EP1085866A1

EP1085866A1 - Use of benzomorphan derivatives as an analgesic

Info

Publication number: EP1085866A1
Application number: EP99931054A
Authority: EP
Inventors: Michael Sattlegger; Michael Przewosny; Werner Günter ENGLBERGER
Original assignee: Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 1998-06-12
Filing date: 1999-06-11
Publication date: 2001-03-28
Also published as: WO1999065485A1; AU4771299A; DE19826365A1

Abstract

The present invention relates to the use of benzomorphan derivatives of the general formula (I) as analgesic agents, wherein X is oxygen or sulphur; R<1> is C1-C8 alkyl, C3-C6 alkenyl, C3-C6 alkinyl or aryl; R<2> is hydrogen, C1-C8 alkyl, C3-C6 alkenyl or C3-C6 alkinyl; R<3> is hydrogen or C1-C6 alkyl; R<4> is C1-C8 alkyl; R<5> is C1-C8 alkyl; R<6> is C1-C8 alkyl; and R<7> and R<8> represent independently hydrogen, C1-C8 alkyl, halogen, OH, C1-C8 alkoxy, -O-acyl, -CN, -NO2, -NH2, -NH(C1-C8 alkyl) or -N(C1-C8 alkyl)2. The alkyl radicals may be the same and represent -NH-acyl or N-acyl-(C1-C8 alkyl) in their diastereomeric, enantiomeric, basic or physiologically-acceptable acid-salt forms.

Description

Use of benzomorphan derivatives as an anaesthetic

The invention relates to the use of benzomorphan derivatives of the general formula I,

in which:

X oxygen or sulfur;

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 ⁴ Ci-Cg-alkyl; R ⁵ Ci-Cg-alkyl;

R ⁶ 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. When considering the pathophysiological aspects of pain development, 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, among other things, 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. Such are known Phenomena in particular in chronic inflammation processes such as rheumatoid arthritis. The inflammation-demanding tissue hormones and transmitters (histamine, serotonin, prostaglandins, interleukin 1) released in the area of the nocis sensor by local inflammation cells 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 (μi, μ ₂ , Kι, κ ₂ , κ ₃ , δi and δ ₂ ) probable.

In addition, there are other receptors and ion channels that are significantly involved in the system of pain development and pain transmission. The 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 cacium ions in the cell interior can be clearly demonstrated. It also turned out that these substances have an independent antinociceptive potential (eg ketamine). It is important that the mechanism of action is completely different, as for example in the case of opiates, because 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.

In addition to this expanded activity profile, the side effect profile of the combined NMDA agonists and μ-agonists could differ from that of the pure μ-agonists (eg reduced respiratory depression, reduced constipation).

These compounds are potentially therapeutically usable as analgesics.

The substance class shows a clear affinity for the μ- 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 μM 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. Bezomorphandeπvate 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 peπnatale asphyxia be ^¬.

Surprisingly, it has now been found that these compounds also have an antinociceptive activity which cannot be derived from the previously known activity in neurodegenerative diseases.

The invention relates to the use of benzomorphan derivatives of the general formula I:

wherein

X oxygen or sulfur;

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 -

Alkmyl;

R3 is hydrogen, Ci-Cg-alkyl;

R ⁴ Ci-Cg-alkyl,

R5 Ci-Cg-alkyl

R6 Ci-Cg-alkyl

R ⁷ and R ⁸ independently of one another hydrogen, Cι-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.

Compounds of the general formula I in which X is oxygen; R ¹ and R ^{2 are} methyl, ethyl, R ^{3 is} hydrogen; R ⁴ to R ^{6 are} methyl, ethyl; R ⁷ hydroxy, methyl, methoxy, acyloxy; R ^{8 can be} hydrogen, methyl, ethyl, hydroxy or lower alkoxy.

In the context of the present invention, the term “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.

In the context of the present invention, the term “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.

In the context of the present invention, the term “alkynyl” is understood to mean straight-chain or branched hydrocarbon radicals with 3 to 6 carbon atoms and with one or more triple bonds. The lower alkyne radical (propargyl) with 3 carbon atoms and with a triple bond, which is optionally with a Halogen radical, which can preferably be substituted by fluorine or more halogen atoms.

In the context of the present invention, the term “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.

In the context of the present invention, the term “acyloxy” is understood to mean an acyl group bound by an oxygen, where acyl has the meaning given above. In the context of the present invention, the term “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.

In the context of the present invention, the term “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.

In the context of the present invention, 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.

In the context of the present invention, the term “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.

In the context of the present invention, the term “halogen” means fluorine, chlorine, bromine and iodine. The following connections are particularly interesting:

A Inhibition of [ ³ H] MK-801 binding to rat brain membrane. B Inhibition of [3H] dihydrmorphine binding to rat brain.

In addition to at least one substituted benzomorphan derivative of the general formula I, 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. The choice of 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. Compounds 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.

Testing for antinociceptive activity in the writhing test on the mouse

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. The animals are placed individually in observation cages. The number of pain-induced stretching movements (so-called writhing reactions = printing through of the body with stretching of the back offenses) is counted 5-20 minutes after the administration of phenylquinone using a push-button counter.

Claims

claims

Use of benzomorphan derivatives of the general formula I

wherein

X oxygen or sulfur;

Rl Ci-Cg-alkyl, C -Cg-alkenyl, C ₃ -Cg-alkynyl, aryl; R ^{2 is} hydrogen, Ci-Cg-alkyl, C -Cg-alkenyl, C ₃ -Cg-

Alkynyl;

R ^{3 is} hydrogen, Ci-Cg-alkyl; R ⁴ Ci-Cg-alkyl; R5 Ci-Cg-alkyl; R6 Ci-Cg-alkyl; R ⁷ and R ^{8 are} independently hydrogen, Cι ~ Cg-

Alkyl, halogen, OH, Ci-Cg-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) mean, in the form of their diastereomers, enantiomers, bases or salts of physiologically tolerated acids, as analgesics. Use of benzomorphan derivatives of the general formula I

wherein

X oxygen or sulfur;

Rl Ci-Cg-alkyl, C -Cg-alkenyl, C ₃ -Cg-alkynyl, aryl;

R 'is hydrogen, Ci-Cg-alkyl, C ₃ -C ₆ alkenyl, C -Cg-

Alkynyl;

R ^{3 is} hydrogen, Ci-Cg-alkyl; R ⁴ Ci-Cg-alkyl; R5 Ci-Cg-alkyl; R6 Ci-Cg-alkyl;

R ⁷ and R ^{8 are} independently hydrogen, Cι ~ Cg-

Alkyl, halogen, OH, -C ~ Cg-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) mean in

Form of their diastereomers, enantiomers, bases or salts of physiologically acceptable acids, for the manufacture of an analgesic.

Use of benzomorphan derivatives according to claim 1 or 2, wherein in the general formula I

X oxygen or sulfur;

R ^{1 is} methyl, ethyl, propyl, isopropyl or phenyl;

R ^{2 is} methyl, ethyl, propyl, isopropyl, allyl or

Propargyl;

R ^{3 is} hydrogen or Ci-C ^ alkyl;

R ^{4 is} methyl, ethyl or isopropyl; RS methyl, ethyl or isopropyl; R ^ methyl, ethyl, propyl, isopropyl;

R ⁷ fluorine, chlorine, hydroxy, Ci-Cj-alkyl, -C ~ C ₃ alkoxy or acyloxy; R ^{8 is} hydrogen, -CC4-alkyl, hydroxy or -C ~ Cg-alkoxy; mean.

4. Use of benzomorphan derivatives according to one of claims 1, 2 or 3, wherein in the general formula I

X oxygen;

R ^{1 is} methyl or ethyl;

R ^{2 is} methyl or ethyl;

R ^{3 is} hydrogen; R ^{4 is} methyl or ethyl;

R ^{5 is} methyl or ethyl;

R ^{6 is} methyl or ethyl;

R ^{7 is} hydroxy, methyl, methoxy or acyloxy;

R ^{8 is} hydrogen, methyl, ethyl, hydroxy or -C ~ C - alkoxy.

5. Use of (-) -IR, 5S, 2 "R-2 '-hydroxy-2- (2-methoxypropyl) -5, 9, 9-trimethyl-6, 7-benzomorphan for the manufacture of an analgesic .

6. Use of (-) -IR, 5S, 2 "R-3 '-hydroxy-2- (2-methoxypropyl) -5, 9, 9-trimethyl-6, 7-benzomorphan for the preparation of an analgesic.

7. Use of (-) -IR, 5S, 2 "S-3 '-hydroxy-2- (2-methoxypropyl) -5, 9, 9-trimethyl-6, 7-benzomorphan for the preparation of an analgesic.

8. Use of (+) -IS, 5R, 2 "S-3 '-hydroxy-2- (2-methoxypropyl) -5, 9, 9-trimethyl-6, 7-benzomorphan for the preparation of an analgesic.