US20080269326A1 - Use of 1-Phenyl-3-Dimethylamino-propane Compounds for Treating Neuropathic Pain - Google Patents

Use of 1-Phenyl-3-Dimethylamino-propane Compounds for Treating Neuropathic Pain Download PDF

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US20080269326A1
US20080269326A1 US12/045,830 US4583008A US2008269326A1 US 20080269326 A1 US20080269326 A1 US 20080269326A1 US 4583008 A US4583008 A US 4583008A US 2008269326 A1 US2008269326 A1 US 2008269326A1
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dimethylamino
phenol
ethyl
methylpropyl
compound
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Thomas Christoph
Elmar Friderichs
Babette-Yvonne Koegel
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Gruenenthal GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of 1-phenyl-3-dimethylaminopropane compounds for the production of medicaments for treating neuropathic, preferably mononeuropathic and/or polyneuropathic pain, particularly preferably polyneuropathic pain, and also preferably diabetic neuropathic pain, preferably diabetic peripheral neuropathic pain, and furthermore preferably for treating diabetic peripheral neuropathy.
  • nociceptive pain The normal physiological pain sensation, which serves as a protective function for the organism, is transmitted via nerve fibres as a response to corresponding painful stimuli. This is referred to as nociceptive pain.
  • This nociceptive pain may be acute or chronic, somatic or visceral, and may be present with or without an inflammatory component.
  • Appropriate stimuli may be mechanical (e.g. pressure), thermal (e.g. heat) or chemical (e.g. acid).
  • electrical stimuli may be perceived as painful.
  • neuropathic pain In contrast to nociceptive pain—and also in most cases not treatable with the same means—neuropathic pain (a non-nociceptive pain; for a review see Hansson et al., 2001 Neuropathic Pain; Pathophysiology and Treatment in Progress in Pain Research and Management, Vol. 21 eds. Hansson et al. IASP Press, Seattle; Bridges et al., 2001 Br J Anaesthesia 87:12-26) is characterized by the occurrence of spontaneous pain and/or pain triggered by abnormal stimuli. Spontaneously occurring pain results for example from so-called ectopic activity of the pain-conducting nerve fibres. In this case the nerve fibre sends a pain signal from the periphery to the central nervous system even though there was no appropriate stimulus.
  • Allodynia is defined as a painful sensation produced by a normally non-painful stimulus. Allodynia is not restricted to neuropathic pain. Thus, allodynia occurs for example in non-neuropathic conditions such as sunburn or arthritis. The underlying mechanisms of allodynia differ however in principle from one another and can be classified by a detailed medical case history and investigation.
  • a further example of abnormal pain sensation is hyperalgesia.
  • a normally painful stimulus is perceived as producing a more severe pain than would be the case in a healthy situation.
  • This type of increased pain perception occurs not only in neuropathic pain but also for example in inflammatory pain, where however it has a different cause (inflammation) than in neuropathic pain.
  • Various metabolic diseases may be the cause of neuropathic changes and may subsequently be implicated in neuropathic pain.
  • An example of such a neuropathy is diabetic neuropathy, which occurs in a large number of patients suffering from diabetes mellitus and may be associated with a large number of clinical symptoms such as a feeling of numbness, tingling sensation, or pain.
  • the most common form of diabetic neuropathy is distal symmetrical sensomotor polyneuropathy.
  • Neuropathic pain occurs inter alia after damage to peripheral or central nerves and can therefore be induced and observed in animal experiments by targeted lesions of individual nerves.
  • Two possible animal models are the nerve lesion according to Bennett (Bennett and Xie, 1988 Pain 33:87-107) as well as that according to Chung (Kim and Chung, 1992 Pain 50:355-363).
  • Bennett the nerve lesion according to Bennett (Bennett and Xie, 1988 Pain 33:87-107) as well as that according to Chung (Kim and Chung, 1992 Pain 50:355-363).
  • Bennett the sciatic nerve is bound unilaterally with loose ligatures; in the Chung model two spinal nerves are bound unilaterally.
  • the development of symptoms of neuropathic pain can be observed and quantified by means of thermal or mechanical allodynia.
  • a known animal model for investigating diabetic neuropathy is the induction of diabetes in rodents by administration of a single dose of streptozotocin, an antibiotic extract from Streptomyces acromogenes, which selectively damages the ⁇ cells of the pancreas. After some time the animals exhibit typical symptoms of diabetic neuropathic pain, such as for example mechanical, thermal or chemical hyperalgesia (Courteix et al., 1993 Pain 53:81-88).
  • neuropathic pain among other things, gabapentin is used, which however is relatively ineffective, and then only at significant dosages.
  • morphine is also often used, the range of side effects of which are, as is known, not without problems. Against the background of the prior art there was therefore a need for compounds with a favorable ratio of effectiveness to side effects, and to provide compounds for the treatment of neuropathic pain.
  • An object of the present invention was accordingly to discover compounds that are effective in treating neuropathic pain, in particular polyneuropathic pain and especially diabetic pain.
  • a further object of the invention was to provide a new method of effectively treating neuropathic pain without excessive side effects.
  • the present invention provides for the use of a 1-phenyl-3-dimethylaminopropane compound corresponding to formula I
  • the compounds optionally may be used in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixture ratio; in the prepared form or in the form of their acids or their bases or in the form of their salts, in particular the physiologically compatible salts, or in the form of their solvates, in particular the hydrates.
  • the neuropathic pain to be treated may preferably be mononeuropathic and/or polyneuropathic pain, particularly preferably polyneuropathic pain, and furthermore preferably diabetic neuropathic pain, especially preferably diabetic peripheral neuropathic pain.
  • the method of the invention may also preferably be used for treating diabetic neuropathy, and most preferably for treating diabetic peripheral neuropathy.
  • neuropathic pain in particular polyneuropathic pain, which is one of the most difficult types of pain to treat.
  • NSAID analgesics and to ⁇ -opioid agonists, antidepressants and anticonvulsants available on the market, or whose pain cannot be adequately treated with other non-opioid analgesics, antidepressants and anticonvulsants.
  • the present application provides for the use of the substance (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, a centrally active analgesic, which has a dual mode of action ( ⁇ -opioid receptor agonist and an inhibitor of noradrenaline uptake) coupled with low opioid-typical side effects, in contrast to opioids currently used and available on the market, for the treatment of polyneuropathic, preferably diabetic neuropathic and more particularly diabetic peripheral neuropathic pain.
  • alkyl and cycloalkyl radicals are understood to denote saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or monosubstituted or polysubstituted.
  • C 1-2 -alkyl denotes C1- or C2-alkyl
  • C 1-3 -alkyl denotes C1-, C2- or C3-alkyl
  • C 1-4 -alkyl denotes C1-, C2-, C3- or C4-alkyl
  • C 1-5 -alkyl denotes C1-, C2-, C3-, C4- or C5-alkyl
  • C 1-6 -alkyl denotes C1-, C2-, C3-, C4-, C5- or C6-alkyl
  • C 1-7 -alkyl denotes C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • C 1-10 -alkyl denotes C1-, C
  • C 3-4 -cycloalkyl denotes C3- or C4-cycloalkyl
  • C 3-5 -cycloalkyl denotes C3-, C4 or C5-cycloalkyl
  • C 3-6 -cycloalkyl denotes C3-, C4-, C5- or C6-cycloalkyl
  • C 3-7 -cycloalkyl denotes C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3-8 -cycloalkyl denotes C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
  • C 4-5 -cycloalkyl denotes C4- or C5-cycloalkyl
  • C 4-6 -cycloalkyl denotes C4-, C5- or C6-cycloalkyl
  • C 4-7 cycloalkyl denotes C4-, C5-, C6
  • cycloalkyl also includes saturated cycloalkyls in which one or two carbon atoms are replaced by a heteroatom S, N or O.
  • cycloalkyl however in addition also includes in particular monounsaturated or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring, provided that the cycloalkyl does not form an aromatic system.
  • the alky and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-di-methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF 2 , CF 3 or CH 2 OH as well as pyrazolinone, oxopyrazolinone, [1,4]dioxan
  • substituted within the meaning of the present invention denotes the substitution of at least one (optionally also several) hydrogen atom(s) by F, Cl, Br, I, NH 2 , SH or OH, in which “polysubstituted” and “substituted” in the case of polysubstitution is understood to mean that the substitution occurs multiply with the same or different substituents on different as well as on the same atoms, for example triple substitution on the same C atom as in the case of CF 3 , or at different sites, as in the case of —CH(OH)—CH ⁇ CH—CHCl 2 .
  • substituents in this connection are F, Cl and OH.
  • the hydrogen atom may also be replaced by OC 1-3 -alkyl or C 1-3 -alkyl (in each case monosubstituted or polysubstituted, or unsubstituted) in particular by methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3-6 is understood to denote —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 -
  • the term (CH 2 ) 1-4 is understood to denote —CH 2 , —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —
  • the term (CH 2 ) 4-5 is understood to denote —CH 2 —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, etc.
  • aryl radical is understood to denote ring systems with at least one aromatic ring, but without heteroatoms in even only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or monosubstituted or polysubstituted.
  • a heteroaryl radical is understood to denote heterocyclic ring systems with at least one unsaturated ring, which may contain one or more heteroatoms from the group nitrogen, oxygen and/or sulphur and may also be monosubstituted or polysubstituted.
  • heteroaryl compounds examples include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.
  • salt is understood to denote any form of the active constituent according to the invention in which this adopts an ionic form or is charged, and is coupled to a counter ion (a cation or anion) or is present in solution.
  • the term is also understood to include complexes of the active constituent with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salts in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or a physiologically compatible cation.
  • physiologically compatible is understood to mean that the substance, in particular the salt as such, is compatible when used in humans or mammals, and therefore for example does not act in a non-physiological manner (e.g. is not toxic).
  • physiologically compatible salt with anions or acids is understood within the meaning of the present invention to denote salts of at least one of the compounds according to the invention—generally protonated, for example on the nitrogen atom—as cation with at least one anion, which are physiologically compatible, especially when used in humans and/or mammals.
  • the term is understood within the meaning of the present invention to denote the salt formed with a physiologically compatible acid, namely salts of the respective active constituent with inorganic or organic acids, which are physiologically compatible, especially when used in humans and/or mammals.
  • physiologically compatible salts of specific acids are salts of the following: hydrochloric acid, hydrobromic acid, sulphuric 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 1 ⁇ 6 -benzo[3]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
  • the hydrochloride salt is particularly preferred.
  • physiologically compatible acid is understood within the meaning of the present invention to denote salts of the respective active constituent with inorganic or organic acids, which are physiologically compatible, especially when used in humans and/or mammals.
  • the hydrochloride is particularly preferred.
  • physiologically compatible acids include the following: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1 ⁇ 6 -benzo[3]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipo
  • physiologically compatible salts with cations or bases is understood within the meaning of the present invention to denote salts of at least one of the compounds according to the invention—generally a (deprotonated) acid—as anion with at least one, preferably inorganic, cation, which are physiologically compatible, especially when used in humans and/or mammals.
  • Particularly preferred are the salts of the alkali and alkaline earth metals, but also salts with NH 4 + , in particular however (mono) or (di) sodium, (mono) or (di)potassium, magnesium or calcium salts.
  • salt formed with a physiologically compatible cation is understood within the meaning of the present invention to denote salts of at least one of the respective compounds as anion with at least one inorganic cation, which are physiologically compatible, especially when used in humans and/or mammals.
  • Particularly preferred are the salts of the alkali and alkaline earth metals, but also NH 4 + , in particular however (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
  • 1-phenyl-3-dimethylaminopropane compound of Formula I used according to the invention is selected from the group consisting of:
  • Particularly preferred substances include:
  • Especially preferred compounds are:
  • compositions of the invention which comprise one or more of the aforementioned compounds according to the invention, are useful for treating neuropathic pain, preferably mono- and/or polyneuropathic pain, particularly preferably polyneuropathic pain, furthermore preferably diabetic neuropathic pain, more preferably diabetic peripheral neuropathic pain, and in addition preferably for treating diabetic neuropathy, and particularly preferably for treating diabetic peripheral neuropathy.
  • the compositions contain at least one aforementioned active constituent used according to the invention, as well as optionally suitable additives and/or auxiliary substances.
  • Suitable additives and/or auxiliary substances within the scope of the present invention include all substances known to persons skilled in the art for producing galenical formulations.
  • the selection of these auxiliary substances as well as the amounts to be used depend on whether the medicament is to be administered orally, intravenously, intraperitonealy, intradermally, intramuscularly, intranasally, buccally or topically.
  • suitable preparations may take the form of tablets, chewable tablets, coated pills, capsules, granules, drops, juices or syrups, while for parenteral, topical and inhalative administration, suitable preparations may be formulated as solutions, suspensions, readily reconstitutable dry preparations as well as sprays.
  • a further possible form is as suppositories for rectal administration.
  • Examples of percutaneous administration forms include use in a depot in dissolved form, in a carrier film or a plaster, optionally with the addition of agents promoting penetration of the skin.
  • auxiliary substances and additives for oral administration forms include disintegrants, lubricants, binders, fillers, mold release agents, optionally solvents, taste enhancers, sugars, in particular carriers, diluents, colorants, antioxidants, etc.
  • suppositories there may be used inter alia waxes or fatty acid esters, and for parenteral application agents there may be used carriers, preservatives, suspension aids, etc.
  • the compounds according to the invention may be released in a delayed manner from orally, rectally or percutaneously usable preparation forms.
  • Retard formulations in particular in the form of a “once daily” preparation, which need to be taken only once a day, are especially preferred for use in treating many medical indications for which the active substances of the invention are suitable.
  • the amounts of active constituent to be administered to patients vary depending on the patient's weight, type of application, and the severity of the medical condition. Preferred are medicaments that contain at least 0.05 to 90.0% of the active constituent, in particular low active dosages, in order to avoid side effects. Normally 0.1 to 5000 mg/kg, in particular 1 to 500 mg/kg and preferably 2 to 250 mg/kg of body weight of at least one compound used according to the invention are administered. However, the administration of 0.01-5 mg/kg, preferably 0.03 to 2 mg/kg and especially 0.05 to 1 mg/kg of body weight is also preferred and customary.
  • auxiliary substances for inclusion in the pharmaceutical compositions according to the invention include water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, ground nut oil, soya bean oil, lecithin, sodium lac
  • Medicaments and pharmaceutical compositions according to the invention may be prepared using agents, equipment, methods and processes known in the prior art for producing pharmaceutical formulations, such as are described, for example, in “Remington's Pharmaceutical Sciences”, edited by A. R. Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985), in particular in Part 8, Chapters 76 to 93.
  • the active constituent of the medicament can be granulated with a pharmaceutical carrier, for example conventional tablet constituents such as maize starch, lactose, sucrose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as for example water, in order to form a solid composition that contains the active constituent in homogeneous distribution.
  • a pharmaceutical carrier for example conventional tablet constituents such as maize starch, lactose, sucrose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as for example water, in order to form a solid composition that contains the active constituent in homogeneous distribution.
  • a homogeneous distribution is understood here to mean that the active constituent is distributed uniformly over the whole composition, so that the latter can be subdivided without any problem into identically active unit dose forms such as tablets, pills or capsules.
  • the solid composition
  • the tablets or pills of the medicament according to the invention or of the compositions according to the invention can also be coated or compounded in some other way so as to produce a dose form having delayed release.
  • Suitable coating agents are inter alia polymeric acids and mixtures of polymeric acids with materials such as for example schellac, cetyl alcohol and/or cellulose acetate.
  • the medicaments prepared according to the invention exhibit only slight side effects, it can for example be advantageous, in order to avoid certain forms of dependence, to employ apart from the aforementioned compound according to the invention also morphine antagonists, in particular naloxone, naltrexone and/or levallorphan.
  • morphine antagonists in particular naloxone, naltrexone and/or levallorphan.
  • morphine and compound 10 see Example 0 hereinafter
  • the invention also relates to a method for treating neuropathic pain, for treating neuropathic, preferably mononeuropathic and/or polyneuropathic pain, particularly preferably polyneuropathic pain, and in addition preferably for treating diabetic neuropathic pain, preferably diabetic peripheral neuropathic pain, and in addition preferably for treating diabetic neuropathy, particularly preferably diabetic peripheral neuropathy, in which at least one of the aforementioned compounds is used according to the invention.
  • Sprague-Dawley rats weighing 140-160 g are provided with four loose ligatures of the right sciatic nerve under nembutal narcosis.
  • the animals develop a hypersensitivity in the paw innervated by the damaged nerve, which after a healing phase of one week is quantified over about four weeks by means of a 4° C. cold metal plate (cold allodynia). The animals are observed for two minutes on this plate and the number of retractive movements of the damaged paw are measured.
  • the effect of the substance is determined with reference to the base value before application of the substance, at four different times over a period of one hour(15, 30, 45 and 60 minutes after application) and the resultant area under the curve (AUD) as well as the inhibition of cold allodynia at the individual measurement points is expressed in percent effect with reference to the vehicle control (AUD) and to the initial value (individual measurement points).
  • the compounds all show a marked and dose-dependent inhibition of cold allodynia in Bennett animals and of tactile allodynia in Chung animals. Moreover, in Chung animals in some cases a surprisingly long action duration of up to 30 hours after i.p. application is observed.
  • Diabetic animals exhibit a reduced mechanical reaction threshold and thus a mechanical hyperalgesia compared to control animals that had simultaneously received vehicle solution instead of streptozotocin.
  • the maximum pressure exerted on the rear paw was 250 g.
  • the end point of the mechanical reaction threshold in grams was determined based on the reaction of the animal (withdrawal of the rear paw, vocalisation or evasive reaction).
  • % MPE (post-test ⁇ pre-test)/(250 ⁇ pre-test) ⁇ 100.
  • ED50 values dose at which 50% maximum inhibition occurred were determined by regression analysis from the % MPE values at the time of the maximum effect.
  • test substance having a presumably opioid action mechanism in patients who are tolerant or treatment-resistant to morphine.
  • Bennett animals that have developed a tolerance to morphine, the tested compounds still exhibited a significant anti-allodynic action.
  • the action of test substances in naive (non-morphine-tolerant) animals and morphine-tolerant animals is compared in Table 4. Morphine (Mor) understandably no longer exhibits any effect, whereas the other tested compounds produce a marked inhibition of cold allodynia in these animals.
  • Morphine 10 mg/kg i.p.], Compound 9 [10 and 21.5 mg/kg i.p.], Compound 10 [0.46 and 1 mg/kg i.p.], Compound 4 [21.5 mg/kg i.p.] and Compound 11 [21.5 mg/kg i.p.] were tested analogously to Example 1.
  • mice Male Sprague Dawley rats (140-180g, Janvier, France) are kept under standard conditions (06.00-18.00 hours light, 18.00-06.00 hours darkness; 20°-24° C. room temperature; 35-70% relative atmospheric humidity, tap water and standard feed as desired) in groups of five animals in Macrolon type 4 cages.
  • the median value of five tests defines the withdrawal threshold of a test time point.
  • the animals are tested on both rear paws before and at various times after administration of the substance or vehicle.
  • the difference between the test value and pre-test for the ipsilateral and contralateral side is determined, and the result is expressed as the mean value (MW) and standard error of the mean (SEM) for the groups consisting in each case of 10 animals.
  • the difference between the mean difference values of the ipsilateral and contralateral side defines the hypersensitivity induced by mononeuropathy.
  • the statistical significance of the effect of a substance is determined on the basis of the difference values compared to the vehicle group for the ipsilateral and contralateral side, by means of bifactorial variance analysis and post hoc analysis according to Bonferroni.
  • Rats receive a single i.p. dose of Streptozotocin (STZ, Sigma Aldrich Chemie, Germany) or vehicle (0.1 mM citrate buffer, pH 4.6). After one week the blood sugar values are determined and animals treated with STZ that have a blood sugar value of ⁇ 17 mM are classed as diabetic in the experiment. Diabetic animals develop a hypersensitivity in the rear paws. The hypersensitivity to a pressure stimulus can be measured using a pressure pain instrument (algesiometer; Ugo Basile, Italy) according to the method of Randall and Selitto (Arch. Int. Pharmcodyn. 1957; 111: 409-19) in diabetic animals compared to healthy control animals of the same weight, in the third week after STZ treatment.
  • STZ Streptozotocin
  • vehicle 0.1 mM citrate buffer, pH 4.6
  • Diabetic and healthy animals are tested before and at various times after administration of the substance or vehicle. For each animal the difference between the test value and pre-test is determined, and for the groups, each consisting of ten animals, the result is expressed as the mean value (MW) and standard error of the mean (SEM). The difference between the mean difference values of the diabetic and healthy animals defines the polyneuropathy-induced hypersensitivity. The statistical significance of the effect of a substance is determined on the basis of the difference values with respect to the vehicle group for diabetic and healthy animals by means of bifactorial variance analysis and post hoc analysis according to Bonferroni.
  • Contralateral measurement values are not included in this analysis.
  • the highest dosage group of 10 mg/kg i.v. full inhibition of the mononeuropathically-induced withdrawal threshold reduction is reached after 30 minutes.
  • the contralateral withdrawal threshold is also raised in a dose-dependent manner.
  • the statistically significant minimal effective dose is 10 mg/kg.
  • (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)hydrochloride 9 shows a dose-dependent increase of the withdrawal threshold in the rear paw of diabetic rats.
  • the statistically significant minimal effective dose is 0.3 mg/kg.
  • the mean difference value between the withdrawal threshold of naive control animals and the withdrawal threshold of polyneuropathic animals is in this series of experiments 43 g .
  • Complete inhibition of the polyneuropathically-induced withdrawal threshold reduction is thus achieved at values (test value ⁇ pre-test value) of ⁇ 43 g in diabetic animals. Time points at which this value is reached or exceeded are shown in grey in the table.
  • Measurement values of naive animals are not included in this analysis.
  • the highest dosage group of 1 mg/kg i.v. complete inhibition of the polyneuropathically-induced withdrawal threshold reduction is reached after 15 minutes and 30 minutes.
  • the withdrawal threshold of healthy control animals is also raised in a dose-dependent manner.
  • the statistically significant minimal effective dose is 1 mg/kg.

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6248737B1 (en) * 1994-07-23 2001-06-19 Gruenenthal Gmbh 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI1685829T1 (sl) * 2002-11-22 2008-08-31 Gruenenthal Gmbh Uporaba (1RS,3RS,6RS)-6-dimetilaminometil-1- (3-metoksi-fenil)-cikloheksan-1, 3-diola za zdravljenje vnetne bolečine
BRPI0710682B8 (pt) * 2006-04-28 2021-05-25 Gruenenthal Gmbh combinação farmacêutica compreendendo 3-(3-dimetilamino-1-etil-2-metil-propil)-fenol e paracetamol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6248737B1 (en) * 1994-07-23 2001-06-19 Gruenenthal Gmbh 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
US6344558B1 (en) * 1994-07-23 2002-02-05 Gruenthal Gmbh 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effect

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