WO1999053924A1 - Agent analgesique - Google Patents

Agent analgesique Download PDF

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Publication number
WO1999053924A1
WO1999053924A1 PCT/JP1999/001982 JP9901982W WO9953924A1 WO 1999053924 A1 WO1999053924 A1 WO 1999053924A1 JP 9901982 W JP9901982 W JP 9901982W WO 9953924 A1 WO9953924 A1 WO 9953924A1
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Prior art keywords
compound
group
substituted
unsubstituted
dihydro
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PCT/JP1999/001982
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English (en)
Japanese (ja)
Inventor
Junichi Shimada
Tomomi Shirai
Yuko Okamura
Nobuo Kosaka
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU33440/99A priority Critical patent/AU3344099A/en
Publication of WO1999053924A1 publication Critical patent/WO1999053924A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical invention, and more particularly, to an analgesic containing a piperidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • Acute pain is pain due to irritation, which may cause tissue damage. Pain due to injury such as a fracture or cut, inflammatory pain such as appendicitis, and postoperative pain are classified as acute pain.
  • narcotic analgesics such as morphine, non-steroid anti-inflammatory drugs (NSAIDs), or local anesthetics are mainly used. If acute pain persists for a long period of time, the normal function of the pain sensory system may be impaired, which may cause chronic pain. Therefore, it is desired to develop a drug that can exert a superior analgesic effect.
  • Neuropathic pain is caused by damage to the peripheral nervous system or central nervous system, dysfunction, etc., and even intractable drugs such as morphine and other obioids do not respond sufficiently. Also called pain.
  • Diseases associated with neuropathic pain include, for example, diseases exhibiting hyperalgesia parodynia, such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, and prolonged pain after surgery or trauma.
  • pharmacotherapy for neuropathic pain is a combination of analgesics such as anti-inflammatory analgesics and obioids, and adjuvant analgesics such as antidepressants, antiepileptics, antiarrhythmics, and GABAergic drugs.
  • analgesics such as anti-inflammatory analgesics and obioids
  • adjuvant analgesics such as antidepressants, antiepileptics, antiarrhythmics, and GABAergic drugs.
  • effective treatments for neuropathic pain have not
  • quinazoline derivatives having adenosine uptake inhibitory activity and useful for protecting myocardium and preventing or treating inflammation such as paw edema are known (International Publication WO94 / 19). 342, WO 96/06 841), and it is also known that these compounds are useful for treating nephritis (WO 97/29749). Also, in Chemical 'Pharm. Bulletin' (Chem. Pharm. Bull.), Vol.
  • An object of the present invention is to provide a medicine capable of exhibiting an excellent analgesic action.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems.
  • the compound represented by the following general formula (I) has an excellent analgesic effect, and is useful for acute pain and neuropathic pain. It has been found that the compound is useful as an active ingredient of a medicament for preventing and / or treating prion.
  • the present invention has been completed based on these findings.
  • R 1 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a halogen atom
  • R 2 , R ⁇ R ⁇ and R 5 independently represent a hydrogen atom, a halogen atom, an amino group, a substituted Or unsubstituted mono- or di-lower alkylamino group, substituted or unsubstituted lower alkanoylamino group, nitro group, cyano group, substituted or Unsubstituted lower alkyl group, hydroxyl group, substituted or unsubstituted lower alkoxy group, substituted or unsubstituted lower alkylthio group, carboxyl group, substituted or unsubstituted lower alkoxycarbonyl group, substituted or unsubstituted lower group Arukanoi group, a substituted or unsubstituted Ararukiruokishi group, or a substituted or unsubstituted lower grade Arca
  • R 6 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group; 3 is N or C—R 15 (wherein: 15 is a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl Represents a group, a substituted or unsubstituted lower alkylthio group or a mercapto group).
  • Y 1 — Y 2 — Y 3 represents the following formula (( ⁇ , Formula Formula Formula) , Or formula (g):
  • R 11 is a hydrogen atom, a substituted or unsubstituted lower alkyl group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkylsulfonyloxy group A substituted or unsubstituted arylsulfonyloxy group, a halogen atom, or NR 16 R 17 (wherein R 16 and R 17 are each independently a hydrogen atom, a substituted or unsubstituted lower alkyl group, Or an unsubstituted cycloalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aralkyl group, or R 16 and R 17 are substituted or unsubstituted together with adjacent N.
  • R 12 is a hydrogen atom, a substituted or unsubstituted lower alkyl group, Shiano group, a carboxyl group, or a substituted or unsubstituted lower Represents a group represented by alkoxycarbonyl represents a double Le group];
  • R Ma, R 8, R and R 1Q it it independently a hydrogen atom, a substituted or unsubstituted lower alkyl group, arsenate Dorokishiru group, a substituted or unsubstituted Represents a substituted lower alkoxy group, or a substituted or unsubstituted aralkyloxy group, or a methylenedioxy group, an ethylenedioxy group, or an adjacent two selected from R 7 , R 8 , R 9 , and R 1Q ;
  • Equation (h) The following equation (h):
  • R 13 and R 14 each independently represent a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl group.
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is a substituted or unsubstituted lower alkyl group
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • n is 0,
  • X 1 — X 2 is a group represented by the formula (a) or (b) wherein R 6 is a substituted or unsubstituted lower alkyl group
  • X 3 is C—R 15 (wherein, R 15 is a hydrogen atom)], wherein Y 1 — Y 2 — Y 3 is a group represented by the formula (c), wherein R 11 is a hydrogen atom or NR 16 R 17 (wherein, R 16 and R 17 together with the adjacent N form a substituted or unsubstituted heterocyclic group)], and R 7 is a hydrogen atom
  • R 8 is a substituted or unsubstituted lower alkoxy group
  • R 9 is a substituted or unsubstitute
  • the analgesic including a salt thereof as an active ingredient is provided which, as a further preferred embodiment of these, R 3 is a methyl group, R 6 is a methyl group, R 11 is hydrogen atom or a morpholino group R 8 and R 9 are ethoxy groups, or R 8 and R 9 are taken together to form formula (h), wherein R 13 and R "are ethyl groups and Z is 0.
  • the above-mentioned analgesic comprising as an active ingredient a piperidine derivative or a pharmacologically acceptable salt thereof represented by the group
  • a medicament in the form of a pharmaceutical composition comprising the above-mentioned active ingredient and a pharmaceutical additive is provided, and is preferably used for the prevention and / or treatment of acute pain or neuropathic pain.
  • a medicament is provided.
  • use of the piperidine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for the production of the above-mentioned medicine; and acute pain or neuropathic pain A method for prevention and / or treatment, comprising the step of administering to a mammal, including a human, an effective amount of a piperidine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. A method is provided.
  • R 1 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a halogen atom.
  • the term lower alkyl group refers to a straight or branched chain alkyl group, for example, having 1 to 8 carbon atoms, Preferably, it means an alkyl group having about 1 to 4 carbon atoms. More specifically, examples of the lower alkyl group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group. Group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group or the like.
  • the functional group when a functional group other than an alkyl group is referred to as “lower”, the functional group has 1 to 8 carbon atoms (2 to 8 carbon atoms for an alkenyl group or the like), preferably 1 to 4 carbon atoms ( This means that the alkenyl group has 2 to 4 carbon atoms).
  • the term “halogen atom” may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the substitution position of R 1 on the piperidinyl group and the substitution position of the (CH 2 ) n group on the piperidinyl group are not particularly limited.
  • R 1 is a hydrogen atom
  • (CH 2 ) It is preferred that the ⁇ group be bonded to the 4-position.
  • a hydrogen atom can be suitably used as R 1 .
  • R ⁇ R ⁇ R and R 5 may be the same or different and each independently represents a hydrogen atom, a halogen atom, an amino group, a substituted or unsubstituted mono- or di-lower alkylamino group, a substituted or unsubstituted lower alkano.
  • a mono- or di-lower alkylamino group a lower alkanoylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a lower alkanoyl group, an aralkyloxy group, an aralkyl group, a lower alkanoyloxy group, Alternatively, when a lower alkylsulfonyloxy group is used, the lower alkyl group specifically described above can be preferably used as the alkyl moiety constituting each group.
  • R 2 , R ⁇ R 4 , and R 5 for example, when R 3 is a lower alkyl group such as a methyl group or an ethyl group, and R 2 , ⁇ and R 5 are all hydrogen atoms
  • Tables 1 to 1 to 16 and Table 4 of International Publication No. WO94 / 193324; and Table 3 of International Publication WO96 / 066841 The combinations described in Table (1) and Table 3 (2) are suitable.
  • n represents 0, 1, or 2, and it is preferable that n is 0.
  • the piperidinyl group substituted by R 1 is bonded to the nitrogen atom adjacent to X 2 without via an alkylene group.
  • X 1 — X 2 represents a group represented by the above formula (a) or (b), wherein R 6 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted Represents a lower alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group; X 3 represents N or C—R 15 , wherein R 15 is a hydrogen atom, substituted or unsubstituted Represents a lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted lower alkylthio group, or a mercapto group.
  • lower alkenyl group refers to a straight-chain or branched alkenyl group having one or more, preferably one, double bond and having 2 to 8 carbon atoms. , Preferably about 2 to 4 alkenyl groups. More specifically, for example, a vinyl group, an aryl group, a methyl acryl group, a crotyl group, a 3-butenyl group, a 2-pentenyl group, a 4-pentenyl group, a 2-hexenyl group, a 5-hexenyl group, etc. It can be used as an alkenyl group.
  • aryl group used in the present specification includes, for example, a monocyclic, bicyclic, or tricyclic aryl group having 6 to 14 ring carbon atoms.
  • it includes a phenyl group, a naphthyl group, a biphenyl group, an anthryl group and the like.
  • an aralkyl group, an aralkyloxy group, or an arylsulfonyloxy group when used, the aryl group described above may be used as the aryl group constituting each group. it can.
  • the term aralkyl group is, for example, an aralkyl group having 7 to 13 carbon atoms. It includes a kill group, more specifically, a benzyl group, a phenethyl group, or a benzhydryl group.
  • Y 1 —Y 2 —Y 3 represents a group represented by any one of the above formulas (c), (d), (e), (f), and (g).
  • R 11 is a hydrogen atom, a substituted or unsubstituted lower alkyl group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkylsulfonyloxy group A substituted or unsubstituted arylsulfonyloxy group, a halogen atom, or NR 16 R 17 (wherein R 16 and R 17 are each independently a hydrogen atom, a substituted or unsubstituted lower alkyl group, Represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted
  • R 12 is a hydrogen atom, a substituted or unsubstituted lower alkyl group, Shiano group, a carboxyl group or a substituted or non-location, It represents a lower alkoxycarbonyl two Le group.
  • a cycloalkyl group having 3 to 10 ring carbon atoms can be used, and more specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group , Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like.
  • heterocyclic group formed by R 16 and R 17 taken together with the adjacent N examples include a virolidinyl group, a piperidino group, a homopiperidino group, a piperazinyl group, a morpholino group, a thiomorpholino group, and a homopiperazinyl group. Can be mentioned.
  • R 7 , R 8 , R 9 , and R ll) may be the same or different and each independently represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, Or a substituted or unsubstituted aralkyloxy group, or a methylenedioxy group, an ethylenedioxy group, or a group represented by the above formula (h) when two adjacent groups selected from R 7 , RR 9 , and R 1Q are taken together. Represents the group to be used.
  • R 13 and R 14 may be the same or different and each independently represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkyl group.
  • the two adjacent groups are not particularly limited.
  • R 8 and R Preferably it is 9 .
  • the other two groups are preferably hydrogen atoms.
  • R 7 and R 1Q are a hydrogen atom, and R 8 and R 9 together form a group represented by the above formula (h).
  • the term ⁇ substituted or unsubstituted '' means that the substituent is not substituted by another type of functional group, or one or two or more of the same or other types. It is substituted by a functional group, preferably 1 to 3 functional groups of the same or another type. When there are two or more such functional groups, they may be the same or different.
  • the functional group on the substituted alkyl group, the substituent having the substituted alkyl moiety or the substituted alkenyl group include a halogen atom, a nitro group, a cyano group, a hydroxyl group, a lower alkoxy group, a carboxy group, and a lower alkoxycarbonyl group.
  • Examples of the functional group on the substituted aryl group or the substituent having the substituted aryl group include a halogen atom, a lower alkyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a hydroxyl group and a lower group.
  • Examples thereof include an alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanol group, a methylenedioxy group, and a trifluoromethyl group.
  • Examples of the functional group on the substituted heterocyclic group include a halogen atom, a lower alkyl group, an amino group, a mono- or di-lower alkylamino group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanol group, Examples include a trifluoromethyl group, an aryl group, and an aralkyl group.
  • pharmacologically acceptable salts thereof can be used as the active ingredient of the medicament of the present invention. Further, any hydrate or solvate formed by the compound in free form or a salt thereof may be used as an effective component.
  • Pharmacologically acceptable salts include, for example, acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • the solvent that forms the solvate is not particularly limited as long as it is physiologically acceptable.
  • ethanol can be used.
  • the active ingredient of the medicament of the present invention when the compound represented by the above formula (I) has one or more asymmetric carbons, it includes optical isomers, diastereoisomers and the like. Pure stereoisomers, arbitrary mixtures of these stereoisomers, racemates, etc. can be used. If the compound has a lower alkenyl group, use any geometric isomer or a mixture thereof. Is also possible.
  • Pharmaceutically acceptable acid addition salts include, for example, inorganic salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, citrate, methate
  • pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth salts such as magnesium salt and calcium salt.
  • Examples of pharmacologically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, and the like.
  • Examples of pharmacologically acceptable organic amine addition salts include morpholine And addition salts such as pyridine.
  • the pharmacologically acceptable amino acid addition salt include, for example, addition salts such as lysine, glycine, and phenylalanine.
  • RR 2 , RR 4 , R 5 , n, X 1 —X 2 , and Y 1 —Y 2 —Y 3 have the same meanings as described above, and R 7 , R 8 , R 9 , and R lfl are joined together to form a group represented by the above formula (h), wherein R 13 , R 14 , and Z are as defined above.
  • the other two groups selected are each independently a hydrogen atom, a substituted or unsubstituted lower alkyl group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, or a substituted or unsubstituted aralkyloxy group;
  • the biperidine derivative (IA) which is a methylenedioxy group or an ethylenedioxy group when the two groups are adjacent to each other when they are adjacent, is specifically described in the Examples below.
  • RR 2 , R 3 , R 4 , R 5 , n, and X 1 — X 2 have the same meanings as above, and ⁇ — ⁇ 2 — Equation ( e ) or equation
  • X 1 — X 2 , Y 1 — Y 2 — Y 3 , R 1 to R 5 , R 7 to R 1 () , and n are as defined above, and L is a chlorine atom, a bromine atom, Iodine atom, methanesulfonyloxy group, benzenesulfonyloxy group, or toluenesulfonyloxy group)
  • Compound (I) can be synthesized from compound (II) (for example, can be synthesized according to the method disclosed in International Publication WO 94/19342 or JP-A-8-15137) and compound (III-a).
  • a base such as a tertiary amine such as triethylamine or pyridine, or an alkali metal carbonate such as sodium carbonate or potassium carbonate
  • a suitable solvent such as a lower alcohol such as methanol, ethanol or isopropanol, tetrahydrofuran ( Cyclic ethers such as THF) and 1,4-dioxane; N, N-dimethylformamide (DMF); dimethylacetamide (DMA); N-methylpyrrolidinone; dimethylsulfoxide (DMSO); It can be obtained by reacting in a mixed solvent at a temperature from room temperature to the boiling point of the solvent used for 10 minutes to 48 hours.
  • Production method 2 In compound (I), X 1 —
  • X is C—R 15a (where R 15a represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted aryl group).
  • the compound to be obtained is obtained by converting the compound (IV) obtained according to the method shown in Reference Example into an aromatic hydrocarbon such as benzene or toluene or in the absence of a solvent, in the form of a corresponding orthoester in an amount of 1 equivalent to the solvent amount, for example, Triethyl orthoformate, Trimethyl orthoformate, Triethyl ortho acetate, Triethyl orthopropione And triethyl orthobenzoate and, if necessary, a mineral acid such as sulfuric acid or hydrochloric acid, or an organic acid such as trifluoroacetic acid as a catalyst, at a temperature from room temperature to the boiling point of the solvent. It can be obtained by reacting for ⁇ 48 hours.
  • the compound in which X is C_R 15a (wherein R 15a is as defined above) is obtained by acylating the amino group of the compound (IV) with a corresponding acylating agent. Thereafter, it can also be produced by performing a ring closure reaction under basic conditions.
  • the acylation is carried out using a corresponding acylating agent (for example, an acid anhydride such as acetic anhydride or propionic anhydride, an acid halide such as acetyl chloride, etc.), and if necessary, pyridine, triethylamine, an alkyl metal hydroxide,
  • a corresponding acylating agent for example, an acid anhydride such as acetic anhydride or propionic anhydride, an acid halide such as acetyl chloride, etc.
  • pyridine triethylamine
  • an alkyl metal hydroxide an alkyl metal hydroxide
  • the reaction can be carried out in the presence of a base such as an alkyl metal carbonate and a solvent such as chloroform, dichloromethane, THF, 1,4-dioxane or the like, or without a solvent, at a temperature from 0 ° C. to the boiling point of the solvent used.
  • the ring closure reaction with a base is carried out in the presence of an alkyl metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.) in a suitable solvent, for example, lower alcohols such as methanol, ethanol, isopropanol, tetrahydrofuran (THF), 1,4 —
  • a suitable solvent for example, lower alcohols such as methanol, ethanol, isopropanol, tetrahydrofuran (THF), 1,4
  • THF tetrahydrofuran
  • the reaction can be performed in a cyclic ether such as dioxane or a mixed solvent thereof at a temperature from room temperature to the boiling point of the solvent used. These reactions are usually carried out for 1 to 48 hours.
  • X is C-R 15b compound represented by the aromatic hydrocarbon compound (IV) benzene, and toluene, methanol, Lower alcohols such as ethanol and isopropanol, cyclic ethers such as tetrahydrofuran (THF) and 1,4-dioxane, or a mixed solvent thereof, or in the absence of a solvent, 1 equivalent to a solvent amount of carbon disulfide and 1 equivalent And a solvent amount of an organic base such as pyridine or triethylamine at a temperature from room temperature to about the boiling point of the solvent for 1 to 48 hours.
  • an organic base such as pyridine or triethylamine
  • this compound can be prepared using common alkylating agents (eg, alkyl halides such as methyl iodide, chloroiodide, etc.) using pyridine, triethylamine, alkyl metal hydroxide,
  • alkylating agents eg, alkyl halides such as methyl iodide, chloroiodide, etc.
  • pyridine triethylamine
  • alkyl metal hydroxide By treating in the presence of a base such as an alkyl carbonate and a solvent such as chloroform, dichloromethane, THF, 1,4-dioxane and the like at a temperature from 0 ° C to the boiling point of the solvent used, the compound ( In Ia), X may lead to a compound represented by C—R 15 ( where R 15c represents a substituted or unsubstituted lower alkylthio group).
  • Compound (V-a) can be prepared from compound (II) and compound ( ⁇ -b) (for example, can be synthesized according to the method disclosed in International Publication W094 / 06648) according to the method of Step 1. Obtainable.
  • Step 3-2 Compound (V-b) can be obtained by reducing the nitro group of compound (V-a) (for example, by catalytic reduction or reduction using a metal). Catalytic reduction is usually carried out at room temperature and atmospheric pressure in the presence of a catalyst such as Raney nickel, palladium on carbon (Pd / C), platinum oxide, etc., in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF. Acetic acid, or in water.
  • a catalyst such as Raney nickel, palladium on carbon (Pd / C), platinum oxide, etc.
  • a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF.
  • Acetic acid or in water.
  • the reduction using a metal is carried out at a temperature from room temperature to the boiling point of the solvent used under conditions such as zinc-acetic acid, iron-acetic acid, iron-ferric chloride-ethanol-water, iron-hydrochloric acid, and tin-hydrochloric acid. It can be carried out. (Step 3-3)
  • the compound in which Z is 0 is the compound (V-b) and one or more equivalents of N, ⁇ '-carbonyldiimidazole, phosgene, etc.
  • a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; dichloromethane;
  • a halogenated hydrocarbon ethyl acetate, ether, acetonitrile, DMF, DMSO, etc., or a mixture of these for 10 minutes to 48 hours at a temperature from 0 ° C to the boiling point of the solvent used.
  • those in which Z is represented by S are the compound (V-b) and one or more equivalents of N, N'-thiocarbonyldiimidazole, carbon disulfide, thiophosgene and the like.
  • a base such as a tertiary amine such as triethylamine or pyridine
  • a suitable solvent such as water, a lower alcohol such as methanol, ethanol or isopropanol, a cyclic ether such as THF, 1,4-dioxane, or dichloromethane.
  • R 13a represents a group other than a hydrogen atom in the definition of R 13 ). You can also.
  • the compound (I-c) is prepared by combining the compound (Ib) with 1 to 2 equivalents of the compound represented by the formula R 13a L (wherein R 13a and L have the same meanings as described above) and 1 to 2 equivalents of a base.
  • R 13a L wherein R 13a and L have the same meanings as described above
  • a base for example, in the presence of sodium hydroxide, potassium carbonate, cesium carbonate, etc., in a suitable solvent such as THF, DMF, acetone, methyl ethyl ketone, etc. at a temperature from 0 ° C to the boiling point of the solvent used. It can be obtained by reacting for 10 minutes to 24 hours.
  • Production method 5 In compound (I), Y 1 — ⁇ 2 — ⁇ 3 is represented by formula (c-a) R16 0 17
  • W is a chlorine atom, a bromine atom, an iodine atom, Represents a methanesulfonyloxy group, a benzenesulfonyloxy group, or a toluenesulfonyloxy group
  • Compound (I-d) is obtained by converting compound (Ie) with compound (VI) in an amount of 1 equivalent to solvent, if necessary, tertiary amines such as triethylamine and pyridine, and sodium carbonate and sodium carbonate.
  • solvent for example, lower alcohols such as methanol, ethanol, isopropanol, THF, 1,4-dioxa Cyclic ethers such as DMF, DMA, N-methylpyrrolidinone, DMSO, or a mixture of these, if necessary, in a sealed tube at a temperature N from room temperature to the boiling point of the solvent used. It can be obtained by reacting for minutes to 72 hours. Further
  • potassium iodide, sodium iodide and the like may be appropriately added during the reaction.
  • Primary amine was used as the compound R (NI) and DMF was used as the solvent.
  • the compound (1-1) represented by can also be produced according to the following reaction steps,
  • Compound (1-1) can also be obtained by dehydrogenating compound (I-m).
  • the dehydrogenation is usually carried out using potassium permanganate, palladium on carbon, etc. in a suitable solvent such as water, acetone, nitrobenzene or a mixture thereof at a temperature from room temperature to the boiling point of the solvent used. Can be.
  • a compound having at least one amino group, a substituted or unsubstituted mono- or di-lower alkylamino group or a substituted or unsubstituted lower alkanoylamino group in R 2 to R 5 is preferably
  • the compound can also be produced by reducing the corresponding compound (I) having a nitro group from R 2 to R 5 and, if necessary, alkylating or acylating the compound. The reduction can be carried out, for example, by catalytic reduction or an ordinary method using a metal.
  • Catalytic reduction is usually carried out at room temperature and normal pressure in the presence of a catalyst such as Raney nickel, palladium on carbon (Pd / C), platinum oxide, etc., in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF. , Vinegar
  • a catalyst such as Raney nickel, palladium on carbon (Pd / C), platinum oxide, etc.
  • a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF.
  • Vinegar The reaction can be performed in an acid or the like over 10 minutes to 48 hours.
  • the reduction using a metal can be performed, for example, from room temperature to the boiling point of the solvent used under conditions such as zinc-acetic acid, iron-acetic acid, iron-ferric chloride, iron-hydrochloride, iron-hydrochloric acid, and tin-hydrochloric acid. It can be carried out at a temperature of 10 minutes to 48 hours.
  • the alkylation and acylation of the reduction product may be carried out by a conventional alkylating agent (eg, an alkyl halide such as methyl iodide) or an acylating agent (eg, an acid anhydride such as acetic anhydride, or an acid halide such as acetyl chloride).
  • a conventional alkylating agent eg, an alkyl halide such as methyl iodide
  • an acylating agent eg, an acid anhydride such as acetic anhydride, or an acid halide such as acetyl chloride.
  • a base such as pyridine, triethylamine, an alkyl metal hydroxide or an alkyl metal carbonate and / or a solvent such as chloroform, dichloromethane, THF, 1,4-dioxane, etc., if necessary.
  • a base such as pyridine, triethylamine, an alkyl
  • a compound having at least one hydroxy-substituted alkyl Le group from R 2 to R 5 is an alkyl Can also be manufactured.
  • the reduction is carried out using a reducing agent such as lithium aluminum hydride or sodium borohydride in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, etc.
  • the reaction can be performed at a temperature up to room temperature for 10 minutes to 48 hours.
  • Alkylation is carried out using a conventional organometallic reagent, for example, a Grignard reagent such as methylmagnesium bromide or ethylmagnesium chloride, or an organic lithium reagent such as methyllithium or butyllithium, and an appropriate solvent, for example, dioxane.
  • a conventional organometallic reagent for example, a Grignard reagent such as methylmagnesium bromide or ethylmagnesium chloride, or an organic lithium reagent such as methyllithium or butyllithium, and an appropriate solvent, for example, dioxane.
  • the reaction is usually performed in ether, THF, etc. at a temperature of ⁇ 78 ° C. to room temperature over a period of 10 minutes to 48 hours.
  • compounds that have a least one carboxyl group from R 2 to R 5 are Yotsute in subjecting the compound from the corresponding R 2 having Asechiru group R 5 (I) is in Harohoru unresponsive Can also be manufactured.
  • the haloform reaction is performed according to the method described in Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 72, pp. 1642 (1950), and the like. And chlorine or bromine And a sodium hypohalite solution prepared from an aqueous sodium hydroxide solution.
  • compounds that have a least one hydroxyl group from R 2 to R 5 are Yotsute compounds from the corresponding R 2 having a lower alkoxy group R 5 (I) is to be dealkylated Can also be manufactured.
  • the dealkylation is carried out in the presence of an acid such as hydrobromic acid or hydroiodic acid in the absence of a solvent or in a solvent such as water, acetic acid, a lower alcohol such as methanol or ethanol, or a solvent of 1 equivalent or more.
  • alkali metal salts of thiols such as thiol or thiophenol (sodium salt, potassium salt, etc.) in a solvent such as DMF or DMSO, or Lewis such as boron trichloride, boron tribromide or aluminum trichloride It can be carried out in a solvent such as dichloromethane in the presence of an acid. The reaction is generally completed in 30 minutes to 48 hours at a temperature from room temperature to the boiling point of the solvent used.
  • R 2 to a compound having at least one substituted or unsubstituted lower alkoxy groups R 5 are the corresponding compounds that have a hydroxyl group in R 2 to R 5 and (I) 1 to 2
  • An equivalent amount of a substituted or unsubstituted lower alkyl halide is used in the presence of 1 to 2 equivalents of a base, for example, sodium hydride, potassium carbonate, cesium carbonate, etc., in an inert solvent such as THF, DMF, acetone, methyl ethyl ketone.
  • a base for example, sodium hydride, potassium carbonate, cesium carbonate, etc.
  • an inert solvent such as THF, DMF, acetone, methyl ethyl ketone.
  • the reaction can be carried out at a temperature from 0 ° C. to the boiling point of the solvent used for 10 minutes to 24 hours.
  • a compound having at least one carboxyl group from R 2 to R 5 or R 12 the corresponding compound having a lower alkoxy force Lupo two Le group from R 2 to R 5 or R 12 (I) can also be produced by hydrolysis of The hydrolysis is carried out in the presence of an acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid or a base such as sodium hydroxide or potassium hydroxide in a suitable solvent, for example, a lower alcohol such as water, methanol, ethanol, or isopropanol. , THF, a cyclic ether such as 1,4-dioxane or the like, or a mixed solvent thereof.
  • the reaction is generally carried out for 10 minutes to 48 hours at a temperature between room temperature and the boiling point of the solvent used. finish.
  • compound (I) compounds having a substituted or unsubstituted lower alkyl group R 6, the corresponding compound having hydrogen in R 6 (I) and 1-2 equivalents of substitution young properly is unsubstituted lower alkyl payment
  • an inert solvent such as THF, DMF, acetone, methyl ethyl ketone, etc. in the presence of 1-2 equivalents of a base such as sodium hydride, potassium carbonate, cesium carbonate, etc. It can also be produced by reacting at a temperature from C to the boiling point of the solvent used for 10 minutes to 24 hours.
  • a compound having hydrogen in R 11 is, even cowpea to subjecting the compound having a halogen in the corresponding R 11 a (I) to catalytic reduction mentioned above can manufacturing child.
  • Compound (I) has an effect of suppressing acute pain and hyperalgesia, and is useful as an active ingredient of an analgesic.
  • the medicament provided by the present invention includes, for example, pains caused by injuries such as fractures and cuts, inflammatory pains such as appendicitis, acute pains such as postoperative pains, or diseases accompanied by neuropathic pains, such as shingles It can be administered for post-neuralgia, trigeminal neuralgia, diabetic neuropathy, prolonged pain after surgery or trauma, etc., for the purpose of reducing or eliminating pain and / or preventing pain.
  • the location and cause of pain to which the medicament of the present invention is applied are not particularly limited, and superficial pain such as skin (sharp or dull pain); deep parts of connective tissue, bone, joint, muscle, tendon, etc. Pain (dull pain) or kidney stones, gallstones, ulcers It is expected to be useful for visceral pain caused by ulcers, appendicitis, etc.
  • headache such as migraine or tension headache; neuralgia such as trigeminal neuralgia, glossopharyngeal neuralgia, and intercostal neuralgia; acute or chronic low back pain; abdominal pain caused by gallstones, urinary stones, ⁇ inflammation, cholecystitis, or It is applicable to cancer pain and the like.
  • the target of application of the medicament of the present invention is not limited to the above specific examples, and can be applied to any disease that requires pain prevention and / or treatment. .
  • the medicament of the present invention is applicable to mammals including humans.
  • a substance selected from the group consisting of compound (I) and a pharmacologically acceptable salt thereof can be used, or a hydrate or solvate thereof may be used. . Two or more of these substances may be used in appropriate combination.
  • the substance itself selected from these groups may be administered as the medicament of the present invention.
  • a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmaceutically acceptable additive for a pharmaceutical preparation is used. It is desirable to administer it in form.
  • Such a pharmaceutical composition may contain one or more active ingredients of other pharmaceuticals, for example, one or more of steroid or non-steroid anti-inflammatory agents, antispasmodics, antibiotics, and antibacterial agents. It can be appropriately compounded.
  • compositions to be applied in vivo are prepared by mixing the above-mentioned active ingredients with one or more pharmaceutically acceptable excipients for pharmaceuticals, It can be easily manufactured according to the method.
  • the route of administration of the medicament of the present invention is not particularly limited, but it is desirable to appropriately select the most effective route for treatment and / or prevention.
  • Pharmaceutical compositions suitable for oral administration include, for example, capsules, powders, tablets, granules, fine granules, emulsions, syrups, solutions, suspensions and the like.
  • Suitable pharmaceutical compositions include, for example, inhalants, nebulizers, rectal administration, injections, drops, ointments, creams, transdermal absorbers, transmucosal absorbers, eye drops, nasal drops, drops Ear preparations, tape preparations, patches and the like can be mentioned, but the form of the medicament of the present invention is not limited to these. However, the medicament of the present invention is characterized in that it can exert its efficacy by oral administration, and oral administration is a preferred route of administration of the medicament of the present invention.
  • liquid preparations such as emulsions and syrups include water; saccharides such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; sesame oil and olive oil And oils such as soybean oil; preservatives such as p-hydroxybenzoic acid esters; and additives for pharmaceutical preparations such as flavors such as strobe flavor and peppermint.
  • Solid preparations such as capsules, tablets, powders and granules include excipients such as lactose, glucose, sucrose and mannitol; disintegrants such as starch and sodium alginate; lubricating agents such as magnesium stearate and talc.
  • Agents binders such as polyvinyl alcohol, hydroxypropyl cellulose, and gelatin; surfactants such as fatty acid esters; and plasticizers such as glycerin.
  • liquid preparations in the form of injections, drops, eye drops and the like can be preferably prepared as sterile isotonic liquid preparations.
  • an injection can be prepared using an aqueous medium consisting of a salt solution, a glucose solution, or a mixture of saline and a glucose solution.
  • Rectal preparations can be prepared usually in the form of suppositories, using carriers such as fatty acid, hydrogenated fat or hydrogenated carboxylic acid.
  • a non-irritating carrier which disperses the above-mentioned substance as an active ingredient as fine particles to facilitate absorption can be used.
  • Such carriers include, for example, lactose, glycerin and the like, and the form of the preparation can be selected from aerosol, dry pad and the like.
  • the diluents, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers exemplified for the oral preparations
  • One or more additives for pharmaceutical preparations selected from the above can be used as appropriate.
  • the pharmaceutical additives used for the production of the medicament of the present invention are not limited to those described above, and any additives that can be used by those skilled in the art may be used.
  • the dose and the number of times of administration of the medicament of the present invention are not particularly limited.
  • an adult (60 kg) —l to 900 mg, preferably l to 200 m per day is appropriate. It is.
  • the above dosages can be administered once or several times a day. In any case, the above dosage and frequency of administration may be adjusted as appropriate, taking into account factors such as the route of administration, the age and weight of the patient, the degree of pain to be treated and / or prevented, and the type of underlying disease. desirable.
  • EtOH in Examples and Reference Examples Et 2 0, EtOAc, CDC1 3, DMF, and DMSO, which it ethanol, Jefferies chill ether, acetic E Ji Le, black hole Holm, N, N-dimethyl formamidine de, dimethyl Represents sulfoxide.
  • Example 1 3-Ethyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-1,2,4-dioxoquinazoline-13-yl) 1 1-Biberidyl] 1H-imidazo [4,5-g] quinazoline-2-one (Compound 1)
  • Second step The crude product obtained in the first step is dissolved in 20 ml of methanol, to which 0.4 ml (3.00 mmol) of triethylamine and synthesized by the method described in WO 94/1 9342 1 , 2,3,4-Tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-biperidyl) quinazoline 'hydrobromide (Compound c) 354mg (l.OOmmol) and 1 hour Heated to reflux. The solvent was distilled off under reduced pressure, and the residue was treated with water. After extraction with chloroform, the organic layer was washed and dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (Developing solvent: black form / methano
  • Example 8 210 mg (0.40 mmol) of the compound obtained in Example 8 was dissolved in 5 ml of N-methylpyrrolidinone, 0.2 ml (2.0 tmol) of morpholine was added to the solution, and the mixture was heated and stirred at 140 ° C. for 1 hour. . The reaction solution was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from ether to give the title compound as white crystals (207.7 mg, yield 91%).
  • Example 16 3-Ethyl-2,3-dihydro-8- [4- (3,4-dihydro-6-methyl-14-oxoquinazoline-13-yl) 1 1 —Piperidyl] 1 1-methyl— 1 H-imidazo [4,5-g] quinazoline 1 2-one (compound 16)
  • the title compound was obtained as white crystals (yield 31%) according to the method of Example 3 except that compound 15 obtained in Example 15 was used instead of compound 1.
  • Example 15 The title compound was obtained as white crystals according to the method of Example 3 except that the compound 15 obtained in Example 15 was used instead of the compound 1 and that chloroiodyl was used instead of methyl iodide. (Yield 28%).
  • Example 18 3-Ethyl-1,2,3-dihydro-1-8- [4- (3,4-dihydro-1-6-methyl-4-oxoquinazoline-1 3-) 1) -Piperidyl] 1-11-Provyl-1H-imidazo [4,5-g] quinazoline-12-one (Compound 18) Compound 15 obtained in Example 15 was used in place of Compound 1. The title compound was prepared in the same manner as in Example 3 except that propyl iodide was used in place of methyl iodide. Obtained as color crystals (yield 26).
  • the title compound was obtained as white crystals according to the method of Example 14 except that the compound k obtained in the first step of Example 15 was used instead of the compound b (yield: 39%).
  • Second step Dissolve 710 mg (2.50 liters) of the compound obtained in the first step in 20 ml of DMF, add 890 mg (2.50 liters) of compound c, potassium carbonate 1.04 (7.50 liters) and potassium iodide After adding 20 mg (0.12 ol) and heating at 13 ° C. for 5 hours, the reaction solution was allowed to cool, and water was added, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from a mixed solvent of ethanol and ether to give the title compound as 1.1 (yield 86%) as white crystals.
  • the title compound was obtained as white crystals (yield 26%) according to the method of Example 28 except that the compound 27 obtained in Example 22 was used instead of the compound 25.
  • the title compound was obtained as white crystals (yield 22%) according to the method of Example 28 except that the compound 29 obtained in Example 24 was used instead of the compound 25.
  • Second step Dissolve 1.05 g (1.75 t ol) of the free base obtained in the first step in 20 ml of ethyl acetate, add an excess of saturated hydrogen chloride / ethyl acetate solution dropwise at room temperature, and stir for 10 minutes. did. The precipitated crystals were collected by filtration, washed with ethyl acetate, and recrystallized from ethanol to give 0.93 g (yield 84%) of the title compound as white crystals.
  • Example 36 1, 3 Jechiru - 2, 3-dihydro-5- [4- (1, 2, 3, 4-tetrahydronaphthalene-1, 6-dimethyl-one 2 , 4-Dioxoquinazoline-3-yl) — 1-piperidyl] —8— (4-methyl-1-piperazinyl) -1-H-imidazo [4,5-g] phthalazin-2-one 'dihydrochloride (Compound 36) The title compound was obtained as white crystals according to the method of Example 33 except that N-methylbiperazine was used instead of morpholine (two-step yield: 44 ⁇ ⁇ ).
  • the title compound was obtained as white crystals according to the method of Example 33 except that pyrrolidine was used instead of morpholine (two-step yield: 38%).
  • the title compound was obtained as white crystals according to the method of Example 33, except that hexamethyleneimine was used instead of morpholine (two-step yield: 46%).
  • the title compound was obtained as white crystals according to the method of Example 33 except that propylamine was used instead of morpholine and DMF was used instead of N-methylpyrrolidinone (two-step yield: 29%).
  • the title compound was obtained as white crystals according to the method of Example 33 except that dipropylamine was used instead of morpholine (two-step yield: 133 ⁇ 4).
  • Example 13 except that the compound 28 obtained in Example 23 was used instead of the compound 26.
  • the title compound was obtained as white crystals (yield 54%) according to the method of the first step of Example 33 except that the compound 29 obtained in Example 24 was used instead of the compound 26.
  • the title compound was obtained as white crystals (yield 50%) according to the method of the first step of Example 33 except that the compound 30 obtained in Example 25 was used instead of the compound 26.
  • Example 54 1,3-Diethyl-2,3-dihydro-8- [4- (1,2,3,4-tetrahydro-1,6-dimethyl-2 , 4-Dioxoquinazolin-1-yl)-1-piperidyl] — 1 H-imidazo [4,5-g] quinolin-2-one (compound 54) 2.30 g (6.49 marl ol) of Compound c was dissolved in 20 ml of N-methylpyrrolidinone, and the solution obtained in Reference Example 18 was added to the solution obtained in Reference Example 18 to obtain the 8-chloro-1,3-dimethyl-2,3-dihydro-1H-imidazo [4 , 5—g] quinoline-2-one (compound 1) 1.4 ( ⁇ (5.08 thigh 01) and N, N-diisopropylethylamine 2.65 ml (15.2 cafe ol) were added and
  • the compound can be synthesized by the method described in JP-A-54-154797, JP-A-54-154797, and 4-H-imidazo [4, [5-g]
  • the title compound was obtained as white crystals (yield 16%) according to the method of Example 54 except that quinolin-2-one was used.
  • the title compound was obtained as white crystals according to the method of the first step of Example 33 except that the compound 60 obtained in Example 60 was used instead of the compound 26 (yield: 39%).
  • Example 64 1,3-Jetyl-2,3-dihydro-5- [4- (1,2,3 1,4-tetrahydro-1,6-dimethyl-1,2,4-dioxoquinazoline-13-yl) -1-piperidyl] 1-morpholino 1 H-imidazo [4,5-g] isoquinoline-2-one (Compound 64)
  • Example 12 was repeated except that the compound 63 obtained in Example 62 was used instead of the compound 26.
  • the title compound was obtained as white crystals according to the method of the first step of 33 (yield 1250.
  • Example 68 6-chloro mouth—3— [1- (6,7-dimethoxy-4-quinazolinyl) —4-piperidyl] —3,4-dihydro-1 4 3-oxoquinazoline (compound 68)
  • compound cb 3- (1-ethoxycarbonyl-4-biperidyl) -1-6-chloro-1,3,4-dihydro-14-oxoquinazoline (compound da) obtained in Reference Example 25 is used.
  • the title compound was obtained as white crystals according to the method of Example 67 (44% yield).
  • Example 69 (dec.): 3- [ 1- (6, 7- dimethyl Tokishi 4-quinazolinyl) -4 Pipe lysyl] -3, 4-dihydro-6 —Nitro-1-oxoquinazoline (compound 69) 3- (1-ethoxycarbonyl-2- 4-beriberidyl) obtained in Reference Example 26 instead of compound cb —3,4-dihydro-16-nitro-14-oxoquinazoline The title compound was obtained as white crystals according to the method of Example 67 except that (compound ea) was used (yield 27 Colour
  • Example 70 6-Bromo-3- [1- (6, 7-dimethyl butoxy one 4 Kinazoriniru) one 4-piperidyl] -3, 4-dihydro-one 4- Okisokinazorin (Compound 70) Except for using 6-promo-3- (1-ethoxycarbonyl-14-piperidyl) -1,3,4-dihydro-4-oxoquinazoline (compound fa) obtained in Reference Example 27 in place of compound cb, The title compound was obtained as white crystals according to the method of Example 67 (yield 7750.
  • Example 67 Example 6 was repeated except that 6-acetyl-3- (1-ethoxycarbonyl-14-piperidyl) -1,3,4-dihydro-4-oxoquinazoline (compound ga) obtained in Reference Example 28 was used instead of compound cb. The title compound was obtained as white crystals according to the method described in (1) (yield 56%).
  • the title compound was prepared according to the method of Example 67 except that the compound da obtained in Reference Example 25 was used instead of the compound cb, and 2,4-dichloro-1,6,7-dimethoxyquinazoline was used instead of the compound ia.
  • Example 74 265 mg (0.5 t ol) of the compound 74 obtained in Example 74 was dissolved in 3 ml of DMF, and 0.30 ml (0.75 t ol) of (1-ethoxyvinyl) tributyltin was added to a catalytic amount of bis (triphenylphosphine). ) Palladium (II) chloride was added, and the mixture was stirred at 120 ° C for 2 hours. The reaction solution was cooled to room temperature, 2 ml of a 4N aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 1 hour.
  • reaction solution was neutralized with a 2N aqueous sodium hydroxide solution, and this was Mouth extracted with holm.
  • the organic layer is washed successively with a dilute aqueous solution of ammonium fluoride and saturated saline, dried and concentrated, and the residue obtained is purified by silica gel column chromatography.
  • Example 72 The compound obtained in 72, 500 mg (1.07 ⁇ 0 1) 10ml of N - was dissolved in methyl pyrrolidinone, which morpholine 0.9 ml (10.7 thigh ol) and triethylene Chiruamin 0.4 ml (3.21 ⁇ ol), and the mixture was heated and stirred at 130 ° C for 5 hours. The reaction solution was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration. The crude crystals were washed with water and methanol to obtain 529.4 mg (yield: 963 ⁇ 4;) of the free base of the title compound as white crystals.
  • Second step 300 mg (0.58 ol) of the free base obtained in the first step was dissolved in acetone, and 0.02 ml (1.28 ml) of methanesulfonic acid was added dropwise thereto at room temperature, followed by stirring for 5 hours. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with a mixed solvent of methanol and ether to give the title compound as white crystals (354.9 mg, yield 86%).
  • Example 76 The title compound was obtained as white crystals according to the method of Example 76 except that the compound 73 obtained in Example 73 was used instead of the compound 72 (yield: 80%).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that the compound 74 obtained in Example 74 was used instead of the compound 72, and morpholine was used instead of diethanolamine. 83%).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that the compound 74 obtained in Example 74 was used instead of the compound 72 (yield: 24%).
  • Example 75 The title compound was obtained as white crystals according to the method of Example 75 except that the compound 79 obtained in Example 79 was used instead of the compound 74 (yield: 48%).
  • Example 83 The title compound was obtained as white crystals according to the method of Example 76 except that the compound 83 obtained in Example 83 was used instead of the compound 72 (yield: 8150).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 using compound 83 obtained in Example 83 instead of compound 72 (yield 19%).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that Compound 92 obtained in Example 92 was used instead of Compound 72, and morpholine was used instead of diethanolamine. (Yield 993 ⁇ 4).
  • a silica gel column was prepared in the same manner as in Example 94 except that the compound 94 obtained in Example 94 (150 mg, 0.32 fraction) was used and propyl iodide 0.031 ml (0.32 mol) was used instead of methyl iodide.
  • the title compound was obtained as white crystals (154.1 mg, yield 93%) without purification by chromatography.
  • Example 94 Compound 94, 150 (0.32 band01) obtained in Example 94 was suspended in 3 ml of DMF, and sodium 60 hydride (32 mg, 0.8 t ol) was added thereto, followed by stirring at room temperature for 10 minutes. When the reaction mixture became homogeneous, 96 mg (0.48 tmol) of 2-dimethylaminoethyl chloride 'hydrochloride was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and further heated at 80 ° C for 7 hours. .
  • Example 99 3 — ⁇ [1— (2-chloro-1,6-, 7-dimethoxy-14-quinazolinyl) -1,4-piperidyl] methyl ⁇ —3,4 —Dihydro-1,6-dimethyl-4-oxoquinazoline (Compound 99)
  • the title compound was obtained as white crystals (yield: 71%) according to the method of Example 83 except that the compound ja obtained in Reference Example 30 was used instead of the compound he.
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that compound 99 obtained in Example 99 was used in place of compound 72, and morpholine was used in place of diethanolamine (yield 67%).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that the compound 99 obtained in Example 99 was used instead of the compound 72 (yield 4650).
  • H- ⁇ (CDC1 3 ) (5 (ppm): 8.03 (s, 1H), 7.58-7.50 (m, 2H), 6.99 (s, 1H), 6.93 (s, 1H), 4.17-4.10 (m, 4H), 3.97, 3.91 (each, s, 3H), 3.89-3.83 (m, 8H), 3.06- 2.97 (br.-t, 2H), 2.66, 2.48 (each, s, 3H), 2.20-2.15 ( m, 1H), 1.84- 1.80 (br.-d, 2H), 1.73-1.64 (m, 2H).
  • Example 104 3- ⁇ 2- ⁇ 1- [2-bis (2-hydroxyquishethyl) amino-6,7-dimethoxy-1-4-quinazolinyl] —4-piperidyl ⁇ Ethyl——3,4-dihydro-1,2,6-dimethyl-1-oxoquinazoline (compound 104) 4- [2- (2-amino-5-methylbenzoylamino) obtained in Reference Example 39 in place of compound pa ) Ethyl] — 1— [2-bis (2-hydroxyethyl) amino-6,7-dimethoxy-14-quinazolinyl] biperidine (compound sa) was used in the same manner as in Example 102. According to the above, the title compound was obtained as white crystals (two-step yield: 29%).
  • the title compound was white according to the method of Example 67 except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and that 6,7-diethoxy-14-chloroquinazoline was used instead of the compound ia. Obtained as crystals (yield 49%).
  • the compound of the title compound was prepared according to the method of Example 67 except that the compound da obtained in Reference Example 25 was used instead of the compound cb, and that 6,7-diethoxy-14 monoquinoline was used instead of the compound ia. After obtaining the free base, the title compound was obtained as white crystals according to the method of the second step in Example 76 (95% in two steps).
  • the title compound was white according to the method of Example 67 except that the compound ga obtained in Reference Example 28 was used instead of the compound cb, and that 6,7-diethoxy-14-chloroquinazoline was used instead of the compound ia. Obtained as crystals (18% yield).
  • the title compound was prepared in the same manner as in Example 67 except that the compound fa obtained in Reference Example 27 was used in place of the compound cb, and 6,7-jetoxy-1,2,4-dichloroquinazoline was used instead of the compound ia. Obtained as white crystals (81% yield).
  • Example 76 The title compound was obtained as white crystals according to the method of Example 76 except that Compound 108 obtained in Example 108 was used instead of Compound 72 (yield: 58%).
  • Example 76 The title compound was obtained as white crystals according to the method of Example 76 except that the compound 108 obtained in Example 108 was used instead of the compound 72 and N-methylbiperazine was used instead of morpholine (yield 42%).
  • Example 76 The title compound was obtained according to the method of the first step of Example 76 except that the compound 108 obtained in Example 108 was used instead of the compound 72 and ethyl isodipecotate was used instead of morpholine. Yield 42%).
  • Example 1 13 3— ⁇ 1- (2- (4-carboxypiperidino) -1 6,7—J Toxic 4-quinazolinyl] — 4-piperidyl ⁇ —3,4-dihydro-6-methyl 4-oxoquinazoline dimethanesulfonate (Compound 113)
  • Example 1 14 3- ⁇ 1- [2- bis (2-hydroxy E chill) Amino - 6, 7 - diethoxy one 4-quinazolinyl] - 4- Piperidyl ⁇ —3,4-dihydro-16-methyl-14-oxoquinazoline / 2-methanesulfonate (Compound 114)
  • the compound 108 obtained in Example 108 was used in place of the compound 72, and diethanolamine was used instead of morpholine.
  • the title compound was obtained as white crystals (yield 36%) according to the method of Example 76 except for using.
  • Example 76 The title compound was obtained as white crystals according to the method of Example 76 except that compound 108 obtained in Example 108 was used instead of compound 72, and propylamine was used instead of morpholine. 40%).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that compound 109 obtained in Example 109 was used instead of compound 72 and morpholine was used instead of diethanolamine (yield: 67%). ).
  • Example 77 The title compound was obtained as white crystals according to the method of Example 77 except that the compound 109 obtained in Example 109 was used instead of the compound 72 (yield: 15%).
  • Example 75 The title compound was obtained as white crystals according to the method of Example 75 except that the compound 116 obtained in Example 116 was used instead of the compound 74 (yield 24).
  • Example 120 3- [1- (8-main butoxy - 4-quinazolinyl) one 4-piperidines lysine le] -3, 4-dihydro-one 6- Methyl-4-oxoquinazoline (Compound 120) The method of Example 67 except that the compound bd obtained in Reference Example 23 was used in place of the compound cb, and that 4-hydroxy-1,8-methoxyquinazoline was used instead of the compound ia. The title compound was obtained as white crystals (yield 36%).
  • the title compound was prepared according to the method of Example 67, except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and that 4,7-dimethoxyquinazoline was used instead of the compound ia. Obtained as white crystals (yield 42%).
  • Example 67 The title was obtained according to the method of Example 67, except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and 4-chloro-17-methyl-16-methoxyquinazoline was used instead of the compound ia.
  • the compound was obtained as white crystals (yield 26%).
  • Example 67 The procedure was the same as that in Example 67 except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and 2,4-dichloro-6,7-methylenedioxyquinazoline was used instead of the compound ia.
  • the compound was obtained as white crystals (yield 72%).
  • Second step Dissolve 220 mg (0.44 rec. Ol) of the free base obtained in the first step in 20 ml of ethyl acetate, add an excess of saturated hydrogen chloride / ethyl acetate solution dropwise at room temperature, and stir for 10 minutes. . The precipitated crystals were collected by filtration and washed with ether to give the title compound (236.2 mg, yield 86%) as white crystals.
  • the title compound was prepared according to the method of Example 67, except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and 2,4-dichloro-6,7-diisopropoxyquinazoline was used instead of the compound ia.
  • Example 67 The title compound was prepared according to the method of Example 67, except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and 2,4-dichloro-6,7-diisopropoxyquinazoline was used instead of the compound ia.
  • Example 67 The procedure of Example 67 was followed, except that the compound bd obtained in Reference Example 23 was used instead of the compound cb, and 7-benzyloxy-12,4-dichloro-16-methoxyquinazoline was used instead of the compound ia.
  • the title compound was obtained as white crystals (yield
  • Example 13 1 3- [1- (7-Penjiruokishi - 6 main butoxy one 2- Moruhori Roh one 4-quinazolinyl) one 4-piperidyl] -3, 4-dihydro-1-6-methyl-1-oxoquinazoline hydrochloride (Compound 131)
  • Example 125 The title compound was obtained as white crystals (yield 55%) according to the method of Example 125 except that compound 130 obtained in Example 130 was used instead of compound 124.
  • Compound 132 was produced according to the method of Example 10 of International Publication WO 96/06841.
  • Example 68 of International Publication WO 94/1 9342 was converted to a hydrochloride by a conventional method to produce Compound 133.
  • Second step 2,3-dihydro-12-oxo-1H-benzimidazole-5-carboxylic acid which can be synthesized by a known method (for example, a method described in Japanese Patent Application Publication No. 61-207388).
  • Methyl 5.76 g (30.0 tmol) was suspended in 50 ml of DMF, 2.64 g (66.0 marl) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes.
  • 3.73 ml (60.0 tmol) of methyl iodide was added dropwise, and the mixture was further stirred at room temperature for 1 hour.
  • Second step 4.4 g (20.0 t) of the compound obtained in the first step was dissolved in 10 ml of acetic anhydride, and 1.02 ml (25.0 t) of fuming nitric acid was added dropwise, followed by stirring at room temperature for 20 minutes. Ice water was added to the mixture, and the precipitated crystals were collected by filtration and washed with water to give 2,3-dihydro-1, A crude product of 4.0 g of methyl 3-carboxy-1-troth-2-oxo-1-H-benzoimidazo-l-5-carbonate was obtained (yield: 753 ⁇ 4).
  • the title compound was obtained as white crystals according to the method of Reference Example 2 except that propyl iodide was used instead of methyl iodide (4-step yield: 39%).
  • the title compound was obtained as white crystals according to the method of Reference Example 2 except that butyl iodide was used instead of methyl iodide (four-step yield: 18%).
  • 6-amino-1,2,3-dihydro-11,3-dimethyl-12-oxo-1H-benzimidazole-5-carboxylate is replaced with the method of the second to third steps of Reference Example 2.
  • the title compound was prepared according to the method of Reference Example 5 except that the obtained 6-amino-1,3-diethyl-1,2,3-dihydro-2-oxo-1-H-benzoimidazole-1-methyl 5-carboxylate was used. Obtained as white crystals (two-step yield 70%).
  • Reference Example 7 5,8-Dichloro-1,2,3-dihydro-1,3, -dipropyl-1H-imidazo [4, 5 -g] quinazoline-2-one (compound i) 6-Amino-1,2,3-dihydro-1,3-dimethyl-12-oxo-1H-benzoimidazo-l-u
  • the method of the second to third steps of Reference Example 2 was repeated in place of methyl 5-rubinate. According to the method of Reference Example 5, except that 6-amino-1,2,3-dihydro-1,2-oxo-1,3, -dipropyl-1-H-benzoimidazo-1-lu-5-potassium methyl sulfonate obtained according to the method described above was used.
  • the first step a known method [for example, in Journal of Heterocycling. Chem., Vol. 10, page 89, page 1 (1973)] 4,24-Diaminophthalic acid dimethyl 9.24 (41.2 thigh 01), which can be synthesized by the method described in W TJP, was dissolved in 100 ml of acetonitrile, and 10.4 g (63.9 rel) of N, N, -carbodidimidazole was dissolved in 100 ml of acetonitrile. In addition, the mixture was heated and stirred at 60 ° C for 5 hours.
  • Second step 2.50 g (10.0 reference ol) of the compound obtained in the first step was suspended in 45 ml of DMF, 0.88 g (22.0 t ol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. When the reaction solution became homogeneous, 1.37 ml (22.0 liters) of methyl iodide was added dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to stop the reaction. The precipitated crystals were collected by filtration, washed with water, and 2,3-dihydro-1,3-dimethyl-12-oxo-11H-benzimidazole. 2.78 g of a crude product of methyl 1,6-dicarboxylate was obtained (yield: 99%).
  • Second step Dissolve the compound l.OOg (4.58 recited ol) obtained in the first step in a mixed solvent of 2-methyl-1-propanol (10 ml) and water (15 ml). 3.62 g (22.9 marl ol) of potassium acid was gradually added. After heating and stirring at 110 ° C for 1 hour, potassium permanganate (1.45 g, 9.16 mL) was gradually added, and the mixture was heated and stirred at 110 ° C for 1 hour. Thereafter, the mixture was filtered while hot using a filter aid, and the filtrate was concentrated.
  • Third step Dissolve 300 mg (1.08 tmol) of the compound obtained in the second step in a mixed solvent of 3 ml of acetic acid and 3 ml of water, add 0.26 ml of hydrazine monohydrate (5.40 bandol) and heat to reflux for 1.5 hours did. After cooling, the precipitated crystals were collected by filtration and washed with methanol to obtain a crude product of the title compound (102 mg, yield 34%).
  • the title compound was obtained according to the method described in JP-A-54-154797, except that getyl malonate was used in place of ethyl acetate.
  • First step Commercially available 2-hydroxybenzoimidazole is used in place of methyl 2,3-dihydro-12-oxo-1H-benzoimidazole-1-5-carboxylate, and methyl iodide is used. According to the method of the first step of Reference Example 2, 1,3-Jetyl-1,2,3-dihydro-11H-benzimidazole-1-one was obtained in the same manner as in the first step of Reference Example 2 except for using thiol thiol.
  • Second step 875 mg (6.56 t ol) of aluminum chloride is suspended in 3 ml of carbon disulfide, and 1.04 g (5.46 t ol) of the compound obtained in the first step and 0.55 ml (5.76 recitation) of propionyl chloride of 3-chloro mouth are obtained.
  • ol) in 5 ml of carbon disulfide was added dropwise over 5 minutes under ice cooling, followed by stirring at 50 ° C for 4 hours. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure, and 15 ml of sulfuric acid was added dropwise to the obtained residue under ice-cooling, followed by heating and stirring at 100 for 1.5 hours.
  • Second step The title compound was obtained as white crystals according to the method of the first step of Example 2 except that the compound obtained in the first step was used (yield: 883 ⁇ 4).
  • Second step The compound aa obtained in the first step, 1.41 g (4.0 ol) was dissolved in 20 ml of chloroform, and 0.36 ml (4.0 ol) of vinyl chloride formate was added dropwise at room temperature and stirred for 12 hours. did.
  • the solvent was distilled off under reduced pressure, ethyl acetate and ether were added to the residual oily substance, and the precipitated crystals were collected by filtration and washed with ether to obtain 1.29 g of white crude crystals. This was dissolved in 20 ml of methanol, 5 ml of a saturated hydrogen chloride-ethyl acetate solution was added thereto, and the mixture was heated under reflux for 2 hours.
  • Third step The compound ab obtained in the second step, 500 mg (1.61 mol) was suspended in 10 ml of methanol, and 361 mg (1.61 mg) of 4-chloro-1,6-dimethoxyquinazoline (compound ia) was suspended therein. After addition of 0.68 ml (4.83 liters) of triethylamine and heating to reflux for 3 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration.
  • Second step 84.8 g (0.25 mol) of the compound ba obtained in the first step is dissolved in 700 ml of ethanol, 8.4 g of 10% Pd / C is suspended in 20 ml of water, and the mixture is added under a hydrogen atmosphere at room temperature. And stirred vigorously for 12 hours. The reaction solution was filtered using a filter aid, the residue was washed with ethanol, and the filtrates were combined and concentrated under reduced pressure. Ethanol was added to the residue, and the precipitated crystals were collected by filtration, and 73.6 g (97% yield) of 4- (2-amino-15-methylbenzoylamino) -11-ethoxycarbodirubiperidine (compound bb) was obtained. With yellow crystals I got it.
  • the title compound was obtained according to the method of Reference Example 24, except for using 5-cycloisocyanate anhydride instead of isatoic anhydride.
  • reaction solution was neutralized with a 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate.
  • Second step 4-[(2-amino-5-methylbenzoylamino) methyl] — according to the method of the fourth step of Reference Example 22, except that the compound ha obtained in the first step is used instead of the compound ac. 1 Benzyl biperidine (compound hb) was obtained (yield 45%).
  • Third step The title compound was obtained according to the method of Example 66 except for using compound hb obtained in the second step in place of compound ad (yield 54%).
  • the title compound was obtained as white crystals according to the method of Reference Example 31 except that triethyl orthobutyrate was used instead of triethyl orthopropionate (yield: 203 ⁇ 4).
  • Reference Example 35 4-[(2-amino-5-methylbenzoylamino) methyl] -1- (6-, 7-dimethoxy-14-quinazolinyl) pyridine (compound ob)
  • First step To 1.81 g (10.0 t ol) of 5-methyl-2-nitrobenzoic acid was added 20 ml of thionyl chloride and heated at 100 ° C for 2 hours. 20 ml of methane was added (Solvent A), obtained according to the method described in Chemical 'and Pharmaceutical Bretane (Chem. Pharm. Bull.), 38, pp. 3014-3019 (1990) and references cited therein.
  • Second step The title compound was obtained as white crystals according to the method of the fourth step of Reference Example 22 except that the compound oa obtained in the first step was used instead of the compound ac (yield 7850.
  • Step 2 1- (6,7-dimension) according to the method of Example 77, except that compound ra obtained in step 1 is used in place of compound 72 and morpholine is used in place of genamine.
  • Toxin-2-morpholino-4-quinazolinyl) -1- [2- (5-methyl-12-nitrobenzoylamino) ethyl] piperidine (compound rb) was obtained as a white crystal, and then obtained in Reference Example 22.
  • the title compound was obtained as white crystals according to a four-step method (two-step yield: 68%).
  • a tablet having the following composition was prepared by a conventional method.
  • Compound 66, 40 g, lactose 286.8 g, and potato starch 60 g were mixed, and to this was added a 10% aqueous solution of hydroxypropyl cellulose, 120 g.
  • the mixture was kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • 1.2 g of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) having an eight-thigh punch, and tablets (20 mg of active ingredient per tablet) were obtained. Containing) was obtained.
  • RT-15 type manufactured by Kikusui Co., Ltd.
  • a capsule having the following composition was prepared by a conventional method.
  • Compound 132, 200 g, Avicel 995 g and magnesium stearate 5 g were mixed by a conventional method. This mixture is converted into hard capsules using a capsule filling machine (Zanasi, Model — 64). No. 4 (120m capacity per capsule) was filled to give a capsule (containing 20mg of active ingredient per capsule).
  • An injection having the following composition was prepared by a conventional method.
  • Compound 12 and lg were dissolved in 100 g of purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection were added.
  • This mixture was kneaded and emulsified in a conventional manner to 1000 ml with distilled water for injection.
  • the resulting dispersion is aseptically filtered using a 0.2 ⁇ m disposable membrane filter, and aseptically filled into glass vials in 2 ml increments for injection (containing 2 mg of active ingredient per vial) I got
  • a preparation for rectal administration having the following composition was prepared by a conventional method. 678.8 g of Witebzol TM H15 (manufactured by Dynamite Tonobel) and 290.9 g of Witepzol TM E75 (manufactured by Dynamite Tonobel) were melted at 40 to 50 ° C. Compound 133, 2.5 g, potassium monophosphate 13.6 g and sodium dibasic phosphate 14.2 g were uniformly mixed and dispersed therein. Then, the mixture is dispersed and placed in a plastic seat. After filling in the preparation form, the mixture was gradually cooled to give a rectal suppository (containing 2.5 mg of active ingredient per preparation).
  • Test Example 1 Analgesic effect of compound of formula (I)
  • the analgesic effect of the medicament of the present invention was examined by a formalin test.
  • Formalin test is one of the inflammatory pain models, and is widely used to study analgesic effects.
  • Subcutaneous administration of formalin to rats shows biphasic pain behavior.
  • Phase 1 (up to 9 minutes after formalin administration) is acute pain due to direct stimulation of local nerves
  • Phase 2 (10-60 minutes after formalin administration) is phase 1 pain stimulation and continuous pain stimulation due to inflammatory response (Pain Clinic, Vol. 15, pp. 498—502, pp. 199-4).
  • the administration dose of the test compound was 10 g.
  • Compounds 12 and 13 were dissolved in distilled water (Otsuka distilled water, manufactured by Otsuka Pharmaceutical Factory Co., Ltd.). Control groups received their respective solvents.
  • the volume of drug solution administered was 10 L per animal, and a lmg / mL solution was prepared so that the dose would be 10 / g.
  • Formalin was prepared by diluting formaldehyde solution (special grade, 36%, manufactured by Kanto Chemical Co., Ltd.) with distilled water (Otsuka Distilled Water, manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) to 5%.
  • the experiment was performed with 5 animals per group.
  • the animal in which the catheter was indwelled by the method (1) above was kept in a Bollman cage, and 10 minutes before the administration of formalin, 10 / L of the drug solution was intrathecally administered (i.t.) from the catheter to the spinal cord.
  • 10 / L of physiological saline Otsuka Raw Food Infusion, manufactured by Otsuka Pharmaceutical Factory Co., Ltd.
  • the control group received a solvent or distilled water in the same manner.
  • both hind limbs were taken out of the cage so as not to hinder the movement, and 50 L of 5% formalin was subcutaneously administered to the dorsal side of the left hind limb using a 30G injection needle (intraocular injection needle, manufactured by Nipro Medical Co., Ltd.).
  • a 30G injection needle intraocular injection needle, manufactured by Nipro Medical Co., Ltd.
  • the movement of shaking the foot was measured and used as an index of pain response. Measurements were taken every minute from 1 to 6 minutes after formalin administration and every 5 minutes from 10 to 60 minutes. The experiment was stopped if severe stress symptoms were observed before and during the measurement.
  • the results are shown in Table 11.
  • Compound 66, compound 132, and compound 133 showed analgesic activity in both phase 1 and phase 2.
  • Compound 12 showed excellent pain-suppressing activity in phase 2.
  • Test example 2 Acute toxicity test
  • the test compound was orally or intraperitoneally administered to three dd male mice (body weight: 20 ⁇ lg) per group.
  • the mortality on day 7 after administration was observed, and the minimum lethal dose (MLD) value was determined.
  • the MLD of compound 132 was> 100 Omg / kg by oral administration and> 10 Omg / kg by intraperitoneal administration.
  • Compound (I) or a pharmacologically acceptable salt thereof has an analgesic action, and is useful as an active ingredient of a medicament for preventing and / or treating acute pain, neuropathic pain and the like.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent analgésique contenant un dérivé de pipéridine comme principe actif représenté par la formule (I) ou son sel pharmaceutiquement acceptable, dans laquelle R1 représente un hydrogène, alkyle inférieur, etc.; R?2, R3, R4, R5¿ représentent chacun un hydrogène, alkyle inférieur, halogéno, etc.; n représente une valeur comprise entre 0 et 2; X1-X2 représentent un groupe de formule (a) ou (b), dans laquelle R6 représente un hydrogène, alkyle inférieur, etc. et X3 représente N ou C-R?15 (où R15¿ représente un hydrogène, alkyle inférieur, etc.); Y1-Y2-Y3 représente un groupe de formule (c) dans laquelle R11 représente un hydrogène, alkyle inférieur, hydroxyle, etc.; R?7, R8, R9, R10¿ représentent chacun un hydrogène, alcoxy inférieur, etc.
PCT/JP1999/001982 1998-04-17 1999-04-14 Agent analgesique WO1999053924A1 (fr)

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Cited By (15)

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US6358954B1 (en) * 1999-11-09 2002-03-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem PDGF receptor kinase inhibitory compounds, their preparation, purification and pharmaceutical compositions including same
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
WO2008028691A1 (fr) * 2006-09-07 2008-03-13 Bayer Schering Pharma Aktiengesellschaft N-(1-hétarylpipéridine-4-yl)(hét)arylamides utilisés en tant que modulateurs du récepteur ep2
US7910573B2 (en) 2006-06-02 2011-03-22 Bayer Schering Pharma Ag Crystalline forms of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one
US8278469B2 (en) 2009-07-20 2012-10-02 Bayer Pharma Aktiengesellschaft 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives, method of production thereof and use thereof for the treatment of diseases
US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators
US9085603B2 (en) 2010-02-10 2015-07-21 Bayer Intellectual Property Gmbh Progesterone receptor antagonists
US9096640B2 (en) 2009-07-20 2015-08-04 Bayer Intellectual Property 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-diene-11-methylene oxyalkylene aryl derivatives, process for preparation thereof, and use thereof for treatment of diseases
US9096639B2 (en) 2009-07-20 2015-08-04 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-acyloxyalkylene phenyl derivatives, methods for the production thereof and use thereof for treating diseases
US9102701B2 (en) 2009-07-21 2015-08-11 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-diene-11-ethynylphenyl derivatives, methods for the production thereof and use thereof for treating diseases
US9109004B2 (en) 2010-02-10 2015-08-18 Bayer Intellectual Property Gmbh Progesterone receptor antagonists
US9156877B2 (en) 2009-07-20 2015-10-13 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzylidene derivatives, methods for the production thereof and use thereof for treating diseases
US9206219B2 (en) 2009-07-21 2015-12-08 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl derivatives, methods for the production thereof and the use thereof for treating diseases
JP2016192555A (ja) * 2004-10-01 2016-11-10 メルク パテント ゲーエムベーハー 有機半導体を含む電子デバイス
JP2020535124A (ja) * 2017-09-26 2020-12-03 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド 多発性骨髄腫を治療するための新規なｕｓｐ７阻害剤

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JPH09216883A (ja) * 1996-02-09 1997-08-19 Fujisawa Pharmaceut Co Ltd ピラゾロピリジン化合物および該化合物を含有する医薬
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6358954B1 (en) * 1999-11-09 2002-03-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem PDGF receptor kinase inhibitory compounds, their preparation, purification and pharmaceutical compositions including same
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
JP2016192555A (ja) * 2004-10-01 2016-11-10 メルク パテント ゲーエムベーハー 有機半導体を含む電子デバイス
US7910573B2 (en) 2006-06-02 2011-03-22 Bayer Schering Pharma Ag Crystalline forms of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one
WO2008028691A1 (fr) * 2006-09-07 2008-03-13 Bayer Schering Pharma Aktiengesellschaft N-(1-hétarylpipéridine-4-yl)(hét)arylamides utilisés en tant que modulateurs du récepteur ep2
EP1903038A1 (fr) * 2006-09-07 2008-03-26 Bayer Schering Pharma Aktiengesellschaft Dérivés N-(1-hetaryl-piperidine-4-yl)-(het)arylamide utilisées comme modulateurs du recepteur EP2
US9096640B2 (en) 2009-07-20 2015-08-04 Bayer Intellectual Property 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-diene-11-methylene oxyalkylene aryl derivatives, process for preparation thereof, and use thereof for treatment of diseases
US9096639B2 (en) 2009-07-20 2015-08-04 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-acyloxyalkylene phenyl derivatives, methods for the production thereof and use thereof for treating diseases
US9156877B2 (en) 2009-07-20 2015-10-13 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzylidene derivatives, methods for the production thereof and use thereof for treating diseases
US8278469B2 (en) 2009-07-20 2012-10-02 Bayer Pharma Aktiengesellschaft 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives, method of production thereof and use thereof for the treatment of diseases
US10155004B2 (en) 2009-07-20 2018-12-18 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives, method of production thereof and use thereof for the treatment of diseases
US9102701B2 (en) 2009-07-21 2015-08-11 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-diene-11-ethynylphenyl derivatives, methods for the production thereof and use thereof for treating diseases
US9206219B2 (en) 2009-07-21 2015-12-08 Bayer Intellectual Property Gmbh 17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl derivatives, methods for the production thereof and the use thereof for treating diseases
US9085603B2 (en) 2010-02-10 2015-07-21 Bayer Intellectual Property Gmbh Progesterone receptor antagonists
US9109004B2 (en) 2010-02-10 2015-08-18 Bayer Intellectual Property Gmbh Progesterone receptor antagonists
US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators
JP2020535124A (ja) * 2017-09-26 2020-12-03 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド 多発性骨髄腫を治療するための新規なｕｓｐ７阻害剤
EP3687537A4 (fr) * 2017-09-26 2021-06-16 Dana-Farber Cancer Institute, Inc. Nouveaux inhibiteurs d'usp7 pour le traitement du myélome multiple
US11465983B2 (en) 2017-09-26 2022-10-11 Dana-Farber Cancer Institute, Inc. USP7 inhibitors for treating multiple myeloma

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