[go: up one dir, main page]

WO1993003011A1 - Derive d'uree - Google Patents

Derive d'uree Download PDF

Info

Publication number
WO1993003011A1
WO1993003011A1 PCT/JP1992/000993 JP9200993W WO9303011A1 WO 1993003011 A1 WO1993003011 A1 WO 1993003011A1 JP 9200993 W JP9200993 W JP 9200993W WO 9303011 A1 WO9303011 A1 WO 9303011A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
phenyl
general formula
ethyl
pyrrolidinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1992/000993
Other languages
English (en)
Japanese (ja)
Inventor
Makoto Takeuchi
Kazuhisa Takayama
Kenichi Onda
Hiroyuki Motoie
Yasuo Isomura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yamanouchi Pharmaceutical Co Ltd
Original Assignee
Yamanouchi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co Ltd filed Critical Yamanouchi Pharmaceutical Co Ltd
Publication of WO1993003011A1 publication Critical patent/WO1993003011A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a perrea derivative or a salt thereof useful as a medicament having an analgesic action or the like.
  • analgesics are used gradually from weak agonists, and finally morphine, a strong agonist, is used. It is well known that morphine forms dependence.
  • the present inventors have conducted intensive studies and as a result have shown a potent analgesic activity comparable to that of morphine, and can achieve a clinical purpose as a selective ⁇ -receptor agonist with no dependence and low toxicity. This led to the completion of the present invention.
  • the compound of the present invention is clearly distinguished from the above-mentioned known compounds in chemical structure. It is low-toxic without the dependence observed for highly potent drugs such as morphine. In addition, it is a novel compound that has good oral absorption and long-lasting activity—it has receptor agonist activity.
  • the present invention relates to a novel urea derivative represented by the general formula (I) or a salt thereof.
  • R l , R 2 lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, or a group in which R 1 and R 2 can form a ring together with a nitrogen atom.
  • R 3 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, or R 3 and R ⁇ are taken together as a lower alkylene group, a lower alkenylene group, or represented by the formula i.
  • Base is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, or R 3 and R ⁇ are taken together as a lower alkylene group, a lower alkenylene group, or represented by the formula i.
  • R 6 optionally substituted phenyl group
  • R 3 and R 4 may be taken together to form a lower alkylene group, a lower alkenylene group or a lower alkylene group which may have a substituent;
  • FIG. 1 is a graph comparing the duration of the analgesic effect of the compound of the present invention (the compound of Example 21) and the comparative compound (the compound of EP261, 842 Example 1) in the acetic acid writhing method.
  • the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, as the “lower alkyl group”, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group Group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl
  • the “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-probenyl group, an isopropenyl group, a 1-butenyl group.
  • 1,2-butenyl group, 3-butenyl group 2-methyl-1-propenyl group, 2-methylaryl group, 1-methyl-1-propenyl group, 1-methylaryl group, 1,1-dimethylvinyl group, 1-pentenyl group , 2—pentenyl group, 3— Pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl 3-butenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethylaryl group, 1,2-dimethyl-1-propenyl group, 1, 2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl 2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group
  • a “lower alkynyl group” is a linear or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, an I-butynyl group, a 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, I-hexynyl group, 2-hexynyl group, 3-hexynyl group, A hexynyl group, a 5-hexynyl group and the like are preferable, and
  • the “lower alkylene group” is a straight or branched carbon chain having 2 to 6 carbon atoms, and specifically includes, for example, an ethylene group, a propylene group, a tetramethylene group, a 2-methyltrimethylene group, -Echillechille Pentamethylene group, 1,2-getylethylene group and the like.
  • the “lower alkenylene group” is a straight or branched carbon chain having 2 to 6 carbon atoms, and specific examples thereof include a vinylene group, a propenylene group, a butenylene group, a 1-methylvinylene group, — A methylpropylenylene group and the like.
  • cycloalkyl group includes those having 3 to 8 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • Examples of the group in which R 1 and R 2 can form a ring together with a nitrogen atom include 5- to 7-membered nitrogen-containing saturated groups such as a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, and a thiomorpholino group. And a heterocyclic group.
  • Examples of the “carbocyclic group” include a phenyl group, a naphthyl group, an indenyl group, a fluorenyl group, an indanyl group, a biphenylenyl group, an ant'racenyl group, a phenanthrenyl group and the like.
  • heterocyclic group containing one or two oxygen atoms and / or sulfur atoms condensed with a benzene ring the following can be mentioned as typical ones.
  • Substituents which may be substituted on the benzene ring of these "carbocyclic group” or “heterocyclic group” include halogen atom, hydroxyl group, lower alkyl group, lower alkenyl group, lower alkoxy group, lower alkenyl oxy group.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom
  • the “lower alkoxy group” is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group.
  • Sec —butoxy group, tert —butoxy group, ⁇ Examples include benzyloxy (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, and hexyloxy group.
  • lower alkenyloxy group is a linear or branched alkenyloxy group having 2 to 6 carbon atoms. Specific examples include a group in which a hydrogen atom of a hydroxyl group (OH group) is substituted with the above-mentioned lower alkenyl group.
  • the “lower alkylthio group” is specifically a group in which a hydrogen atom of a thiol group (SH group) is substituted with the above-mentioned lower alkyl group.
  • a methylthio group, an ethylthio group, a propylthio group, a butylthio group A "lower alkylsulfinyl (oxy) group” such as a methylsulfinyl (oxy) group, an ethylsulfinyl (oxy) group, a propylsulfinyl (oxy) group, or an isopropylsulfinyl (oxy) group; Group, butylsulfinyl (oxy) group, isobutylsulfinyl (oxy) group, sec-butylsulfinyl (oxy) group, tert-butylsulfinyl (oxy) group, pentylsulfinyl (oxy
  • Examples of the “quaternary alkylsulfonyl (oxy) group” include a methylsulfonyl (oxy) group, an ethylsulfonyl (oxy) group, a propylsulfonyl (oxy) group, an isopropylsulfonyl (oxy) group, and a butylsulfonyl (oxy) group.
  • the “lower alkylsulfonamide group” includes methylsulfonamide group, ethylsulfonamide group, propylsulfonamide group, isopropylsulfonamide group, butylsulfonamide group, isobutylsulfonamide group, sec—butylsulfonamide group, tert Butylsulfonamide group, pentylsulfonamide group, etc.
  • “lower acylamido group” include acetamide group, propionylamide group, butyrylamide group, valerylamide group, isovalerylamide group, etc .
  • Examples of the "alkyl group” include acetyl, propionyl, butyryl, valeryl, and isovaleryl groups.
  • lower acylmethylamino examples include acetylmethylamino, propionylmethylamino, and butyrylmethylamino. , Valerinolemethylamino group, isovalerylmethylamino group and the like.
  • Examples of the "lower alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group and the like.
  • Examples of the alkyl group in the "amino group”, the “mono- or di-alkyl-substituted aminocarbonyl group”, or the “mono- or di-alkyl-substituted aminosulfonyl group” include the aforementioned lower alkyl groups.
  • aryl group examples include a phenyl group and a naphthyl group
  • aralkyl group examples include a benzyl group, a phenyl group, a benzhydryl group and a trityl group.
  • One or more, preferably one to three, of these substituents can be substituted at any position of the benzene ring of the “carbocyclic group” or “heterocyclic group”.
  • Examples of the substituent that can be substituted on the phenyl group represented by R 6 include the above-mentioned substituents on a carbocyclic group or a heterocyclic group, and preferably a nitro group or an amino group. , A hydroxyl group, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a trifluoromethyl group, a cyano group and a lower alkoxy group.
  • R 1 and R 2 are a lower alkyl group or a combination of a saturated monocyclic nitrogen-containing heterocyclic ring together with a nitrogen atom.
  • R 3 and R 4 are a hydrogen atom, a lower alkyl group, and R 3 and R 4 are united by a lower alkylene group or a group represented by the formula
  • R 6 is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfonyloxy group, a lower acylamino group, A carbocyclic group which may be substituted by a lower alkylsulfonamide group, a nitro group, an amino group, a cyano group or an aryl group, or a heterocyclic ring containing 1 to 2 oxygen atoms fused to a benzene ring; Or a salt thereof, wherein R 6 is a phenyl group which may be substituted with a nitro group or an amino group, or more preferably, R 1 and R 2 are combined to form a ring together with a nitrogen atom.
  • R 3 are the same or different represent a hydrogen atom, a lower alkyl group or together with a connexion lower alkylene group, R s is lower alkyl , Halogen atom, triflate Ruo b Fuweniru group substituted with a methyl group or a 3, 4-methylenedioxy O carboxymethyl off We sulfonyl group, R 6 is a compound or a salt thereof Fuweniru group.
  • the compound (I) of the present invention includes optical isomers and diastereomers based on asymmetric carbon atoms.
  • various hydrates and solvates also exist.
  • the compounds of the present invention include all compounds such as isolated forms of these isomers and mixtures thereof.
  • the compound (I) of the present invention has optical isomers based on asymmetric carbon atoms. Geometric isomers exist depending on the type of substituent.
  • the compound of the present invention includes an isolated form of these isomers and a mixture thereof.
  • the compound (I) of the present invention forms a salt.
  • Such salts include salt Mineral acids such as acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, ⁇ acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Acid addition salts with organic acids such as malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid.
  • preferred salts are salts with hydrochloric acid, oxalic acid, maleic acid and fumaric acid.
  • salts with alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as magnesium
  • salts with organic bases such as ammonia and trimethylamine
  • the compound (I) of the present invention can be produced by various synthetic methods utilizing the characteristics of the basic skeleton and the substituent.
  • the typical production method is shown below.
  • the compound (la) of the present invention comprises an amine represented by the general formula (II) and a compound represented by the general formula (III) ) Can be produced by reacting the compound with
  • This reaction is carried out by mixing compound (II) with a corresponding amount of isocyanate or isothiocyanate in an inert solvent.
  • inert solvent include dimethylformamide, dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethyloxetane, ethyl ethoxide, benzene, acetonitrile, and dimethyl sulfoxide.
  • Etc include mixed solvents.
  • the medium is appropriately selected according to the method to be applied.
  • R 5 and R 6 have the same meanings as defined above.
  • the compound (la) of the present invention can be produced by reacting an amine represented by the general formula (II) with an amine represented by the general formula (IV) and a carbonyl dihalide represented by the general formula (V). .
  • This reaction is carried out by reacting the compound (II) with a corresponding amount of the compound (IV) and the compound (V) in the above inert solvent at room temperature or under heating.
  • the compound (la) of the present invention comprises an amine represented by the general formula (II) and an amine represented by the general formula (IV) Can be produced by reacting an amine represented by the following formula with carbon dioxide or carbon disulfide represented by the general formula (VI).
  • compound (II) is reacted with a corresponding amount of compound (IV) and compound (IV).
  • (VI) is carried out in the above-mentioned inert solvent, preferably under heating.
  • R 1 , R 2 , R 3 , R 5 , and R 6 have the above-mentioned meanings.
  • R 7 means the above-mentioned lower alkyl group.
  • the compound (lb) of the present invention can be produced by reacting an amine represented by the general formula (II) with an aminoformate represented by the general formula (VII). This reaction is carried out by reacting compound (II) with a corresponding amount of compound (VII) in the presence of a Lewis acid in the above-mentioned inert solvent, preferably under heating.
  • Z means a halogen atom means a sulfonyl group
  • R 1 , R: R 3 .R 5 , and R 6 have the above-mentioned meaning.
  • This production method is a method for producing a target compound in which R 4 is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a cycloalkyl group in the general formula (I).
  • the reaction of this production method is a substitution reaction with a halide or a sulfonate represented by the formula (VIII).
  • a reaction-corresponding amount of the starting compound is usually prepared in a suitable inert solvent in the presence of a base such as sodium hydride. The reaction is carried out under cooling or at room temperature and optionally under heating.
  • A represents an alkylene group having 2 to 6 carbon atoms or an alkenylene group having 2 to 6 carbon atoms.
  • R 1 , R 2 , R 5 , R 6 and Z have the same meanings as described above.
  • This production method is a method for producing a target compound in which R 3 and R 4 in Formula (I) are an alkylene group or an alkenylene group formed in a form.
  • This reaction is carried out by reacting a compound represented by the general formula (Id) with a corresponding amount of ⁇ , —dihalogen (or disulfonyl) alkyl (or argen).
  • the reaction conditions are the same as in the fifth production method. 0
  • the compound (Ie) of the present invention is a compound represented by the formula (X): General It can be produced by reacting phosgene (thiophosgene) represented by the formula (XI), carbonyldiimidazole (CDI) or thiocarbonyldiimidazole. '
  • Another method for producing the target compound, which is a thiourea derivative is to convert a urea derivative into a thiourea derivative.
  • This conversion reaction can be easily carried out by heating the urea derivative (Ic) with phosphorus pentasulfide or Lawesson's reagent.
  • the production method comprises reducing the compound represented by the general formula (ig) to obtain the compound represented by the general formula (I) Is a method for producing a compound represented by the formula: The reduction is carried out with lithium aluminum hydride, borante-tetrahydrofuran complex, etc. The reaction solvent is getyl ether, tetrahydro cifuran, benzene or the like.
  • the compound of the present invention thus produced can be isolated or purified as it is, or as a salt thereof by a conventional salt-forming treatment. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of mouth chromatography.
  • the racemic compound can be converted to a diastereomer salt with a general optically active acid (such as tartaric acid) by using an appropriate starting compound or by a general racemic resolution method. Etc.] can lead to stereochemically pure isomers.
  • the compound (I) of the present invention shows good oral absorption and has a selective and long-lasting c-receptor activating activity. And, because of its extremely low affinity for other obioid receptors, it is expected that the formation of dependence on morphine, etc. based on the receptor, and the occurrence of side effects such as discomfort and hallucinations based on the sigma-receptor will be small. You.
  • the compounds of the present invention are extremely useful as independent central analgesics.
  • the compounds (I) of the present invention also include compounds that exhibit pharmacological effects such as an anti-inflammatory effect, a diuretic effect, and a neuroprotective effect in addition to analgesic activity. It is also useful as an anti-inflammatory, diuretic, and neuroprotective agent.
  • the pharmacological activity of the compound of the present invention was confirmed using the following test method.
  • mice Male ICR mice (SLC) weighing about 25 g were ⁇ 12 animals were used. The tail of the mouse tail (anal side) is pinched with crenne adjusted to 500 g pressure. The analgesic effect is determined using the bite reaction to the ridge and Klemme caused by this as an index. This method was performed in advance, and mice that did not show a biting response within 2 seconds were excluded. The test compound was dissolved in physiological saline and injected subcutaneously or orally, and the analgesic effect was evaluated at 15 and 30 minutes. Judgment criteria are as follows: Complete analgesia (+): A chewing reaction does not occur even after 6 seconds or more after application of Klemme. In order to prevent organizational damage, the application of Klemme was limited to 15 seconds.
  • Partial pain relief The one that bites in 2 to 6 seconds after applying Klemme.
  • No analgesia (1) Those that bite within 2 seconds.
  • the whole brain was homogenized in 10 volumes of ice-cooled 0.32 M sucrose solution, and then at 900 Xg for 10 min. Centrifuge. The supernatant was centrifuged at 11,500 X g for 20 minutes, and the resulting pellet was suspended in 0.05 M Tris buffer (pH 7.4). After centrifugation at 11,500 X g for 20 minutes, the pellet was resuspended in 0.05 M Tris buffer (pH 7.4). After incubation at 37 ° C for 30 minutes, the mixture was centrifuged at 1,500 ⁇ g for 20 minutes. The pellet obtained here was suspended in 0.05 M Tris buffer (pH 7.4) and incubated at 180 ° C. saved. It was melted at the time of use and used for experiments.
  • SLC Hartley male guinea pig
  • the receptor binding test was performed according to the method of Gillan & Kosterlitz (Br. J. Pharmacol., 77, 461, 1982).
  • the experiment for binding to the ⁇ -receptor was carried out at an incubation temperature and time of 25 ° C. and 45 minutes in the above-mentioned / one receptor binding experiment.
  • the ligand used was tritium-labeled 3 nm DTG (1,3-Di (tolyl) guanidine).
  • the results of the above experiments are summarized in the table below. It is clear from this result As is evident, the compound of the present invention had an analgesic activity equal to or higher than that of morphine hydrochloride or the comparative compound, and showed excellent A: —selectivity. '
  • a group of 69 I male mice weighing 2731 g was used.
  • the test compound was orally administered 50 minutes, 110 minutes or 1 0 minutes before the administration of acetic acid.
  • distilled water was used instead of the test compound.
  • Was orally administered Inject 0.1 ml of 0.6% WZV acetic acid solution per 10 g body weight intraperitoneally. The number of writhing episodes between 5 and 15 minutes after acetic acid administration was measured.
  • the rising suppression rate of each individual was calculated according to the following formula, and the average value and standard error were calculated for each group.
  • the significance test of the drug administration group was performed by Wilcoxon U-Test. The result is shown in FIG.
  • test compound was administered subcutaneously immediately before measuring the locomotion with an experimental animal locomotion measuring device (ANIMEX IIIA; manufactured by SHIMADZU).
  • ANIMEX IIIA experimental animal locomotion measuring device
  • DMS0 physiological saline containing 10% DMS0 was subcutaneously administered instead of the test compound.
  • Spontaneous locomotor activity for 10 to 20 minutes after administration of the test compound was measured.
  • Formulations containing the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared by using tablets, buccals, and the like, using commonly used pharmaceutical carriers, excipients and other additives. It is prepared into powders, fine granules, granules, capsules, pills, oral liquids (including syrups), injections, suppositories, etc., and is administered orally or parenterally.
  • Pharmaceutical carriers and excipients include solid or corrugated non-toxic pharmaceutical substances. Examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones. .
  • the clinical dose of the compound of the present invention is appropriately determined in consideration of the disease, body weight, age, sex, administration route, etc. of the patient to which the compound is applied. mg, preferably 0.5 to 50 mg, intravenously, for adults, 0.01 to 100 mg / day, preferably 0.1 to: LO mg, divided into single doses or 2 to 4 doses Administration.
  • the starting compounds of the present invention include novel compounds, and their production methods are shown in Reference Examples.
  • IR is an infrared absorption spectrum
  • MS is a mass spectrum
  • mp is a melting point
  • Example 6 The same treatment as in Example 1 was conducted using 3-chlorophenyl isothiocyanate in place of 2-chlorophenyl isothiocyanate described in Example 1, and treated in the same manner as in Example 1.
  • Example 6 The same treatment as in Example 1 was conducted using 3-chlorophenyl isothiocyanate in place of 2-chlorophenyl isothiocyanate described in Example 1, and treated in the same manner as in Example 1.
  • Example 2 The same treatment as in Example 1 was carried out using 4-methoxyphenyl isothiocyanate instead of 2-chlorophenyl isothiocyanate described in Example 1, and treated in the same manner as in Example 1.
  • Example 9 The same treatment as in Example 1 was repeated, except that 1-naphthyl isothiocyanate was used instead of 2-chlorophenyl isothiocyanate described in Example 1, to give (S) -1-methyl-3- (1-naphthyl) 111 [1-Phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below. Example 9
  • Example 2 The same treatment as in Example 1 was performed using 4-fluorophenyl isothiocyanate instead of 2-chlorophenyl isothiocyanate described in Example 1, and treated with (S) -1- (4-fluorophenyl) -13-methyl-3 — [1-Fuen 2- (1-pyrrolidinyl) ethyl] Thiourea and hydrochloride were obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.
  • Example 13 The same treatment as in Example 13 was carried out except that 4,3 sec-butylphenyl isothiocyanate was used instead of the 3,4 "methylenedioxyphenyl isothiocyanate described in Example 13 to obtain 11 (41 sec-butyl phenylene).
  • 3-Methyl-3-[(1S) -phenyl-2- (1-1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained, whose chemical structural formula and physicochemical properties are as shown in the table below.
  • Example 13 The same treatment as in Example 13 was repeated, except that 3,4,5-trimethoxyphenyl isothiocyanate was used in place of the 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to give (S) —1-methylethylene 1 1- [1-phenyl-2- (1-pyrrolidinyl) ethyl] 1-3-1 (3,4,5-trimethoxyphenyl) thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.
  • Example 13 The same procedure as in Example 13 was repeated, except that 3,4-methylenedioxyphenylisothiocyanate described in Example 13 was replaced by 3,4-dichloromethaneisothiocyanate to obtain (S) —11 ( 3,4-Dichloro mouth phenyl) 1-3-methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained.
  • Example 13 The same treatment as in Example 13 was performed using 5-benzofuranyl isothiocyanate instead of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to obtain (S) -11- (5-benzofuranyl).
  • S 3,5-methylenedioxyphenyl isothiocyanate
  • ) 3-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.
  • Example 13 The same treatment as in Example 13 was repeated, except that 4-benzofuranyl isothiocyanate was used in place of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to give (S) -11- (4-benzofuranyl).
  • 1-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.
  • Example 13 The same treatment as in Example 13 was performed using 2-fluorenyl isothiocyanate instead of the 3,4-methylenedioxyphenyl isothiocyanate described in Example 13.
  • Lithium aluminum hydride 68 mg of tetrahydrofuran 8 ml suspension in a suspension of 1- (5-benzofuranyl) 1-2-oxo-1-3- [2-oxo-1 1-phenyl-2- (1-pyrrolidinyl) ethyl]
  • An 8 mg solution of Omg in tetrahydrofuran was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 1.5 hours. After a saturated sodium hydrogen carbonate solution was added to the reaction solution, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. After adding 2 Om 1 of water to the residue, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate.
  • the filtrate was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with a mouth-mouth form. After drying the form layer over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • OmgZ tablet Compound Bl.Og, lactose 106.4 g and corn starch 48 g are mixed uniformly, and to this is added 40% hydroxypropylcellulose 10% aqueous solution and granulated using a granulator. Add 0.6 g of magnesium stearate to the granulated granules and compress into 16 Omg tablets (1 000 tablets).
  • Compound B 1.0 g, mannite 770 g and corn starch 19 1. Og were mixed uniformly, added with 10% aqueous polyvinylpyrrolidone 300 ml, granulated with a granulator, and used as a powder. 1 kg).
  • Compound B 1.0 g, corn starch 191.0 g, and calcium stearate 1 g are mixed uniformly, and filled into a No. 3 capsule at 20 Omg to prepare a capsule (100 capsules).
  • the sample is then heat-sterilized with autocrepe (100 samples).
  • the ampoule is heat-sterilized with an autoclave (100 samples).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un nouveau dérivé d'urée représenté par la formule générale (I) ou à un de ses sels, présentant un rôle d'activateur du récepteur λ et utile comme analgésique à action centrale.
PCT/JP1992/000993 1991-08-08 1992-08-04 Derive d'uree Ceased WO1993003011A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP3/223280 1991-08-08
JP22328091 1991-08-08
JP3/309952 1991-10-29
JP30995291 1991-10-29

Publications (1)

Publication Number Publication Date
WO1993003011A1 true WO1993003011A1 (fr) 1993-02-18

Family

ID=26525374

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/000993 Ceased WO1993003011A1 (fr) 1991-08-08 1992-08-04 Derive d'uree

Country Status (3)

Country Link
CN (1) CN1069490A (fr)
AU (1) AU2390892A (fr)
WO (1) WO1993003011A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684041A (en) * 1996-02-01 1997-11-04 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
WO1998046561A1 (fr) * 1997-04-11 1998-10-22 Otsuka Chemical Co., Ltd. Derives de benzene, derives de benzofurane et procedes de production de ces derives
WO2004069826A1 (fr) * 2003-02-04 2004-08-19 F. Hoffmann-La Roche Ag Derives de malonamide utilises comme inhibiteurs de la gamma-secretase
JP2008508229A (ja) * 2004-07-27 2008-03-21 アバンテイス・フアルマ・エス・アー 複素環置換された環状尿素誘導体、その調製及びキナーゼ阻害剤としてのその薬学的使用
US7544679B2 (en) 2007-02-02 2009-06-09 Hoffman-La Roche Inc. 6-oxo-6,7-dihydro-5h-dibenzo[b,d]azepin-7-yl derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102485714B (zh) * 2011-10-09 2013-07-24 连云港盛和生物科技有限公司 一种羰基化合成索拉菲尼的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61218518A (ja) * 1985-01-22 1986-09-29 ゼネカ・インコーポレイテッド トリフルオロメチルケトン置換されたペプチド誘導体、その製法及びこれを含有するエラスタ−ゼ介在組織変性疾病の治療剤
WO1991000725A2 (fr) * 1989-07-07 1991-01-24 Abbott Laboratories Antagonistes cck analogues d'acides amines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61218518A (ja) * 1985-01-22 1986-09-29 ゼネカ・インコーポレイテッド トリフルオロメチルケトン置換されたペプチド誘導体、その製法及びこれを含有するエラスタ−ゼ介在組織変性疾病の治療剤
WO1991000725A2 (fr) * 1989-07-07 1991-01-24 Abbott Laboratories Antagonistes cck analogues d'acides amines

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684041A (en) * 1996-02-01 1997-11-04 The Procter & Gamble Company Dihydrobenzofuran and related compounds useful as anti-inflammatory agents
WO1998046561A1 (fr) * 1997-04-11 1998-10-22 Otsuka Chemical Co., Ltd. Derives de benzene, derives de benzofurane et procedes de production de ces derives
WO2004069826A1 (fr) * 2003-02-04 2004-08-19 F. Hoffmann-La Roche Ag Derives de malonamide utilises comme inhibiteurs de la gamma-secretase
US7375099B2 (en) 2003-02-04 2008-05-20 Hoffmann-La Roche Inc. Malonamide derivatives
RU2330849C2 (ru) * 2003-02-04 2008-08-10 Ф.Хоффманн-Ля Рош Аг МАЛОНАМИДНЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ γ-СЕКРЕТАЗЫ
JP2008508229A (ja) * 2004-07-27 2008-03-21 アバンテイス・フアルマ・エス・アー 複素環置換された環状尿素誘導体、その調製及びキナーゼ阻害剤としてのその薬学的使用
US7544679B2 (en) 2007-02-02 2009-06-09 Hoffman-La Roche Inc. 6-oxo-6,7-dihydro-5h-dibenzo[b,d]azepin-7-yl derivatives

Also Published As

Publication number Publication date
CN1069490A (zh) 1993-03-03
AU2390892A (en) 1993-03-02

Similar Documents

Publication Publication Date Title
AU2001234175B2 (en) Novel cyclic amide derivatives
Moltzen et al. Bioisosteres of arecoline: 1, 2, 3, 6-tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1, 2, 3-triazoles. Synthesis and muscarinic activity
AU679049B2 (en) Antipsychotic benzimidazole derivatives
JPWO1993003011A1 (ja) ウレア誘導体
CA2045359C (fr) 1-indolyalkyl-4-(alkoxypyrimidinyl)piperazines
TW200815431A (en) Azabenzimidazolyl compounds
AU2003262420A1 (en) Derivatives of N-[phenyl(piperidin-2-yl)methyl]benzamide, the preparation method thereof and application of same in therapeutics
US10246414B2 (en) Allosteric modulators of CB1 cannabinoid receptors
KR100602929B1 (ko) 알파-1 아드레날린성 길항제로서 퀴나졸린 유도체
JPH0222758B2 (fr)
RU2114833C1 (ru) Арил-конденсированные 2,4-диазепиновые соединения, промежуточные продукты, антиаритмический агент и композиция
GB1583753A (en) Piperidine derivatives processes for their preparation and pharmaceutical compositions containing them
JPS596868B2 (ja) 新規イソキノリン誘導体の製造方法
WO1993003011A1 (fr) Derive d'uree
JPH0657693B2 (ja) ムスカリン様レセプター拮抗薬
JP4018145B2 (ja) α２―アドレナリン受容体アゴニスト活性を有する４―［（チエン―２―イル）メチル］イミダゾール誘導体
US4424225A (en) Thienobenzodiazepinones, pharmaceutical compositions thereof and method of use thereof
TW200817322A (en) Compounds having activity at the GlyT1 transporter
JPH02300184A (ja) インドール誘導体
HK24194A (en) Pyrrolo[1,2-a][4,1]benzoxazepines, process for their preparation, pharmaceutical compositions containing these compounds and therapeutical use
EP2464646B1 (fr) Procédé pour la préparation d'inhibiteurs de la cathepsine s
KR100824506B1 (ko) 퀴나졸리논 유도체
US4345081A (en) Spiro[indoline-3,4'-piperidine]s
AU636972B2 (en) 4-{3-(4-oxothiazoldinyl)}butynylamines, a process for their preparation and their use as medicaments
JPS624288A (ja) 新規なジアゼピノン化合物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH CS DE DK ES FI GB HU JP KR LK LU MG MN MW NL NO PL RO RU SD SE US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

EX32 Extension under rule 32 effected after completion of technical preparation for international publication

Ref country code: UA

EX32 Extension under rule 32 effected after completion of technical preparation for international publication

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: UA

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)

Ref country code: KZ

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA