8 carbon atoms which is bonded via an oxygen atom.
  • a lower alkoxy radical having 1 to 3 carbon atoms is preferred.
  • the term “ammo” is understood to mean an NH 2 function which can optionally be substituted by one or two Ci-Cg-alkyl-aryl or aralkyl radicals, which may be the same or different.
  • Alkylammo stands for example for methylammo, ethylammo, propylammo, 1-methylethylammo, butylammo, 1-methylpropylammo, 2-methylammo or 1, 1-dimethylethylammo.
  • dialkylammo means dimethylammo, diethylamino, dipropyla mo, dibutylammo, di- (1-methylethyl) ammo, di- (1-methylpropyl) ammo, di-2-methylpropylamine, ethyl methylammo or Methylpropylammo, which may be mentioned as examples.
  • halogen means fluorine, chlorine, bromine and iodine.
  • the analgesics which can be prepared according to the invention using compounds of the general formula I contain carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid medicinal forms in the form of injection solutions, drops or juices semi-solid dosage forms in the form of oral gels, ointments, creams, gels or suppositories or as solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • auxiliary substances and the amounts to be used depends on whether the medicinal product is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example Infections on the skin, mucous membranes and eyes should be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalation administration.
  • compositions of the formula I according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration are suitable percutaneous administration preparations.
  • Formulations which can be used orally or percutaneously can release the compounds of the formula I according to the invention in a delayed manner.
  • the preparations are prepared in the customary manner known to the person skilled in the art.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. 5 to 500 mg / kg of at least one substituted benzomorphan compound of the general formula I are usually applied.
  • the antinociceptive activity can be demonstrated in phenylquinone-induced writhing on the mouse, modified according to IC Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959).
  • Male NMRI mice with a weight of 25-30 g are used for this.
  • Groups of 10 animals per substance dose become 0.3 ml / mouse of a 0.02% aqueous solution of phenylchmon (phenylbenzoquinone, Sigma, Deisenhofen, Germany) 10 minutes after intravenous administration of a compound according to the invention; preparation of the solution with the addition of 5% ethanol and up- storage in a water bath at 45 ° C) applied intraperitoneally.
  • phenylchmon phenylbenzoquinone
  • the animals are placed individually in observation cages.

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  • Health & Medical Sciences (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)

Abstract

L'invention concerne l'utilisation comme analgésiques de dérivés de benzomorphane de la formule générale (I), dans laquelle X représente oxygène ou soufre; R1 est alkyle C¿1?-C8, alcényle C3-C6, alcinyle C3-C6, aryle; R?2¿ est hydrogène, alkyle C¿1?-C8, alcényle C3-C6, alcinyle C3-C6; R?3¿ est hydrogène, alkyle C¿1?-C6; R?4¿ est alkyle C¿1?-C8; R?5¿ est alkyle C¿1?-C8; R?6¿ est alkyle C¿1?-C8; R?7 et R8¿ représentent, indépendamment l'un de l'autre, hydrogène, alkyle C¿1?-C8, halogène, OH, alcoxy C1-C8, -O-acyle, -CN, -NO2, NH2, -NH(alkyle C1-C8), -N(alkyle C1-C8)2, les radicaux alkyle pouvant être identiques, -NH-acyle ou bien -N-acyl-(alkyle C1-C8), sous forme de leurs diastéréomères, énantiomères, bases ou sels d'acides physiologiquement tolérables.
PCT/EP1999/004020 1998-06-12 1999-06-11 Utilisation de derives de benzomorphane comme analgesique WO1999065485A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU47712/99A AU4771299A (en) 1998-06-12 1999-06-11 Use of benzomorphan derivatives as an analgesic
EP99931054A EP1085866A1 (fr) 1998-06-12 1999-06-11 Utilisation de derives de benzomorphane comme analgesique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1998126365 DE19826365A1 (de) 1998-06-12 1998-06-12 Verwendung von Benzomorphanderivaten als Analgetikum
DE19826365.1 1998-06-12

Publications (1)

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WO1999065485A1 true WO1999065485A1 (fr) 1999-12-23

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EP (1) EP1085866A1 (fr)
AU (1) AU4771299A (fr)
DE (1) DE19826365A1 (fr)
WO (1) WO1999065485A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013167963A1 (fr) * 2012-05-11 2013-11-14 Purdue Pharma L.P. Composés de type benzomorphane utilisés en tant que modulateurs des récepteurs aux opiacés
EP3333156A3 (fr) * 2012-11-09 2018-09-26 Purdue Pharma L.P. Analogues de benzomorphane et leur utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10153345A1 (de) * 2001-10-29 2003-05-08 Gruenenthal Gmbh Substituierte 1H-Chinoxalin-2-on-Verbindungen und substituierte 4-Aryl- und 4-Heteroarylcyclohexan-Verbindungen

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004960A1 (fr) * 1978-04-26 1979-10-31 Acf Chemiefarma Nv Dérivés de 9.9-diméthyl-6.7-benzomorphane, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0521422A1 (fr) * 1991-07-02 1993-01-07 Boehringer Ingelheim Kg Benzomorphanes et leur utilisation comme médicaments
WO1997006146A1 (fr) * 1995-08-03 1997-02-20 Boehringer Ingelheim Kg Nouveau procede de preparation de norbenzomorphane d'un intermede lors de la preparation de derives de benzomorphane interessants sur le plan pharmaceutique, notamment de (-)-(1r,5s,2'r)-3'-hydroxy-2-(2-methoxypropyle)-5,9,9-trimethyle-6,7-benzomorphane
DE19740110A1 (de) * 1997-09-12 1999-03-18 Boehringer Ingelheim Pharma Substituierte 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocin-10-ole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004960A1 (fr) * 1978-04-26 1979-10-31 Acf Chemiefarma Nv Dérivés de 9.9-diméthyl-6.7-benzomorphane, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0521422A1 (fr) * 1991-07-02 1993-01-07 Boehringer Ingelheim Kg Benzomorphanes et leur utilisation comme médicaments
WO1997006146A1 (fr) * 1995-08-03 1997-02-20 Boehringer Ingelheim Kg Nouveau procede de preparation de norbenzomorphane d'un intermede lors de la preparation de derives de benzomorphane interessants sur le plan pharmaceutique, notamment de (-)-(1r,5s,2'r)-3'-hydroxy-2-(2-methoxypropyle)-5,9,9-trimethyle-6,7-benzomorphane
DE19740110A1 (de) * 1997-09-12 1999-03-18 Boehringer Ingelheim Pharma Substituierte 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocin-10-ole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CARTER A.J. ET AL: "BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex.", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, (1995) 275/3 (1382-1389)., XP002118768 *
GRAUERT, MATTHIAS ET AL: "N-methyl-D-aspartate receptor channel block by the enantiomeric 6,7-benzomorphans BIII 277 CL and BIII 281 CL", J. PHARMACOL. EXP. THER. (1998), 285(2), 767-776, 1998, XP002118767 *
GRAUERT, MATTHIAS ET AL: "Synthesis and Structure-Activity Relationships of 6,7-Benzomorphan Derivatives as Antagonists of the NMDA Receptor-Channel Complex", J. MED. CHEM. (1997), 40(18), 2922-2930, 1997, XP002090488 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013167963A1 (fr) * 2012-05-11 2013-11-14 Purdue Pharma L.P. Composés de type benzomorphane utilisés en tant que modulateurs des récepteurs aux opiacés
EP3333156A3 (fr) * 2012-11-09 2018-09-26 Purdue Pharma L.P. Analogues de benzomorphane et leur utilisation

Also Published As

Publication number Publication date
AU4771299A (en) 2000-01-05
DE19826365A1 (de) 1999-12-16
EP1085866A1 (fr) 2001-03-28

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