WO1996022276A1 - Derives d'ethylamine et medicaments - Google Patents

Derives d'ethylamine et medicaments Download PDF

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Publication number
WO1996022276A1
WO1996022276A1 PCT/JP1996/000086 JP9600086W WO9622276A1 WO 1996022276 A1 WO1996022276 A1 WO 1996022276A1 JP 9600086 W JP9600086 W JP 9600086W WO 9622276 A1 WO9622276 A1 WO 9622276A1
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Prior art keywords
ethylamine
dimethyl
compound
elemental analysis
acid
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PCT/JP1996/000086
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English (en)
Japanese (ja)
Inventor
Masao Murase
Kozo Hamada
Tetsuo Asaki
Original Assignee
Nippon Shinyaku Co., Ltd.
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Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to AU44589/96A priority Critical patent/AU4458996A/en
Publication of WO1996022276A1 publication Critical patent/WO1996022276A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals

Definitions

  • the present invention provides an ethylamine derivative having a 5-opioid receptor agonist action and useful as a medicine.
  • Obioid refers to a substance that has a morphine-like pharmacological action and binds to the obioid receptor.
  • Opioid receptors are classified into three subtypes, ⁇ 5, ⁇ ), and contribute to inflammation, immunity, blood pressure, cerebral protection, etc. through different receptor subtypes.
  • the Obioid receptor agonist is more painful but dependent.
  • Obioid receptor agonists are also known to contribute to immune suppression.
  • the ⁇ -Obioid receptor agonist has a tt pain effect but is less dependent, and is being developed as a pain medicine.
  • the ⁇ -Obioid receptor agonist contributes to the enhancement of immunity in addition to the painful action.
  • the / i and ⁇ 5 obiooid receptors contribute to central urinary control.
  • DPDPE is known as a typical example of peptide agonists with high selectivity for the Obioid receptor, but is currently used as a reagent because it is degraded in the body by intravenous or oral administration. It is just being done.
  • Obioid receptors 5 Obioid receptors :!
  • the only known non-peptide agonists are the tetracyclic SB 205607, TAN-67, difluoromethylbiperazinine conductors BW373-U86 and SNC 80.
  • compounds similar to the compound of the present invention include Refetamine hydrochloride ((-)-NN-dimethyl-1.2-diphenylethylamine hydrochloride) is known (see JP-B-36-24083).
  • Refetamine hydrochloride ((-)-NN-dimethyl-1.2-diphenylethylamine hydrochloride) is known (see JP-B-36-24083).
  • the phenyl group substituted at the 1-position of ethylamine is non-exchangeable.
  • the pharmacological properties of this drug are mainly local anesthetic effects and effects on the autonomic nervous system.
  • an ethylamine derivative in which the 1-position of ethylethylamine is substituted with catechol or lebrucinol a compound in which the amino portion of ethylamine is unsubstituted, or a compound in which only one is alkylated at alkyl
  • catechol or lebrucinol a compound in which the amino portion of ethylamine is unsubstituted
  • a compound in which only one is alkylated at alkyl
  • an ethylamine derivative in which the 1-position of ethylamine is SfII with catechol or lebrucinol is known as an intermediate for the production of pharmaceuticals or an adrenergic agonist.
  • one of the amine moieties is substituted with alkyl 3- [1- (alkylamino) -2-phenethyl] catechol derivative (CA 92: 22365; 91: 20149: 85: 56544.85: 185; 83: 43011 etc.) and 3-U- (alkylamino) -2-phenethyl] lebrucinol derivatives (CA 85: 56544 etc.) have adrenergic action, inotropic action on the heart and knee, and lipid decomposition action.
  • the amide moiety is absent and the I-position of ethylamino is a 3-hydroxyphenyl group.
  • 3- (Tamino-2-F-X-Nethyl) phenol is known as an intermediate for the production of pharmaceuticals having painful effects (CA 104: 148472; 93: 95018; 87: 84784; 84: 180286).
  • the 3-position of phenyl which is the 1-position of ethylamine, is hydroxy or an alkoxy, alkoxycarbonyl or alkenylcarbonyl derivative derived therefrom.
  • An object of the present invention is to provide an excellent compound which has a novel structure, has a low Hatin property, and has a ⁇ -Obioid receptor agonist action which is highly selective for a Obioid receptor.
  • the present inventors have synthesized various compounds having a novel structure, and the compounds represented by the following general formula (i) are excellent (a) at the time of examination.
  • the present inventors have found that the compound has an agonist function as an obioid receptor and has low toxicity, and thus completed the present invention.
  • R 1 and R 2 are the same or different and each represents an alkyl group or an alkenyl group.
  • R 3 represents an aryl group which may be substituted or an aromatic heterocyclic group which may be substituted. Such aromatic heterocyclic groups contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur.
  • R 4 represents hydrogen, acyl, alkoxycarbonyl, or a radical which may be substituted by one or two alkyls.
  • R s represents hydrogen, halogen or alkyl.
  • the chemical structure of the compound of the present invention is characterized in that The 3-position of the nil is substituted by hydroxy or an acyloxy, alkoxycarbonyloxy or rubamoyloxy derivative derived therefrom and at the same time the amine moiety is disubstituted by the same or different alkyl or alkenyl. It is in the point.
  • the alkyl is a prime or straight prime
  • 1 to 6 e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl And the like. Among them, those having a prime number of 1 to 4 are preferable.
  • Alkenyl includes straight-chain or branched-chain ones having 2 to 6 carbon atoms, such as vinyl, aryl, isobrodinyl, 2-methallyl, 2-butenyl, and 3-butenyl. be able to. Among them, those having a prime number of 2 to 4 are preferred.
  • aryl examples include those having 6 to 12 carbon atoms, for example, phenyl, naphthyl, bif Xnil and the like.
  • aromatic heterocyclic group examples include a 5- to 6-membered ring containing at least one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a bond to a carbon atom in a fused form thereof. Can be used.
  • Specific examples of the aromatic heterocyclic group include, for example, 3- or 4-pyridyl, 2-, 3- or 6-benzofuranyl, 2-, 3- or 6-quinolyl, or 5- or 6-benzocenyl, etc.c
  • Such aryl group or aromatic heterocycle has at least one identical or different S-substituent at any position fi. You may.
  • Such S substituents include alkyl, aryl, alkoxy, aryloxy, alkylthio, Selected from the group consisting of hydroxyalkyl, alkoxyalkyl, trifluoroalkyl, acyl, hydroxy, chloro, rhogen, cyano, carboxy, alkoxycarbonyl optionally substituted with halogen, or alkyl, aralkyl and alkoxy. And carbamoyl or sulfamoyl which may be substituted by one or two identical or different at ⁇ groups.
  • alkyl, aryl, alkoxy, aryloxy, alkylthio, hydroxyalkyl, alkoxyalkyl, trifluoroalkyl, acyl, alkoxycarbonyl, aralkyl, and halogen contained in these a groups or substituents are those described above. Can be mentioned.
  • alkoxy examples include straight or branched ones having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-ethoxy, tert-butoxy and the like.
  • the above aryls can be selected from the above.
  • alkylthio examples include straight-chain or branched ones having 1 to 4 carbon atoms, such as methylthio, ethylthio, n-bromovirthio, isopropylthio, ⁇ -butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like. Can be mentioned.
  • alkyl of the hydroxyalkyl examples include those described above. Specific examples thereof include hydroxymethyl, hydroxyethyl, hydroxybu mouth building, hydroxybutyl and the like.
  • the number of carbon atoms in the straight or branched carbon is 2 to 8, for example, methoxymethyl, ethoxymethyl, methoxypropyl, methoxybutyl, methoxethyl, methoxydibutyl and the like.
  • Trifluoroalkyl includes carbon atoms 1 to 10
  • Examples of the acyl include formyl, alkanoyl, optionally substituted aroyl, aralkylcarbonyl, and alkenylcarbonyl.
  • Examples of the alkanol include straight-chain or branched ones having 1 to 5 carbon atoms, such as acetyl, propionyl, butyryl, isoptyryl, octyleryl, isonocyclyl, and vivaloyl.
  • Examples of aroyl include those having 7 to 11 carbon atoms, such as benzoyl and naphthoyl. Such aryls may be S-substituted with amino, alkoxy, halogen or acyloxy.
  • the aralkyl of aralkyl the aforementioned ones can be used.
  • Examples of the alkenyl of alkenylcarbonyl include those described above.
  • alkoxy of the alkoxycarbonyl those described above can be mentioned.
  • aralkyl examples include those having 7 to 10 carbon atoms, for example, benzyl, phenethyl, phenylbrovir, and phenylxylbutyl.
  • Halogen includes chlorine, fluorine, bromine and iodine.
  • R 1 and R 2 alkyl having 1 to 4 carbon atoms is preferable. Methyl is preferred.
  • R 3 a substituted aryl is preferred, particularly an aryl substituted with an alkoxy, an alkoxyalkyl, an acyl, an alkoxycarbonyl or a naphthyl which may be fibrated with fluorine. Is preferred.
  • Hydrogen is preferred as R réelle
  • the active substance of the compound of the present invention is preferably a water cord, and more preferably a blood drag to enhance the portability.
  • R is preferably acyl, alkoxycarbonyl, or rubamoyl optionally substituted with monovalent or two alkyls.
  • Salts of the compound ( ⁇ ) included in the present invention include, for example, salts of inorganic acids such as hydrochloric acid, acid, definite acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and the like, or hydrochloric acid, tartaric acid, lactic acid, Examples thereof include salts of organic acids such as citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid.
  • the salt having a carboxy group as the ffi group include metal salts such as sodium, potassium, calcium, and aluminum.
  • the compound represented by the formula [I] according to the present invention can be produced, for example, by the following method.
  • R 1, R 2, R 3, R « and R s are as defined above.
  • R * 1 is
  • R * 1 is the protective group Ar hydroxyl substituted Ariru, X represents a halogen.
  • C method (R a is R, in the substitution For a reel)
  • R 1 , R 2 , R 1 ′, and X are as defined above.
  • R and R represent alkyl, carboxy, or alkoxycarbonyl.
  • R ′, R ′, R 3 , and R s are the same as defined above.
  • I3 ⁇ 4 represents acyl, alkoxycarbonyl, or carbamoyl.
  • R ′ and R 2 are alkyl
  • Compound [II] is subjected to an alkylation reaction, and if necessary, protected.
  • the compound [I] can be produced by removing the group.
  • the alkylation reaction of compound (1 1], aldehyde corresponding to the alkyl represented by compound [II] with R> or R a e.g., formaldehyde in the case of methyl-de, ⁇ in the case of Echiru Se Toarudehi
  • the reaction can be carried out either by a direct reaction or by reaction with an alkylating agent corresponding to the alkyl group represented by R 1 or R i.
  • the alkylation using the base agent is usually carried out in a solvent in the presence of an acid (eg, an organic acid such as formic acid-5t acid, an inorganic acid such as humic acid or hydrobromic acid). Done at 100'C.
  • an acid eg, an organic acid such as formic acid-5t acid, an inorganic acid such as humic acid or hydrobromic acid.
  • the reducing agent include sodium borohydride, sodium borohydride, lithium aluminum hydride, lithium borohydride, lithium borohydride, lithium borohydride, and the like.
  • Metal hydride diborane can be used.
  • the solvent varies depending on the reducing agent used, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and getyl ether, and acetonitril can be used.
  • the amount of the aldehyde and the reducing agent used is usually about 0.5 to 10 mol per 1 mol of the compound [II].
  • the reaction time varies depending on the starting materials, the reducing agent used, and the type of solvent, but is usually 0.5 to 24 hours.
  • the catalytic reduction method is usually carried out in a solvent at normal pressure or under pressure at 0 to 80 ° C.
  • a solvent alcohols such as methanol and ethanol, carboxylic acids such as ⁇ , esters such as ethyl ethyl K, ethers such as dioxane tetrahydrofuran, and water can be used.
  • Catalysts include palladium on carbon, Raney nickel, platinum oxide Etc. can be used.
  • the catalyst is based on 1 mol of the compound [II].
  • reaction time varies depending on the type of the starting material, the catalyst used, and the solvent, but usually 0.5 to 48 hours is appropriate.
  • Alkylation with the alkylating agent is usually performed in a solvent at about 0-100.
  • the alkylating agent an alkyl halide, a dialkyl sulfate or the like corresponding to the alkyl group is used.
  • the halogen in the alkyl halide include chlorine, bromine, and iodine.
  • the amount of these alkylating agents varies depending on the alkylating agent used, but is usually about 2 to 2.5 mol per 1 mol of compound (II).
  • the reaction is carried out in the presence of a base (eg, an inorganic base such as triamine, sodium tricarbonate, sodium bicarbonate, potassium carbonate, sodium phosphate).
  • a base eg, an inorganic base such as triamine, sodium tricarbonate, sodium bicarbonate, potassium carbonate, sodium phosphate.
  • reaction solvent examples include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dimethoxetane, getyl ether, and dioxane; hydrocarbons such as benzene, toluene, and xylene; Non-protonic polar solvents such as ⁇ , ⁇ -dimethylformamide and dimethylsulfoxide; ketones such as acetone and methylethylketone; acetonitrile or a mixture thereof
  • the reaction time is an alkylating agent to raw materials and use may vary depending on the type of the solvent, is suitably usually 30 minutes to 24 hours.
  • R, or R 2 is alkyl and the other is hydrogen
  • the deprotection reaction of the hydroxyl group can be performed by a method known per se.
  • a cyanide conductor [III] is reacted with a Grignard reagent or a lithium compound, and the protecting group is removed to form [Ia] (where R and R in the formula (I) may be R, R * Wherein R is hydrogen.
  • the Grignard reagent or lithium compound can be easily produced by a usual method.
  • the reaction is carried out in a solvent inert to the reaction at 178 to 100, preferably at 120 to 100.
  • ethers such as anhydrous tetrahydrofuran, dimethyl ether, getyl ether, diisopropyl ether, dioxane, and dimethoxetane are most preferred.
  • glymes such as ethylene glycol dimethyl ether and hydrocarbons such as benzene, toluene, xylene, n-pentane, n-hexane and petroleum ether can be used. These solvents can be used as a mixture.
  • the reaction time varies depending on the raw materials and the type of solvent used, but is usually 0.5 to 24 hours.
  • Grignard reagents and lithium compounds are usually used in an amount of 1 mol or more, preferably 1 to 3 mol, per 1 mol of the cyanogen derivative [III]. I do.
  • the deprotection reaction of a hydroxyl group can be performed by a method known per se.
  • nucleophile examples include ethylene oxide, formaldehyde, alkyl aldehyde, dialkyl ketone, N.N-dimethylformamide, acid halide, nitrogen dioxide, and chlorine dioxide.
  • Succinate S The reaction time varies depending on the starting materials and the type of solvent used, but is usually 0.5 to 24 hours. Usually, n-butyllithium is used in an amount of at least equimolar to the compound (Ib), preferably from 1.0 to 1.2 mol. It is used in an equimolar amount or more, preferably up to 2 mol, relative to the compound [Ib].
  • the deprotection reaction of a hydroxyl group can be performed by a method known per se.
  • hydroxyl group (but hydrogen) Yaa Mi amino group (!? 1, R J is hydrogen) may, if necessary, and coercive 3 ⁇ 4 with a protecting group usually used, after subjected to the reaction,
  • the protecting group can be removed by a method known per se.
  • the amino-protecting group include benzyl and benzyloquinone
  • I 2 Rubonyl, trifluoroacetyl and the like can be used.
  • the hydroxyl group methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydrobiranyl, t_butyl, benzyl, trimethylsilyl, t_butyldimethylsilyl, etc. can be used.
  • the hydroxyl group is protected with a benzyl group, it undergoes debenzylation at the same time as the contact and reduction, and becomes the hydroxyl group of the rice bran.
  • the phenol derivative [Id] (where R «is hydrogen in the formula [1]) is converted to an acid halide, an acid anhydride, or an acid in the presence of a group such as sodium hydride, triethylamine, or pyridine. Reacting with rubamic acid halide, or condensing agent such as DCCU, 3-dicyclohexyl carpoimide, WSC (water-soluble carpoimide / tolethyl-3- (3-dimethylaminobutyral pill carpoimide))
  • the compound [Ie] can be produced by reacting with carboxylic acid, carbamic acid, etc.
  • the reaction can be carried out by reacting anhydrous ethers such as tetrahydrofuran and getyl ether, dichloromethane, chloroform, etc.
  • the reaction is carried out at ⁇ 40 to 70, preferably at 20 to 25.
  • the reaction time varies depending on the raw materials and the type of solvent used, but is usually 0. . Five ⁇ 24 hours is appropriate, such as sodium hydride, triethylamine, pyridine, DCC,
  • (Ie) can also be synthesized by adding a phenol derivative [Id] to an isocyanate.
  • the reaction is carried out in a solvent such as toluene, benzene, getyl ether, NN-dimethylformamide or in a solvent.
  • the reaction is carried out at 0-150'C.
  • the reaction time varies depending on the raw materials and the type of solvent used, but is usually 0.5 to 24 hours.
  • Acids, bases, or cuprous chloride (CuCl) may be used as a catalyst.
  • the isocyanate is used in an equimolar amount or more, preferably 1.0 to 1.2 mol, based on the phenol derivative [Ie].
  • R s , R 41 , Ar, and X are as defined above.
  • a compound is obtained by adding a Grignard reagent or an organic lithium reagent to the benzonitrile derivative [IV], and further passing the adduct.
  • [IIa] (wherein, in the formula [II], R ⁇ 3 may be S), and R ⁇ 3 is (hydroxyl-protecting group).
  • the addition reaction of the Grignard reagent or organolithium reagent to the benzonitrile derivative (IV) is carried out in a solvent inert to the reaction. It is carried out at 78-100, preferably at 78-50'C.
  • ethers such as anhydrous tetrahydrofuran, getyl ether, diisopropyl ether, dioxane, and dimethoxetane are most preferable.
  • glides such as ethylene glycol dimethyl ether, and hydrogen peroxides such as benzene, toluene, xylene, n-pentane, n-hexane and petroleum ether can also be used.
  • These solvents can be used as a mixture.
  • the reaction time varies depending on the starting materials and the type of solvent used, but is usually 0.5 to 10 hours.
  • the Grignard ⁇ drug ⁇ organic lithium reagent is usually used in an amount of 1 mol or more, preferably 1 to 10 mol, per 1 mol of the benzonitrile derivative [IV].
  • a reducing agent for example, a metal hydride compound such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or lithium borohydride can be used.
  • the amount of the reducing agent to be used is generally 0.5 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound [IV].
  • the reaction time varies depending on the raw materials and the type of solvent used, but is usually 0.5 to 24 hours.
  • R ′, R 2 , R s , and R * 3 are as defined above.
  • a compound [III] is produced by reacting a benzaldehyde derivative [V] with a cyanide compound in the presence of an amino compound [VI]. be able to.
  • the amino compound is in the form of a free radical or an acid addition salt, and is used in an amount of 1 to 10 mol per 1 mol of the compound [V].
  • the cyanide compound for example, potassium cyanide, sodium cyanide, hydrogen cyanide, copper (I) cyanide, acetate cyanide hydride and the like are used. Use 1 to 10 moles.
  • reaction solvent water, alcohols such as methanol and ethanol, and other solvents such as dioxane, pyridine, toluene, benzene, ethyl ether and ether can be used. These solvents can be used as a mixture.
  • the reaction is carried out at 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C., which varies depending on the type of the starting material and the solvent used, and the reaction time is suitably 1 to 24 hours.
  • the adduct (VII) is treated with a base such as lithium diisopropylamide, reacted with a benzyl halide derivative, and then hydrolyzed with an acid to give a benzyl furketone derivative
  • a base such as lithium diisopropylamide
  • a benzyl halide derivative reacted with a benzyl halide derivative
  • hydrolyzed with an acid to give a benzyl furketone derivative
  • This reaction is carried out in a solvent inert to the reaction at a temperature of from 1 to 100, preferably from 1 to 78'C to 50'C.
  • ethers such as trahydrofuran, getyl ether, disoviril ether, dioxane, dimethoxetane, etc.
  • solvents can be used in combination. In general, 0.5 to 24 hours is appropriate, depending on the type of carboxylic acid, etc.
  • a suitable group such as lithium diisopropylamide is 1 to 5 mol per 1 mol of the adduct [VII].
  • the benzyl halide derivative is preferably used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the adduct [VII]
  • the hydrolysis with an acid is performed in an amount of 5 to 10 mol. Use hydrochloric acid in excess.
  • the compound [IIb] can be produced by adding an amine to the benzylfurketone derivative (VIII) and subjecting it to a reduction reaction.
  • the addition reaction of the amine to the derivative [V! II] is carried out in a solvent inert to the reaction at 0 to 100, preferably 20 '(: to 80'C.
  • alcohols such as methanol, ethanol, propanol, isopropanol, and n-butanol.
  • the amines ammonium formate, ammonium phosphate, ammonium chloride and the like can be used.
  • the reaction time varies depending on the starting materials and the type of solvent used, but is usually 0.5 to 24 hours.
  • Amines are usually benzylphenol ketone derivatives
  • (VIII) 1 mole or more, preferably 1 to 10 moles per mole of the adduct
  • the reduction reaction of the adduct is carried out in the same solvent as the above-mentioned addition reaction in the presence of a reducing agent at 20 to 150.
  • the reducing agent include metal hydrides such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and lithium borohydride.
  • the amount of the compound to be used is generally 0.5 to 10 mol, preferably up to 5 mol, per 1 mol of compound (VIII)
  • the reaction time varies depending on the raw materials and the kind of the solvent used, but is usually 0.5 to 24 mol. Time is appropriate.
  • a starting material in which R 3 is aryl can also be produced by the following method.
  • the imine derivative [IX] can be produced by adding a free base or acid addition salt of an amide to the benzaldehyde derivative (Va).
  • the amine in the form of a free base or an acid addition salt is used in an amount of 1 to 10 moles per mole of the benzaldehyde derivative (Va), and the reaction solvent is water, alcohol such as methanol or ethanol. , Acetonitrile, tetrahydrofuran, etc. Can be used. These solvents can be used as a mixture.
  • the reaction is carried out at 0 to 100, preferably 20'C to 80'C, depending on the raw materials and the type of solvent used, and the reaction time is suitably 0.5 to 24 hours.
  • the compound (IIc) can be produced by adding a Grignard reagent or an organolithium reagent to the imine derivative [IX].
  • the Grignard addition reaction of the drug or the organolithium reagent is carried out in a solvent inert to the reaction at a temperature of 1 78 '(: ⁇ 100, preferably -78 ⁇ ( ⁇ 50'C.
  • ethers such as anhydrous tetrahydrofuran, dimethyl ether, diisopropyl ether, dioxane, and dimethoxetane, as well as limes such as ethylene glycol dimethyl ether, benzene, toluene, xylene, n-pentane, Hydrogens such as n-hexane and petroleum ether can also be used, and these solvents can be used in combination. The amount depends on the type of raw material and the solvent used, or it is usually appropriate for 0.5 to 10 hours.
  • the Grignard reagent or organolithium reagent is usually equimolar or more per mole of benzaldehyde conductor (Vb). Preferably, 1 to 10 moles are used.
  • a starting material in which the compound (IIb) (in the formula [II], is R "(hydroxyl-protecting group) can also be prepared by the following method.
  • the phenylacetic acid conductor [X] can be converted to a compound [XI] by esterification by dehydration reaction with an alcohol or the like, and then retaining a phenolic hydroxyl group.
  • the protecting group benzyl, methoxymethyl, methoxyethoxymethyl and the like are suitably used.
  • Compound [I] has an asymmetric carbon and has optical isomers, and each isomer and a mixture thereof are included in the present invention. It is usually obtained in racemic form. These racemates have pharmacological activity as they are, but can be separated into the respective isomers if desired.
  • a mixture of isomers can be obtained by a known optical resolution method, for example, optically active rubonic acid (eg,)-or (-)-tartaric acid, hi)-or (-)-lingoic acid, etc.) Can be separated by optically active sulfonic acid (eg, (+) ⁇ camphorsulfone ⁇ etc.) and separated by crystallization, physically separated using an optically active column, etc.
  • optically active waste compound [II], [III], [Ib] or [Id] S configuration or R configuration ft
  • the compound (1) of the present invention can form the above-mentioned ⁇ ⁇ by a known method.
  • the hydrochloride of the compound [I] of the present invention can be obtained by converting the compound of the present invention [I] to an alcohol of hydrogen hydride. Alternatively, it can be obtained by dissolving in ft-ethyl acetate solution.
  • a compound having a carboxy can form a clay by a known method.
  • the clay include alkali metal salts such as sodium * and potassium, and alkaline metals such as calcium salts.
  • the alkali metal of the compound of the present invention (I) is preferably prepared by adding one equivalent of sodium hydroxide or potassium hydrate in an alcoholic solvent to the compound of the present invention [I] having carboxy.
  • the alkaline earth metal of the compound [I] of the present invention can be obtained by dissolving the alkali gold metal produced by the above method in water, methanol, ethanol or a mixed solvent thereof. And can be obtained by adding 1 equivalent of calcium iodide, etc.
  • the present invention also includes a solvate (including a hydrate) of the compound [I] of the present invention or a salt thereof.
  • the solvate can usually be obtained by recrystallizing the solvate from the corresponding solvent or three or more mixed solvents containing the corresponding solvent.
  • the hydrate of the compound [I] of the present invention It can be obtained by recrystallizing compound [I] from hydroalcoholic alcohol.
  • the compound (1) of the present invention may take a polymorphic form, which is also included in the present invention.
  • the target compound [I] produced in this manner can be converted to a free base form, a added clay form or a gold clay form by means known per se, for example, It can be simply manufactured by phase transfer, solvent extraction, crystallization, fractional distillation, chromatography and the like.
  • the compound of the present invention has a ⁇ -Obioid receptor agonist action as described later, a drug having few side effects such as dependence, respiratory depression or constipation, for example, painkillers, immunostimulants, anti-AIDS drugs It can be used as a therapeutic agent for urinary frequency and urinary incontinence.
  • the compound of the present invention when administered as a medicament, the compound of the present invention may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example,
  • composition containing 0.1% to 99.5, preferably 0.5% to 90%.
  • the pharmaceutical composition is desirably administered in a unit dosage form.
  • the pharmaceutical composition of the present invention can be administered by injection, compositional administration, topical administration (such as transdermal administration), or transdermally. Of course, they are administered in dosage forms suitable for these administration methods. For example, oral administration is particularly preferred.
  • the dosage as a medicament is preferably adjusted in consideration of the patient's age, weight, etc., the administration route, the nature and extent of the disease, etc.
  • 1 Per day in the range of 0.1 l / g to 100 mg human, preferably in the range of 500 ug to 30 mg human. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.
  • ft Oral administration is in solid or liquid dosage units, for example, powders, losers, syrups, sugar coatings, capsules, laxatives, agents, lusters, sieves, drops, sublingual tablets It can be performed by other dosage forms.
  • the powder is produced by making the active substance finely divided. Powders are prepared by commingling the active substance with a quick bulk and then combining with the similarly refined pharmaceutical carrier, for example, »flour, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, coloring agents, coloring agents, fragrances and the like may be mixed.
  • the similarly refined pharmaceutical carrier for example, »flour, edible carbohydrates such as mannitol, and the like.
  • flavoring agents, preservatives, coloring agents, coloring agents, fragrances and the like may be mixed.
  • Capsule ⁇ ⁇ should be filled with powder or powdered powder or powdered powder as described above or saccharified as described in ⁇ ⁇ above into capsule hull such as gelatin capsule. It is manufactured by Lubricants and glidants, such as loidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, are mixed with the powdered material and then * You can also perform the operation. Add disintegrants and solubilizers, such as carboxymethylcellulose, carboxymethylcellulose calcium, high-density hydroxypropyl pillcellulose, croscarmellose sodium, carboxymethylsodatinum, calcium carbonate, and sodium This can improve the efficacy of the drug when the capsule is taken.
  • Lubricants and glidants such as loidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, are mixed with the powdered material and then * You can also perform the operation.
  • the fine powder of this product is mixed with vegetable oil, polyethylene glycol, glyce
  • the suspension is suspended in a detergent or a surfactant and wrapped in a gelatin sheet to form a soft capsule.
  • Powder mixtures can be obtained by mixing the appropriately powdered material with the above-mentioned diluents and bases and, if necessary, binding agents (eg, carboxymethylcellulose sodium, methylcellulose, hydroxymethyl virmethylcellulose, gelatin, polyethylene Vinylpyrrolidone, polyvinyl alcohol, etc.), dissolution retarders (eg, varaffin), resorbents (eg, 3 ⁇ 4) and adsorbents (eg, bentonite, kaolin, dicalcium phosphate)
  • the powder mixture is first moistened with a binder such as syrup, »powder paste, gum arabic, cellulose or a solution of a high-molecular substance, mixed with « Azusa, and then dried and immobilized.
  • binding agents eg, carboxymethylcellulose sodium, methylcellulose, hydroxymethyl virmethylcellulose, gelatin, polyethylene Vinylpyrrolidone, polyvinyl alcohol, etc.
  • dissolution retarders eg, varaffin
  • the powder is first impregnated and then obtained. It is also possible to crush the slag in the form of a slag and turn it into a kidnapper.
  • the condyla made in this way can be made by adding stearinic acid, stearinic acid, talc, mineral oil and other oils as lubricants. The mixture thus lubricated is then tableted, and the thus produced material can be coated with a film coating.
  • the drug may be directly tableted after being mixed with a fluid inert carrier without going through the step of II ablation and slag formation as described above.
  • solutions, syrups, elixirs etc. It can be in dosage unit form »so that a given amount contains a certain amount of the drug.
  • Syrup is produced by dissolving the compound in an aqueous solution of a suitable flavor
  • elixir is produced by using a non-toxic alcoholic carrier.
  • Formulations are formulated by dispersing the compound in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, boroxyethylene sorbitol esters
  • preservatives eg, ethoxylated isostearyl alcohols, boroxyethylene sorbitol esters
  • flavoring agents eg, palmit oil, saccharin
  • dosage unit formulations for oral administration may be microbubulated.
  • the formulation can also provide extended or sustained release by extending the working time by coating or embedding in polymers, waxes and the like.
  • Intrathecal administration can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, solution or form ss.
  • a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection for example, solution or form ss.
  • a fixed amount of the compound is suspended or dissolved in a non-toxic liquid carrier suitable for the purpose of injection, such as an aqueous or oily medium, and the aqueous solution or solution is then sterilized.
  • a non-toxic liquid carrier suitable for the purpose of injection such as an aqueous or oily medium
  • Non-toxic salts or salt solutions may be added to make the injection isotonic.
  • stabilizers, preservatives, emulsifiers and the like can be used in combination.
  • compounds can be dissolved or insoluble in low-melting water, such as solids such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol, registered trademark), and high-esters (such as palmitic) (Myristyl formate)) and suppositories produced by dissolving or dissolving them in a mixture thereof.
  • low-melting water such as solids such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol, registered trademark), and high-esters (such as palmitic) (Myristyl formate)) and suppositories produced by dissolving or dissolving them in a mixture thereof.
  • reaction solution was reduced in pressure to half or less, added with 100 ml of a saturated aqueous solution of NaHCt, adjusted to pH 8 and extracted with ethyl acetate (50 ml x 3), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. did.
  • the obtained yellow oil was purified by silica gel column chromatography (CHCl,: MeOH-50: 1) to give 7.4 g (yield 37%) of the desired compound as a yellow oil:shire
  • 8-Amino-2-naphthol was subjected to a Schiemann reaction to obtain 8-fluoro-2-naphthol. Then, it was reacted with trifluoromethansulfonic anhydride in a pyridine solvent to give a triplet.
  • phenol is dissolved in a mixed solution of diamine, radium diacetate, DPPP (1,3-Bis (diphenylphosphino) propane) and triethylamine. It was reacted with flammable to obtain 8-fluoro-2-naphthoic acid methyl ester. This was centrifuged with diisobutylaluminum hydride and Jfi-treated with thionyl chloride to synthesize 2-chloromethyl-8-fluoronaphthalene.
  • the raw material 4-ethoxymethylbenzyl chloride was synthesized by reacting commercially available a.a'-dichloro-p-xylene with sodium ethoxide in an ethanol solvent. ,
  • the mixture was diluted with 150 ml, washed with 100 ml of water, and 200 ral of saturated NaHCO aqueous solution.
  • the ether was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 7 C-)-N, N-dimethyl-toluene (3-hydroxyl-cynyl) -2- (2-naphthyl) ethylamine hydrochloride and) -NN-dimethyl-1- (3-hydroxylphene) Nil)-2- (2-naphthyl) ethylamine diacid
  • Example 1 (+)-N, N-dimethyl-l- (3-hydroxyphenyl) -2- (4-isopropoxy-xynyl) ethylamine — diacid and (-)- ⁇ , ⁇ -dimethyl-1 -(
  • Tttt C. 64.38; H. 6.60; N. 4.17
  • Example 4 The free base of 5 was subjected to optical resolution by preparative chiral HPLC (chiral cell 0D column, n-hexane: 2-propanol: getylamine-95: 5: 0.1), and then as a hydrochloride (+) The body and (one) body were obtained.
  • the target compound was obtained by operating the compound obtained in (1) in the same manner as in Example 1 (2) and (3).
  • Example 5 6 The compounds of Examples 56 to 60 were synthesized in the same manner as in Example 55.
  • Example 5 6 The compounds of Examples 56 to 60 were synthesized in the same manner as in Example 55.
  • Example 5 6 The compounds of Examples 56 to 60 were synthesized in the same manner as in Example 55.
  • Example 63 to 65 The compounds of Examples 63 to 65 were synthesized in the same manner as in Example 62.
  • Example 6 3 The compounds of Examples 63 to 65 were synthesized in the same manner as in Example 62.
  • Example 6 3 The compounds of Examples 63 to 65 were synthesized in the same manner as in Example 62.
  • Example 6 3 The compounds of Examples 63 to 65 were synthesized in the same manner as in Example 62.
  • the target compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 7.
  • (+)-NN-dimethyl-1- (3-hydroxyphenyl) -2- (2-naphthyl) ethylamine obtained in Example 7 was dissolved in 3 ml of pyridine, and 3 ml of anhydrous acetic acid was added.
  • the reaction solution was poured into ice water, saturated aqueous NaHCO was added, and the mixture was made alkaline, extracted with ethyl acetate, washed with water, and dried over anhydrous MgS (h.
  • the residue was purified by column chromatography (CHC1 Me0H O0: l) to give a pale yellow oil (0.22 g).
  • Example 7 0.3 g of (0-NN-dimethyl-1- (3-hydroxyphenyl) -2- (2-naphthyl) ethylamine obtained in Example 7 was dissolved in 3 ml of tetrahydrofuran, and triethylamifuran was dissolved. 0.2 g of Virgin yl chloride and 0.14 g of After dropping the trahydrofuran solution at room temperature, the mixture was stirred at ttt for 24:00. Water was added to the reaction solution, and the mixture was extracted with acid ethyl.
  • Example 46 (- ⁇ , (-dimethyl-2- (4-ethoxymethylphenyl) -1- (3-hydroxydiphenyl) ethylamine
  • To 300 mg of toluene was added 170 mg of ⁇ -propyl succinate, dissolved in 5 ml of toluene, and heated under reflux for 4 hours, the toluene was distilled off, and the residue was subjected to silica gel chromatography (chloroform: methanol- 50: 1) to give 370 rag of the target compound as a colorless oil, which was dissolved in 6 ml of ⁇ ethyl, 2 ml of a 21% HCl-AcOEt solution was added, and the solvent was distilled off under reduced pressure to obtain hydrochloric acid clay
  • Example 47 Under an argon stream, 62 mg of 60% hydrogenated sodium chloride was added to 1 ml of dry tetrahydrofuran, and the solution obtained in Example 47 was used.
  • Tttt C, 64.03; H. 7.16; N. 3.56
  • Example 4 N-dimethyl-2- (4-ethoxymethylphenyl) -toluene (3-hydroxydiphenyl) ethylamine 300 mg and isatoic anhydride 196 mg in NN-dimethylformamide solution 3 ml. 122 ng of 4-dimethylaminopyridine was added, and the mixture was stirred at 80'C for 4 hours. The mixture was allowed to cool to room temperature, and the reaction tt was diluted with water and extracted with ethyl acetate. The organic ⁇ was washed with water, dried over anhydrous MgS0, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (CHCl,: MeOH-40: l) to give the desired compound.
  • the target compound was obtained in the same manner as in Reference Example 3 and Example 1 using 3- (methoxymethoxy) -4-methylbenzaldehyde.
  • 3-Chloro-5-methoxif 15.00 g of t-nor was dissolved in pyridine, and 29.36 g of trifluoromethanesulfonic anhydride was added dropwise under ice-cooling. After filtrating the chamber fi and stirring for 2 hours, the reaction mixture was diluted with water and extracted with ether.o 10X Hydrochloric acid, washed with water, dried over anhydrous MgS (, and the solvent was distilled off. was gotten.
  • 3-chloro-5-methoxyphenyl trifluoromethanesulfonate 27.34 g, palladium (II) SlE acid 2.llg, 1.3-bis (diph: t-nylphosphino) propane 3.88 g, triethylamine 35 m 200 ml of ethanol, 1,2-dichloroethane, lOOral and 180 ml of dimethylsulfoxide were mixed, and carbon monoxide was bubbled in. The mixture was heated to 70'C, stirred for 2 hours, and then bubbling was stopped.
  • reaction mixture was diluted with water, extracted with ether, washed with 10 hydrochloric acid, saturated aqueous NaHCO, aqueous solution, and water, dried over anhydrous MgSt, and the solvent was distilled off.
  • -( ⁇ -hexane: ethyl acetate 4: 1) to give 17.67 g of a pale yellow oil.
  • the starting material 2-chloro-5-hydroxybenzaldehyde
  • the starting material was synthesized according to the method of HH Hodgson et al. [J. Chem. So. 149 (1926)] and used in Reference Example 3 and Example 1. Similarly, the target compound was obtained.
  • Example 1 (2) The compound obtained in Example 1 (2) was heat-treated with hydrobromic acid, and the target compound was obtained as a hydrochloride by a conventional method.
  • Rat brain (excluding cerebellum) or guinea pig cerebellum is homogenized in Tris-HCl buffer (50 mM, pH 7.4), centrifuged at 40,000 g for 20 minutes, and the precipitate is suspended in the buffer. Chrysanthemums were used as food.
  • Rat brain (excluding the cerebellum) was homogenized in Tris hanic acid buffer solution (50 mM, pH 7.4), and after a quick centrifugation for 40.0008 for 20 minutes, the precipitate was suspended in the buffer solution to obtain a membrane product.
  • Rat brain membranes The inhibitory effect of test substance on [J H] Narutoruin Doll (0.2 nM) binding to ⁇ , Na * ( ⁇ ) presence or transliteration solid under lurking standing.
  • the sodium coefficient of the test substance was determined by dividing the Ki value of test item »in the presence of N by the Ki value in the absence of Na *. The results are shown in Table 1.
  • Table 1 Obioid receptor nucleus inhibitory action Co-drug pKi (M) ⁇ -S selective Na
  • the compound of the present invention exhibited a high affinity for the 5-obideoid receptor with a Ki value of ⁇ ⁇ or less. Furthermore, it showed 41-340 times 5-selectivity as compared with the u-iobioid receptor. It had high 5-affinity and selectivity that was equal to or higher than that of DPDPB. Since both ⁇ affinity and selectivity are high, it is suggested that the compound of the present invention can be used as an immunostimulant and / or a therapeutic agent for pollakiuria / urinary incontinence.
  • the compound of the present invention binds extremely strongly to the 5-obideoid receptor as compared to the control compound, and exhibits agonist activity. Therefore, the compound of the present invention is independent of pain, an immunostimulant, As a urination control agent, It can be used for treatment and prevention of various types of pain, immunodeficiency, frequent urination and urinary incontinence.

Abstract

Composé de formule générale (I) ou un de ses sels pharmacocompatible, ou l'un de ses hydrates, dans laquelle R1 et R2 représentent chacun indépendamment alkyle ou alcényle; R3 représente aryle facultativement substitué ou un groupe hétérocyclique facultativement substitué comportant au moins un hétéroatome sélectionné dans le groupe constitué de l'oxygène et du soufre dans l'hétérocycle aromatique; R4 représente hydrogène, acyle, alcoxycarbonyle ou facultativement carbamoyle à substitution mono ou di-alkyle facultative; et R5 représente hydrogène, du alogéno ou alkyle.
PCT/JP1996/000086 1995-01-20 1996-01-19 Derives d'ethylamine et medicaments WO1996022276A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1055665A1 (fr) * 1999-05-28 2000-11-29 Pfizer Products Inc. Dérivés de la 3-(3-hydroxyphényl)-3-amino-propionamide
WO2001040225A1 (fr) * 1999-11-30 2001-06-07 Toray Industries, Inc. Traitement curatif ou preventif pour polyurie ou incontinence urinaire
WO2001047866A1 (fr) * 1999-12-27 2001-07-05 Grünenthal GmbH Composes 1-2-naphtol/bases de mannich substitues
WO2002059074A1 (fr) * 2001-01-26 2002-08-01 Sankyo Company, Limited Analogue de benzylamine
WO2002080918A1 (fr) * 2001-04-02 2002-10-17 Toray Industries, Inc. Agent therapeutique ou prophylactique en cas de miction frequente ou d'incontinence urinaire
WO2005033073A2 (fr) 2003-10-01 2005-04-14 Adolor Corporation Derives heterocycliques spirocycliques et leurs methodes d'utilisation
US7282508B2 (en) 2001-10-15 2007-10-16 Janssen Pharmaceutica N.V. Substituted 4-phenyl-4-(1H-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta opioid agonists
US7576207B2 (en) 2006-04-06 2009-08-18 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US7598261B2 (en) 2005-03-31 2009-10-06 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
EP2399577A1 (fr) 2006-09-12 2011-12-28 Adolor Corporation Utilisation de composés spiro pour améliorer la fonction cognitive

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50105677A (fr) * 1974-01-29 1975-08-20

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50105677A (fr) * 1974-01-29 1975-08-20

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1055665A1 (fr) * 1999-05-28 2000-11-29 Pfizer Products Inc. Dérivés de la 3-(3-hydroxyphényl)-3-amino-propionamide
WO2001040225A1 (fr) * 1999-11-30 2001-06-07 Toray Industries, Inc. Traitement curatif ou preventif pour polyurie ou incontinence urinaire
US6774136B2 (en) 1999-12-27 2004-08-10 Gruenenthal Gmbh Substituted 1 and 2 naphthol mannich bases
WO2001047866A1 (fr) * 1999-12-27 2001-07-05 Grünenthal GmbH Composes 1-2-naphtol/bases de mannich substitues
US7202242B2 (en) 1999-12-27 2007-04-10 Gruenenthal Gmbh Substituted 1 and 2-naphthol Mannich bases
US7504393B2 (en) 2001-01-26 2009-03-17 Btg International Limited Benzylamine analogues
US7504437B2 (en) 2001-01-26 2009-03-17 Btg International Limited Benzylamine analogues
US7514475B2 (en) 2001-01-26 2009-04-07 Btg International Limited Benzylamine analogues
WO2002059074A1 (fr) * 2001-01-26 2002-08-01 Sankyo Company, Limited Analogue de benzylamine
WO2002080918A1 (fr) * 2001-04-02 2002-10-17 Toray Industries, Inc. Agent therapeutique ou prophylactique en cas de miction frequente ou d'incontinence urinaire
US7282508B2 (en) 2001-10-15 2007-10-16 Janssen Pharmaceutica N.V. Substituted 4-phenyl-4-(1H-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta opioid agonists
US7338962B2 (en) 2003-10-01 2008-03-04 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
WO2005033073A2 (fr) 2003-10-01 2005-04-14 Adolor Corporation Derives heterocycliques spirocycliques et leurs methodes d'utilisation
US7638527B2 (en) 2003-10-01 2009-12-29 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US7906646B2 (en) 2003-10-01 2011-03-15 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US8071611B2 (en) 2003-10-01 2011-12-06 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US7598261B2 (en) 2005-03-31 2009-10-06 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US8022060B2 (en) 2005-03-31 2011-09-20 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
US7576207B2 (en) 2006-04-06 2009-08-18 Adolor Corporation Spirocyclic heterocyclic derivatives and methods of their use
EP2399577A1 (fr) 2006-09-12 2011-12-28 Adolor Corporation Utilisation de composés spiro pour améliorer la fonction cognitive

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