WO2005094826A1 - 止痒剤 - Google Patents
止痒剤 Download PDFInfo
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- WO2005094826A1 WO2005094826A1 PCT/JP2005/006015 JP2005006015W WO2005094826A1 WO 2005094826 A1 WO2005094826 A1 WO 2005094826A1 JP 2005006015 W JP2005006015 W JP 2005006015W WO 2005094826 A1 WO2005094826 A1 WO 2005094826A1
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- C07—ORGANIC CHEMISTRY
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- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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Definitions
- the present invention relates to an antipruritic comprising a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof as an active ingredient, which is useful for treating itch associated with various diseases. .
- Itching is known to be expressed in various skin diseases accompanied by inflammation, and also to be perceived for medical diseases, pregnancy, parasitic infection, and sometimes for drug or psychogenic reasons. I have. It is an area where research has been delayed due to difficulties in quantitative and objective evaluation, and the mechanism of the development of itch has not yet been fully elucidated. Histamine, substance P, bradykinin, proteinase, prostaglandin, opioid peptide, and the like.
- antihistamines have been mainly used as inner ⁇ agents for the treatment of pruritus
- external agents such as antihistamines, corticosteroids, non-steroid anti-inflammatory agents, Menthol, phenol, salicylic acid, tar, crotamiton, capsaicin and humectants (urea, hirudoid, petrolatum, etc.) have been used.
- antihistamines corticosteroids
- non-steroid anti-inflammatory agents Menthol, phenol, salicylic acid, tar, crotamiton, capsaicin and humectants (urea, hirudoid, petrolatum, etc.
- Menthol Menthol
- phenol phenol
- salicylic acid tar
- crotamiton crotamiton
- capsaicin and humectants urea, hirudoid, petrolatum, etc.
- problems such as the time required for onset of action,
- Non-Patent Document 1 a finding indicating the relationship between a compound having a morphinan skeleton and pruritus, when morphine is administered intraepithelial or intrathecally, itching is induced contrary to the compound used in the present invention.
- Non-Patent Document 2 the pruritus induced by intrathecal administration of morphine was suppressed by naloxone, an opioid antagonist (Non-patent Document 2), and the strong pruritus induced by cholestatic patients with hepatic impairment was Opioid antagonist (Non-Patent Document 3) has also been reported.
- a 6-chain-chain-substituted morphinan compound having an antipruritic effect and represented by the following general formula is disclosed (Patent Document 1).
- Non-Patent Documents 2 and 3 morphinan compounds having a nitrogen-containing cyclic substituent are described in Non-Patent Documents 2 and 3, but are disclosed only for analgesics and antitussives (Patent Documents 2 and 3).
- Non-patent Documents 4, 5, and 6 only describe compounds, but especially for use V, and no description! ⁇ (Non-patent Documents 4, 5, and 6) (Polituria 'urinary incontinence)
- the use of a therapeutic agent is disclosed later than the priority date of the present application (Patent Document 4).
- the compound has a nitrogen-containing cyclic substituent at the 6-position of the morphinan structure, which has a certain link between the structure and pharmacological activity of the compound via the obioid receptor and the antipruritic effect according to the present invention. No remarkable and useful antipruritic effect of the antipruritic agent of the present invention is analogized.
- Non-Patent Document 1 J. H. Jaffe and W. R. Martin, Goodman and Gilman's Pharmacological Basis of Therapeutics, Macmillan, New York, 1985
- Non-Patent Document 2 J. Bernstein et al, J. Invest. Dermatol, 78, 82-83, 1982
- Non-Patent Document 3 J.R.Thornton and M.S.Losowsky, Br.Med.J “297, 1501-1504, 1988
- Non-Patent Document 4 C. Simon et al., Tetrahedron, 50, 9757-9768, 1994
- Non-Patent Document 5 C. Simon et al "Synth. Commun" 22, 913-921, 1992
- Non-Patent Document 6 LM Sayre et al "J. Med. Chem., 27, 1325-1335, 1984
- Patent Document 1 International Publication WO 98/23290
- Patent Document 2 JP-B-41 18824
- Patent Document 3 JP-B-41-18826
- Patent Document 4 International Publication WO 04/33457
- the present invention provides a compound represented by the general formula (I)
- R 1 is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkylalkyl having 6 to 8 carbons, aryl having 6 to 12 carbons, carbon Aralkyl having 7 to 13 carbon atoms, alkaryl having 3 to 7 carbon atoms, fulleralkyl (alkyl portion has 1 to 5 carbon atoms), chenylalkyl (alkyl portion has 1 to 5 carbon atoms), or pyridylalkyl (The alkyl moiety represents 1 to 5);
- R 2 and R 3 are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, alkoxy-alkoxy having 3 to 7 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or alkyl having 1 to 5 carbon atoms. Represents canoiloxy;
- -X- is a carbon chain of 2 to 7 carbon atoms that becomes part of the ring structure (unsaturated in carbon chains in which one or more carbon atoms may be replaced by nitrogen, oxygen, or sulfur atoms)
- k represents an integer from 0 to 8.
- R 4 is k substituents on the nitrogen-containing cyclic structure, each of which is independently fluorine, chlorine, bromine, iodine, nitro, hydroxy, alkyl having 1 to 5 carbons, cycloalkylalkyl having 7 to 13 carbons, Aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, isothiocyanato, SR 6 , SOR 6 , SO R 6 , (CH) OR 6 , (CH) COR 6 , (CH)
- K R 4 s force representing COR 6 , SO NR 7 R 8 , CONR 7 R 8 , (CH) NR 7 R 8 , (CH) N (R 7 ) COR 8
- COR 6 represent (CH) CO R 6, SO NR 7 R 8, CONR 7 R 8, (CH) NR 7 R 8, (CH) N (R 7) COR 8
- R 9 is hydrogen, alkyl having 1 to 5 carbons, alkaryl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, hydroxyalkyl having 1 to 3 carbons, (CH) OR 6 , or (CH ) COR 6
- R 1Q and R 11 are combined to represent -0-, -S-, or -CH- , or R 1Q is hydrogen and R 11 is water
- R 6 represents hydrogen, alkyl having 1 to 5 carbons, alkyl having 3 to 7 carbons, aryl having 6 to 12 carbons, or aralkyl having 7 to 13 carbons;
- RR 8 independently represents hydrogen, alkyl having 1 to 5 carbons, or aralkyl having 7 to 13 carbons
- the general formula (I) includes a (+) form, a (-) form, and a (f) form And a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
- the present invention also relates to the use of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the above general formula (I) or a pharmacologically acceptable caro salt with an acid for the production of an antipruritic. provide.
- the present invention provides a method for administering to a patient an effective amount of one or more of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the above general formula (I) and a pharmacologically acceptable acid addition salt thereof.
- a method of pruritus comprising:
- the antipruritic agent of the present invention has an excellent antipruritic effect and has few side effects.
- the antipruritic agent of the present invention comprises, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof. Containing.
- the antipruritic agent of the present invention comprises an active ingredient selected from the group consisting of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) and a pharmacologically acceptable acid addition salt thereof alone. May be included, or may be included in combination of two or more.
- R 1 is preferably hydrogen, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkylalkyl having 6 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, or arylalkyl having 3 to 7 carbon atoms.
- hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, aryl and propyl, particularly hydrogen, cyclopropylmethyl, cyclobutylmethyl and aryl are preferred.
- R 2 and R 3 are hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons.
- hydrogen, hydroxy, methoxy, ethoxy, aryloxy, benzyloxy, acetoxy or propionoxy are preferred.
- hydrogen, hydroxy, methoxy and acetoxy are particularly preferred.
- -X- is a carbon chain having 2 to 4 carbon atoms which becomes a part of the ring structure (however, one of the carbon atoms may be replaced by a sulfur atom, and the carbon chain may contain an unsaturated bond. However, it is preferable that the carbon chain be a carbon chain having 2 carbon atoms which becomes a part of the ring structure.
- k is an integer from 0 to 6! /.
- R 4 is alkyl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, aralkyloxy having 7 to 13 carbons, or four R 4 ⁇ bonded to the same sulfur atom.
- R 4 forces bonded to the same sulfur atom ⁇ ⁇ ⁇ ⁇ U, which also preferably form separately.
- the unsubstituted benzene-fused ring or cyclohexene-fused ring is also preferably unsubstituted.
- substituent R 5 fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbons (particularly methyl, ethyl) , Propyl), aralkyl having 7 to 13 carbon atoms (especially benzyl), hydroxy, alkoxy having 1 to 5 carbon atoms (especially methoxy, ethoxy), trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanate, SR 6, SOR 6, SO R 6 , (CH) OR 6, (CH) COR 6, (CH) CO R 6, SO NR 7 R 8, CONR 7 R 8
- R 8 is preferably independently hydrogen, alkyl having 1 to 5 carbons (especially methyl, ethyl, propyl) or aralkyl having 7 to 13 carbons (especially benzyl), particularly preferably unsubstituted.
- R 9 hydrogen, alkyl having 1 to 5 carbon atoms, aryl, and benzyl are preferable, and hydrogen and methyl are particularly preferable.
- R 1Q and R 11 are preferably -0-, or R 1Q is hydrogen and R 11 is preferably hydrogen, hydroxy or methoxy. Those which are -0- are preferred.
- Pharmacologically preferred acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, lactate, and quaternary salt.
- Organic carboxylate such as acid salt, oxalate, glutarate, malate, tartrate, fumarate, mandelic acid, maleate, benzoate, phthalate, etc., methanesulfonate
- organic sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate and the like.
- hydrochloride, hydrobromide, phosphate, tartar For which an acid salt or a methanesulfonate is preferably used.
- the present invention is not limited to these.
- -X- is a carbon chain having 2 carbon atoms which is a part of a ring structure
- 2 A benzene condensed ring in which R 4 is unsubstituted or substituted with one or more R 5 , R 9 is hydrogen, and R 1Q and R 11 are bonded to each other to form a compound represented by the general formula (la).
- Table 1 shows specific examples of the compound.
- CPM means cyclopropylmethyl
- the 6-position bond is ⁇ or ⁇ .
- -X- is a carbon chain having 3 carbon atoms which is a part of a ring structure
- Z is a valence bond
- 2 benzene fused ring number of R 4 is substituted with R 5 or more unsubstituted or one
- R 9 is hydrogen
- R 10 R 11 are bonded to - 0
- Table below following general formula Ob) is a compound of Table 2 shows specific examples of the compound to be prepared.
- R 1 is cyclopropylmethyl
- R 2 and R 3 are hydroxy
- R 5 is
- a carbon chain having 3 carbon atoms in which -X- is part of a ring structure (in which one carbon is replaced by a sulfur atom), Y, ( o)-, where z is a valence bond and four R 4 bonded to the same sulfur atom are two oxygen atoms
- a benzene condensed ring in which two R 4 are unsubstituted or substituted with one or more R 5 to form a group, is hydrogen, R 1Q , and R 11 are bonded to form -0- in the following general formula (Ic).
- Table 3 shows specific examples of the compounds represented.
- [0049] is named N- [17- (cyclopropylmethyl) -4,5 ⁇ -epoxy-3,14-dihydroxymorphinan-6 ⁇ -yl] - ⁇ -sulfonebenzoic imide.
- the morphinan derivative having a nitrogen-containing cyclic substituent and represented by the general formula (I) and used as an active ingredient of the antipruritic agent of the present invention can be specifically produced by the following method. Monkey
- the acid anhydride (111) and the sulfonic acid derivative ( ⁇ ) are different from the primary amine compound (11, when R 3 is hydroxy, it may be protected with a suitable protecting group such as methoxymethyl). Although it is preferable to use 1 to 20 equivalents, it is possible to use 0.5 to 50 equivalents, and good results are obtained with 1 to 10 equivalents.
- Solvents include non-protonic polar solvents such as DMF, dimethylacetamide, and DMSO; ether solvents such as getyl ether, THF, DME, and dioxane; hydrocarbon solvents such as benzene, toluene, and xylene; dichloromethane; Halogen solvents such as chloroform and 1,2-dichloroethane, alcohol solvents such as methanol, ethanol, propanol and butanol, and acidic solvents such as acetic acid and propionic acid can be used. And closhol form is preferably used.
- bases to be co-existed include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, and organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine. Among them, triethylamine, pyridine, potassium carbonate and sodium carbonate are preferably used.
- the base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, based on the substrate.
- inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, carboxylic acids such as acetic acid, propionic acid and benzoic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid can be used.
- Carboxylic acids such as acetic acid, propionic acid and benzoic acid, especially vinegar Acids are preferably used.
- the amount of the acid to be used is 1-30 equivalents, preferably 1-10 equivalents, relative to the substrate.
- a method in which acetic acid or the like is used as a solvent is also preferable. In this case, an excess acid will coexist.
- the reaction can be carried out usually at a temperature in the range of -20 to 200 ° C, and preferably in the range of 0 to 150 ° C, satisfactory results can be obtained.
- the reaction time is appropriately selected according to the conditions such as the reaction temperature, but a satisfactory result is usually obtained with a 30 minute power and about 30 hours.
- the concentration of the substrate (II) in the reaction system is not particularly limited, but is usually preferably about 1 mmol / L to 1 mol / L.
- R U The general formula (IA) R 2, R 3, R 5 , R 9, R 1Q, inner cyclic imide derivatives of compounds is R U is represented by the same) in the definition, the Mitsunobu reaction described in Tetrahedron. 50, 9757 (1994) It can be manufactured in any way.
- Alkylation or amidation can be performed by a commonly used method in which a base coexists in a solvent.
- Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide and potassium t-butoxide.
- Organic bases such as metal alkoxides, triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used.
- the base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, based on the substrate. However, in the case of the amidation reaction, satisfactory results may be obtained without using a base.
- the solvent examples include aprotic polar solvents such as DMF, dimethylacetamide, and DMSO; ether solvents such as dimethyl ether, THF, DME, and dioxane; hydrocarbon solvents such as benzene and toluene; dichloromethane; Halogen solvents such as chloroform and 1,2-dichloroethane can be used, and among them, DMF, THF and toluene are preferably used. Satisfactory results can be obtained at a reaction temperature of usually -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is appropriately selected according to conditions such as the reaction temperature, but a satisfactory result is usually obtained in about 30 minutes to 100 hours.
- the concentration of substrate (IV) and (V) in the reaction system Is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.
- IC R 1 , R 2 , R U , X and Z are the same as defined above), and can be produced by alkylation or acylation in a solvent in the presence of a base.
- the compound represented by the general formula (IC) used as a starting material in Scheme 3 can be obtained by the methods shown in Schemes 1 and 2.
- an organic lithium reactant such as methyllithium, butyllithium, or LDA
- a metal hydride such as sodium hydride or potassium hydride
- a metal alkoxide such as sodium ethoxide or potassium t-butoxide
- LDA and butyllithium are preferably used.
- the base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, based on the substrate.
- Examples of the solvent include aprotic polar solvents such as DMF, dimethylacetamide, and DMSO; ether solvents such as dimethyl ether, THF, DME, and dioxane; and hydrocarbons such as pentane, hexane, benzene, and toluene.
- aprotic polar solvents such as DMF, dimethylacetamide, and DMSO
- ether solvents such as dimethyl ether, THF, DME, and dioxane
- hydrocarbons such as pentane, hexane, benzene, and toluene.
- a system solvent can be used, and among them, THF and DME are preferably used.
- reaction temperature of usually -100 to 200 ° C, preferably -80 to 150 ° C.
- the reaction time is appropriately selected depending on conditions such as the reaction temperature, but a satisfactory result is usually obtained in 30 minutes to 30 hours.
- concentration of the substrate (IC) in the reaction system is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.
- the deprotection at this time is a general demethylation reaction of phenolic methyl ether, specifically, (1) a method using boron tribromide, or (2) a basic method using boron tribromide. Under the conditions, the method can be carried out with a deviation from the method using an alkyl thiol.
- reaction solvent dichloromethane is preferable among halogen-based solvents such as dichloromethane, chloroform and 1,2-dichloroethane. Satisfactory results can be obtained at a reaction temperature of -50 to 40 ° C even though a reaction temperature of -70 to 50 ° C is preferred. Reaction times of 10 minutes to 10 hours are preferred, and satisfactory results are obtained in 30 minutes to 5 hours. Also the reaction The concentration of the compound represented by the general formula (IF) in the system is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.
- propanethiol is preferably used among alkylthiols such as ethanethiol, propanethiol, and butanethiol as a reactant. Satisfactory results are obtained with 1 to 7 equivalents, although 1 to 20 equivalents are preferred.
- alkylthiols such as ethanethiol, propanethiol, and butanethiol
- Satisfactory results are obtained with 1 to 7 equivalents, although 1 to 20 equivalents are preferred.
- potassium t-butoxide, sodium hydride, potassium hydride and the like are preferable, and potassium t-butoxide is preferably used. Satisfactory results are obtained with 1 to 7 equivalents, although 1 to 20 equivalents are preferred.
- the reaction solvent is preferably an aprotic polar solvent such as DMF or dimethylacetamide, or an ether-based solvent such as THF or DME.
- DMF which is an aprotic solvent
- a reaction temperature of 80 to 150 ° C although a reaction temperature of 50 to 200 ° C is preferred. Satisfactory results are obtained with reaction times of 2 to 8 hours, although 1 to 15 hours are preferred.
- the concentration of the compound represented by the general formula (IF) in the reaction system is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.
- the antipruritic agent of the present invention may be used for skin diseases such as atopic dermatitis, neurogenic dermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, Senile skin Itching, insect bites, photosensitivity, juniper, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies, acne vulgaris, etc.
- skin diseases such as atopic dermatitis, neurogenic dermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, Senile skin Itching, insect bites, photosensitivity, juniper, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis
- the antipruritic agent of the present invention may be used in mammals (for example, mice, rats, wild, muster, egrets, cats, dogs, dogs, higgies, monkeys, and humans). Can do.
- the compound of the present invention is used alone, or for treating or preventing a disease, or for reducing or suppressing symptoms. It can be administered in combination with one or more substances.
- anthelmintic agents such as fipronil, lufenuron, imidacloprid, avenolemectins (eg avermectins), aibamectin, doramectin ( doramectin)), milbemycins, organophosphates, pyrethroids; antihistamines, such as chlorphen-lamin, trimeprazine, diphenhydramine, doxylamine; antifungals, such as fluconazole, ketoconazole, itraconazole (Itraconazole), griseofulvin, amphotericin B; antibacterial drugs, for example, enrofloxacin, manolevofloxacin, ampicillin, amoxicillin;
- the drug may be a free base or a salt thereof, and may be excipients, stabilizers, preservatives, buffers, solubilizing agents, emulsifiers.
- Additives such as a diluent and a tonicity agent may be appropriately mixed.
- Dosage forms include tablets and capsules, granules, powders, syrups and other oral preparations, injections, suppositories, liquids and other parenteral preparations, ointments, creams, patches, and other topical preparations. Administration and the like. External preparations are particularly preferred for treating skin diseases.
- External preparations include fats and oils (preferably vegetable oils, animal oils, waxes, fatty acids, fatty alcohols, mineral oils, turpentine oil, petrolatum, etc.), solvents (preferably water, ethanol, glycerin, propylene glycol, isopropyl alcohol, ethers, etc.), Preservative (preferably paraoxybenzoate, benzoate Acid, salicylic acid, sorbic acid, benzalco-pam, benzet-pom, propylene glycol, chlorobutanol, benzyl alcohol, ethanol, etc., stabilizers (preferably tocopherol, butylhydroxyethanol, dibutylhydroxytoluene, sulfite) , Disodium edetate, etc.), anionic surfactants (preferably potash stone, medicinal stone, zinc desilate, calcium stearate, magnesium stearate, aluminum monostearate, calcium linoleate, Non-ionic surfactants (preferably glyceryl monostea
- the antipruritic agent of the present invention desirably contains the above active ingredient in an amount of 0.00001 to 90% by weight, more preferably 0.0001 to 70% by weight.
- the amount to be used is appropriately selected according to symptoms, age, body weight, administration method, etc., but for adults, injections and external preparations, 0.1 g to lg of active ingredient per day, oral In this case, the dose is 1 ⁇ g to 10 g, which can be administered once or in several divided doses.
- the obtained crude product was dissolved in 2-mL of 2-propanol and 2 mL of chloroform, and 0.2 mL of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 13 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 67 mg (yield 85%: 2steps) of a free form of the title compound. This was used as the tartaric acid salt to obtain the title compound 4.
- mice Male ddY mice were received at 4 weeks of age, preliminarily reared, and used at 5 weeks of age. On the day before the experiment, the rostral back of the mouse was shaved using a clipper. Each compound was dissolved in 10% DMSO. Either the test drug or the vehicle is administered subcutaneously on the rostral back of the mouse, and 30 minutes later, 50- ⁇ L of substance-P (250 nmom / site) dissolved in PBS (Phospahte Buffered Saline) is applied to the hair removal site. Was administered intradermally. Immediately afterwards, they were placed in observation cages (10 * 14 * 22 cm), and the behavior for the next 30 minutes was photographed with a video camera in an unmanned environment.
- substance-P 250 nmom / site
- PBS Phospahte Buffered Saline
- the video was played, and the number of times the mouse pulled the hind limb near the substance-P administration site was counted.
- the experiment was performed with 8 animals per group. If there is a statistically significant difference between the mean number of pulls in the vehicle administration group and the mean number of pulls in the test drug administration group, it is determined that there is an antipruritic effect.
- the dose was shown to be the dose that halved the number of pulls in the group (Table 5).
- the antipruritic agent of the present invention has an excellent antipruritic effect and has few side effects, it is useful for treating pruritus associated with various diseases.
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Description
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/547,441 US7718664B2 (en) | 2004-03-30 | 2005-03-30 | Anti-itching agent |
CA2561509A CA2561509C (en) | 2004-03-30 | 2005-03-30 | Anti-itching agent |
DE602005011113T DE602005011113D1 (de) | 2004-03-30 | 2005-03-30 | Morphinanderivate als mittel gegen juckreiz |
KR1020067019884A KR101233289B1 (ko) | 2004-03-30 | 2005-03-30 | 지양제 |
JP2006511701A JP4882744B2 (ja) | 2004-03-30 | 2005-03-30 | 止痒剤 |
EP05727323A EP1736157B1 (en) | 2004-03-30 | 2005-03-30 | Morphinan derivatives as anti-itching agent |
Applications Claiming Priority (2)
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JP2004-097798 | 2004-03-30 | ||
JP2004097798 | 2004-03-30 |
Publications (1)
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WO2005094826A1 true WO2005094826A1 (ja) | 2005-10-13 |
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PCT/JP2005/006015 WO2005094826A1 (ja) | 2004-03-30 | 2005-03-30 | 止痒剤 |
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US (1) | US7718664B2 (ja) |
EP (1) | EP1736157B1 (ja) |
JP (1) | JP4882744B2 (ja) |
KR (1) | KR101233289B1 (ja) |
CN (1) | CN100586434C (ja) |
AT (1) | ATE414516T1 (ja) |
CA (1) | CA2561509C (ja) |
DE (1) | DE602005011113D1 (ja) |
ES (1) | ES2317219T3 (ja) |
PT (1) | PT1736157E (ja) |
TW (1) | TW200533355A (ja) |
WO (1) | WO2005094826A1 (ja) |
Cited By (8)
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EP1762569A1 (en) * | 2005-09-12 | 2007-03-14 | Alcasynn Pharmaceuticals Gmbh | Novel 6-amino-morphinan derivatives, method of manufacturing them and their application as analgesics |
WO2007055184A1 (ja) * | 2005-11-09 | 2007-05-18 | Toray Industries, Inc. | 機能性腸障害の治療または予防剤 |
WO2007072749A1 (ja) * | 2005-12-21 | 2007-06-28 | Toray Industries, Inc. | 鎮咳剤 |
WO2008143240A1 (ja) * | 2007-05-21 | 2008-11-27 | Toray Industries, Inc. | 特定の有機酸を含有する経口製剤並びに経口製剤の溶出性及び化学的安定性の改善方法 |
WO2008143241A1 (ja) * | 2007-05-21 | 2008-11-27 | Toray Industries, Inc. | 医薬錠剤の製造法 |
WO2008143239A1 (ja) | 2007-05-21 | 2008-11-27 | Toray Industries, Inc. | 結晶性微粉化粒子 |
JP2009528330A (ja) * | 2006-03-03 | 2009-08-06 | サントル・ナシオナル・ドゥ・ラ・ルシェルシュ・シアンティフィーク(セーエヌエールエス) | 神経栄養剤として有用なヒドロキシル化長鎖レスベラトロール誘導体 |
US8470845B2 (en) | 2004-11-04 | 2013-06-25 | Toray Industries, Inc. | Analgesic and methods of treating pain |
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CN101786990B (zh) * | 2010-03-04 | 2012-01-18 | 合肥工业大学 | 一种具有抗痒活性的化合物 |
US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
US20140179727A1 (en) | 2012-12-14 | 2014-06-26 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US20160361393A1 (en) * | 2015-06-11 | 2016-12-15 | Biostat Research, Llc | Topical sting/bite formulation and method of use |
WO2019171333A1 (en) | 2018-03-08 | 2019-09-12 | Victoria Link Ltd | Treatment of demyelinating diseases |
SG11202100580UA (en) | 2018-07-23 | 2021-02-25 | Trevi Therapeutics Inc | Treatment of chronic cough, breathlessness and dyspnea |
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- 2005-03-30 WO PCT/JP2005/006015 patent/WO2005094826A1/ja active Application Filing
- 2005-03-30 JP JP2006511701A patent/JP4882744B2/ja not_active Expired - Fee Related
- 2005-03-30 CN CN200580010569A patent/CN100586434C/zh not_active Expired - Fee Related
- 2005-03-30 PT PT05727323T patent/PT1736157E/pt unknown
- 2005-03-30 ES ES05727323T patent/ES2317219T3/es active Active
- 2005-03-30 EP EP05727323A patent/EP1736157B1/en not_active Not-in-force
- 2005-03-30 KR KR1020067019884A patent/KR101233289B1/ko not_active IP Right Cessation
- 2005-03-30 AT AT05727323T patent/ATE414516T1/de not_active IP Right Cessation
- 2005-03-30 TW TW094109942A patent/TW200533355A/zh unknown
- 2005-03-30 US US11/547,441 patent/US7718664B2/en not_active Expired - Fee Related
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US8470845B2 (en) | 2004-11-04 | 2013-06-25 | Toray Industries, Inc. | Analgesic and methods of treating pain |
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WO2008143240A1 (ja) * | 2007-05-21 | 2008-11-27 | Toray Industries, Inc. | 特定の有機酸を含有する経口製剤並びに経口製剤の溶出性及び化学的安定性の改善方法 |
JP5321454B2 (ja) * | 2007-05-21 | 2013-10-23 | 東レ株式会社 | 医薬錠剤の製造法 |
AU2008254039B2 (en) * | 2007-05-21 | 2013-10-24 | Toray Industries, Inc. | Method for producing pharmaceutical tablet |
JP5564943B2 (ja) * | 2007-05-21 | 2014-08-06 | 東レ株式会社 | 結晶性微粉化粒子 |
US8927011B2 (en) | 2007-05-21 | 2015-01-06 | Toray Industries, Inc. | Method for producing pharmaceutical tablet |
US9084817B2 (en) | 2007-05-21 | 2015-07-21 | Toray Industries, Inc. | Oral preparation comprising specific organic acid, and method for improvement in elution property and chemical stability of oral preparation |
KR101546398B1 (ko) * | 2007-05-21 | 2015-08-26 | 도레이 카부시키가이샤 | 결정성 미분화 입자 |
Also Published As
Publication number | Publication date |
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KR101233289B1 (ko) | 2013-02-14 |
US7718664B2 (en) | 2010-05-18 |
ES2317219T3 (es) | 2009-04-16 |
CA2561509C (en) | 2012-08-28 |
CN1938028A (zh) | 2007-03-28 |
DE602005011113D1 (de) | 2009-01-02 |
EP1736157A1 (en) | 2006-12-27 |
PT1736157E (pt) | 2008-12-31 |
ATE414516T1 (de) | 2008-12-15 |
JPWO2005094826A1 (ja) | 2008-02-14 |
KR20060132953A (ko) | 2006-12-22 |
JP4882744B2 (ja) | 2012-02-22 |
US20080275074A1 (en) | 2008-11-06 |
EP1736157B1 (en) | 2008-11-19 |
TW200533355A (en) | 2005-10-16 |
EP1736157A4 (en) | 2007-06-13 |
CA2561509A1 (en) | 2005-10-13 |
CN100586434C (zh) | 2010-02-03 |
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