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WO2006013873A1 - Médicaments possédant une activité d'inhibition de la cyclooxygénase - Google Patents

Médicaments possédant une activité d'inhibition de la cyclooxygénase Download PDF

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Publication number
WO2006013873A1
WO2006013873A1 PCT/JP2005/014172 JP2005014172W WO2006013873A1 WO 2006013873 A1 WO2006013873 A1 WO 2006013873A1 JP 2005014172 W JP2005014172 W JP 2005014172W WO 2006013873 A1 WO2006013873 A1 WO 2006013873A1
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group
trifluoromethyl
phenol
formula
substituent
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Japanese (ja)
Inventor
Akiko Itai
Susumu Muto
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Institute of Medicinal Molecular Design Inc IMMD
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Institute of Medicinal Molecular Design Inc IMMD
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention selectively inhibits cycloxygenase (hereinafter sometimes abbreviated as “cox”), particularly cycloxygenase-2 (hereinafter sometimes abbreviated as “COX-2”).
  • cox cycloxygenase
  • COX-2 cycloxygenase-2
  • it relates to a medicament having antipyretic, analgesic, anti-inflammatory and anticancer effects.
  • Anti-inflammatory drugs such as aspirin and indomethacin are known to inhibit the production of prostaglandins by inhibiting COX, resulting in anti-inflammatory, antipyretic and analgesic effects.
  • COX-1 is always expressed even in normal conditions and is a prostanoid necessary for life support.
  • COX-2 is hardly expressed during normal time and strongly expressed during inflammation. Therefore, it has been suggested that selective inhibitors of COX-2 can be antipyretic and anti-inflammatory agents with less gastrointestinal disorders.
  • COX-2 selective inhibitors such as celecoxib have been developed so far and have already been promoted in Europe and the United States.
  • N-aryl salicylamide derivatives and Z or N-heteroaryl salicylamide derivatives are, for example, plant growth inhibitors (see Patent Document 1); anti-inflammatory agents (see Patent Documents 2 to 4). And NF- ⁇ inhibitors (see Patent Document 5).
  • these publications do not suggest or have been taught that these derivatives have a selective inhibitory action on COX, especially COX-2.
  • N-arylsalicylamido derivatives and N-heteroarylsalicylamide derivatives are inhibitors of inflammatory site force in production release (see Patent Document 6); NF- ⁇ B activation inhibitors (patents) Reference 7); Immune-related protein kinase inhibitor (see patent document 8); AP-1 and NFAT activation inhibitor (see patent document 9); Antiallergic drug (see patent document 10); Antidiabetic drug (patent document) 11); cancer therapeutic agent (see Patent Document 12); and neurodegeneration It is disclosed as a disease therapeutic agent (see Patent Document 13).
  • these publications do not suggest or teach that these derivatives have a COX, especially COX-2 selective inhibitory action.
  • Patent Document 15 This document exemplifies the following N-pyridyl salicylamide derivatives as salicylamide derivatives included in the pyridine derivative represented by the above formula.
  • this document discloses a method for measuring the inhibitory activity of COX-1 and COX-2, and the result of measuring the inhibitory activity of the pyridine derivative represented by the above formula.
  • the only compound that describes the measurement results of COX inhibitory activity is 2- (2,4-dimethylphenylamino) -5- (2,6-dichlorophenyl-polyamino) pyridine.
  • Specific test results showing that the lithylamide derivatives have COX-1 and Z or COX-2 inhibitory activity should be disclosed.
  • N-aryl salicylamide derivatives and Z or N-heteroaryl salicylamide derivatives NF- ⁇ B inhibitors
  • cytoforce-in production inhibitors see Patent Document 17
  • Inosine-1 5′-monophosphate dehydrogenase inhibitors see Patent Document 18
  • anti-inflammatory agents see Patent Document 19
  • the publications do not suggest or teach that these derivatives have a selective inhibitory action on COX, especially COX-2.
  • Patent Document 1 US Pat. No. 4,358,443
  • Patent Document 2 European Patent Application Publication No. 0221211
  • Patent Document 3 Japanese Patent Laid-Open No. 62-99329
  • Patent Document 4 U.S. Patent No. 6117859
  • Patent Document 5 Pamphlet of International Publication No. 99Z65449
  • Patent Document 6 International Publication No. 02Z49632 Pamphlet
  • Patent Document 7 International Publication No. 03Z103654 Pamphlet
  • Patent Document 8 International Publication No. 03Z103658 Pamphlet
  • Patent Document 9 International Publication No. 03Z103647 Pamphlet
  • Patent Document 10 International Publication No. 03Z103665 Pamphlet
  • Patent Document 11 Pamphlet of International Publication No. 03Z103655
  • Patent Document 12 International Publication No. 03Z103657 Pamphlet
  • Patent Document 13 Pamphlet of International Publication No. 03Z103658
  • Patent Document 14 Japanese Patent Laid-Open No. 4217916
  • Patent Document 15 Pamphlet of International Publication No. 99Z24404
  • Patent Document 16 Pamphlet of International Publication No.02Z076918
  • Patent Literature 17 Pamphlet of International Publication No.02Z051397
  • Patent Document 18 WO99Z55663 pamphlet
  • Patent Document 19 Pamphlet of International Publication No.02Z28819
  • Non-Patent Document 1 “The Lancet Oncology” (UK), 2003, No. 4, No. 10, p.605-615
  • An object of the present invention is to provide a medicament having antipyretic, analgesic, anti-inflammatory and anticancer effects by selectively inhibiting COX, particularly COX-2. More specifically, it is an object of the present invention to provide a COX inhibitor having excellent efficacy and reduced side effects.
  • the present inventors have shown that COX inhibition of salicylamide derivatives, which are generally said to have low toxicity.
  • N-substituted salicylamide derivatives especially N-arylicylamide derivatives, have strong COX inhibitory action, especially selective and strong inhibitory action on COX-2.
  • the present inventors further conducted similar studies with respect to the hydroxyaryl derivative, which is an analog thereof, and completed the present invention.
  • the present invention provides:
  • a medicament having a COX inhibitory action which has the following general formula (I):
  • X represents a linking group having 2 or 5 atoms in the main chain (the linking group may have a substituent! /),
  • A represents a hydrogen atom or a acetyl group
  • E has a substituent! /, May have an aryl group or a substituent, may represent a heteroaryl group,
  • Ring Z is an arylene which may further have a substituent in addition to the groups represented by the formulas O—A and X—E, or the groups represented by the formulas O—A and X—E.
  • the compound represented by (with other substituents !, may represent heteroarenes) and pharmacologically acceptable salts thereof, and hydrates and solvates thereof This provides a medicine containing a selected substance as an active ingredient.
  • a force is a hydrogen atom or a acetyl group
  • Ring Z force In addition to the group represented by the formula OA and the formula X—E, may further have a substituent, or further substituent other than the group represented by the formula OA and the formula X—E Have a! It ’s a heteroarene,
  • E force having a substituent! / May be an aryl group or a substituent, and may be a heteroaryl group as described above;
  • A is a hydrogen atom or a acetyl group
  • Ring Z force In addition to the group represented by the formula OA and the formula X—E, may further have a substituent, or further substituent other than the group represented by the formula OA and the formula X—E Have a! It ’s a heteroarene,
  • A is a hydrogen atom
  • Ring Z force In addition to the group represented by the formula OA and the formula X—E, may further have a substituent, or further substituent other than the group represented by the formula OA and the formula X—E Have a! It ’s a heteroarene,
  • E force 2, 5 The medicament according to (3) above, which is a di-substituted phenyl group;
  • A is a hydrogen atom
  • Ring Z force In addition to the group represented by the formula OA and the formula X—E, may further have a substituent, or further substituent other than the group represented by the formula OA and the formula X—E Have a! It ’s a heteroarene,
  • E force 2,5 is a di-substituted phenyl group (provided that at least one of the substituents is a trifluoromethyl group);
  • A is a hydrogen atom
  • Ring Z is an arylene of C to C (the arene is a group represented by the formula O A and the formula X—E.
  • A is a hydrogen atom
  • Ring Z force is a benzene ring which may further have a substituent in addition to the groups represented by the formulas O A and X—E,
  • E force 2,5 is a di-substituted phenyl group (provided that at least one of the substituents is a trifluoromethyl group);
  • A is a hydrogen atom
  • R z represents a hydrogen atom, a halogen atom, a nitro group, a methyl group, or a methoxy group
  • E is a group selected from the following “substituent group ⁇ -3e”; [Substituent group ⁇ -3e] 2 -Chroguchi 1- (trifluoromethyl) phenol Group, 2, 5 bis (trifluoromethyl) phenol group, 2 fluoro-5 (trifluoromethyl) phenol group, 2-nitro-5 (trifluoromethyl) phenol group, 2-methyl-5 ( Trifluoromethyl) phenol, 2-methoxy-5- (trifluoromethyl) phenol, 2-methylsulfur-5- (trifluoromethyl) phenol, 2- ( 1-pyrrolidyl) -5 (trifluoromethyl) phenol group, 2 morpholino 5 (trifluoromethyl) phenol group, 2 bromo- 5- (trifluoromethyl) phenyl group, 2- (2 naphthyloxy) 5 (trifluoromethyl) phenol group, 2— (2,4 dichlorophenoxy) 5 (trifluoromethyl) phenol 2
  • R z is a halogen atom
  • (10) A is a hydrogen atom
  • R z is a halogen atom
  • R z is a bromine atom
  • A is a hydrogen atom
  • Ring Z may further have a substituent in addition to the group represented by formula OA and formula X—E, or may be further substituted in addition to the group represented by formula OA and formula X—E.
  • A is a hydrogen atom
  • Ring Z may further have a substituent in addition to the groups represented by formula OA and formula X—E.
  • a substituent in addition to the groups represented by iarene or the formula OA and the formula X—E, it has further substituents! It ’s a heteroarene,
  • A is a hydrogen atom
  • Ring Z is an arylene of C to C (the arene is a group represented by the formula O A and the formula X—E.
  • A is a hydrogen atom
  • Ring Z force is a benzene ring which may further have a substituent in addition to the groups represented by the formulas O A and X—E,
  • E force 3, 5 is a di-substituted phenyl group (provided that at least one of the substituents is a trifluoromethyl group);
  • A is a hydrogen atom
  • R z represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a methoxy group, a methyl group, Sopropyl group, tert butyl group, 1, 1, 3, 3—tetramethylbutyl group, 2 phenolene—1—yl group, 2, 2—disyanethene—1—yl group, 2—cyan— 2— (Methoxycarbonyl) ethene-1-yl group, 2-carboxy-2-cyanethene-1-yl group, ether group, phenolic group, (trimethylsilyl) ethyl group, trifluoromethyl group, pentafluoroethyl group, Phenyl group, 4 (trifluoromethyl) phenyl group, 4-fluorophenyl group, 2,4 difluorophenol group, 2 phenethyl group, 1-hydroxyethyl group, 1- (methoxyimino)
  • R z is a halogen atom
  • R z is a halogen atom
  • R z is a chlorine atom
  • Another aspect of the present invention is that the compound represented by the general formula (I) and the pharmacologically acceptable
  • a COX inhibitor comprising a selected substance, preferably a COX-2 selective inhibitor; the above general formula (I
  • a method comprising the step of administering a prophylactic and Z or therapeutically effective amount of the above substance to a mammal including a human; a method of selectively inhibiting COX-2 in a mammal including a human, A method comprising the step of administering a prophylactic and Z or therapeutically effective amount of said substance to a mammal animal including a human; a preventive and Z or therapeutic method for febrile disease in a mammalian animal including a human, wherein said prophylactic agent And a method comprising the step of administering Z or a therapeutically effective amount to mammals including humans; a method for preventing and Z or treating pain in mammals including humans, wherein the preventive and Z or therapeutically effective amount of said substance is reduced.
  • Nursing A method comprising the step of administering to a mammal; a method for preventing and / or treating inflammation in mammals including humans, the method comprising administering a prophylactic and Z or therapeutically effective amount of said substance to a mammalian animal including humans And a method for treating cancer in mammals, including humans, comprising the steps of administering a prophylactic and Z or therapeutically effective amount of said substance to a mammal including humans.
  • the medicament of the present invention has a COX inhibitory action, preferably a COX-2 selective inhibitory action, and is useful as a medicament for prevention and Z or treatment of diseases involving COX and COX-2. It is for.
  • Patent Documents 1 to 5 Specific examples of the compound represented by the general formula (I) and pharmacologically acceptable salts thereof, hydrates thereof and solvates thereof include Patent Documents 1 to 5 and Mention may be made of the substances described in 14-19. These substances can be synthesized by the method described in the above patent document or a method analogous thereto. For the understanding of the present invention, the disclosures of Patent Documents 1 to 5 and 14 to 19 are all incorporated herein by reference.
  • the linking group having 2 to 5 atoms in the main chain refers to a linking group in which there are 2 or 5 main chain atoms between rings Z and E. Means.
  • the “number of atoms in the main chain” is counted so that the number of atoms existing between rings Z and E is minimized regardless of the presence or absence of heteroatoms.
  • the number of 1,2 cyclopentylene atoms is 2, the number of 1,3 cyclopentylene atoms is 3, the number of 1,4 phenol atoms is 4, the number of 2,6 pyridine dils is 3. Count as.
  • linking group having 2 or 5 atoms in the main chain is formed by one group selected from the following divalent group ⁇ 1-1, or the following divalent group: It is formed by combining 1 to 4 groups selected from group ⁇ 1 to 2 and 2 groups.
  • each group may be the same or different! /!
  • the “linking group having 2 to 5 atoms in the main chain” is preferably a group selected from the following linking group group ⁇ .
  • the "linking group having 2 or 5 main chain atoms” may have a substituent.
  • substituents when “optionally substituted” is stated with respect to a certain functional group, one or two functional groups are present at chemically possible positions unless otherwise specified. It means that it may have the above “substituent”.
  • the type of substituents present in the functional group, the number of substituents, and the position of substitution are not particularly limited. When two or more substituents are present, they may be the same or different. .
  • Examples of the “substituent” present in the functional group include a halogen atom, oxo group, thixo group, nitro group, nitroso group, cyano group, isocyano group, cyanato group, thiocyanato group, isocyanato group, isothiocyanato group, hydroxy group.
  • sulfar group carboxy group, sulfar carbol group, oxa mouth group, methoxa mouth group, thio carboxy group, dithio carboxy group, force rubamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group, sulfino Group, sulfinamoyl group, sulfeno group, sulfenamoyl group, phosphono group, hydroxyphosphoro group, hydrocarbon group, heterocyclic group, hydrocarbon oxy group, heterocyclic oxy group, hydrocarbon sulfar group, heterocyclic monosulfur group Group, acyl group, amino group, hydrazino group, hydrazono group, diazel group, c Raid group, thioureido group, guazino group, carbamoimidoyl group (amidino group), azido group, imino group, hydroxyamino group,
  • the "substituent” in the definition of "having a substituent may be” may be substituted with the "substituent” at a chemically possible position on the substituent. Good.
  • the type of substituent, The number of substituents and the substitution position are not particularly limited, and when they are substituted with two or more substituents, they may be the same or different. Examples of such groups include, for example, halogenated alkyl carbonyl groups (specific examples: groups such as trifluoroacetyl), halogenated alkyl sulfonyl groups (specific examples: groups such as trifluoromethane sulfol).
  • the substituent of "the linking group may have a substituent" in the definition of "the linking group having 2 or 5 atoms in the main chain” includes the above-mentioned "substituent And a group similar to the “substituent” in the definition of ⁇ , preferably an alkyl group of c1 to c6, more preferably a methyl group. is there.
  • the substituent may be taken together with the substituent of the ring Z or E to form an optionally substituted cyclic group together with the atom to which they are bonded. Examples of such compounds include compounds represented by the general formula (I):
  • examples of A include a hydrogen atom or a acetyl group, preferably a hydrogen atom.
  • arene of “having further substituents in addition to the groups represented by formula OA and formula X—E! / Arene” is monocyclic or condensed poly Cyclic aromatic hydrocarbons such as benzene ring, naphthalene ring, anthracene ring, phenanthate Examples include a len ring and a acenaphthylene ring. Preferred are c to c arenes such as a benzene ring and a naphthalene ring, and more preferred are a benzene ring and a naphthalene ring.
  • a benzene ring is preferred.
  • the “substituent” of the “arene” in addition to the group represented by the formula OA and the formula X—E in the definition of the ring Z is the above “substituent”. Examples thereof include the same groups as the “substituent” in the definition of “may be present”.
  • the substitution position on the arene of the substituent is not particularly limited. Also, when two or more substituents are present, they may be the same or different! /! /.
  • arene optionally having a substituent in addition to the group represented by the formula OA and the formula X—E force is represented by the formula —O—A and the formula —X—E.
  • a benzene ring which may further have a substituent in addition to the group represented by the above formula, preferably, in addition to the groups represented by Formula 1 O-A and Formula X-E, “A benzene ring having three substituents”, and more preferably “a benzene ring having one substituent in addition to the groups represented by the formula OA and the formula X—E”.
  • the substituent is preferably a group selected from the following “substituent group ⁇ -lz”, and more preferably a halogen atom and a tert-butyl group [(1, 1-dimethyl ) Ethyl group], most preferably a halogen atom.
  • R z is preferably a group selected from the following “substituent group ⁇ -2 ⁇ ”, more preferably a halogen atom and a tert butyl group, and most preferably a halogen atom.
  • heteroene in “having further substituents in addition to the groups represented by the formulas OA and X—E!
  • examples of the child (ring atom) include monocyclic or condensed polycyclic aromatic heterocycles containing at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Examples include condensed polycyclic aromatic heterocycles.
  • a 5- to 13-membered monocyclic or condensed polycyclic aromatic heterocyclic ring is preferable, and a thiophene ring, a pyridine ring, an indole ring, a quinoxaline ring, and a force rubazole ring are more preferable.
  • the position of substitution on the heteroarene of the substituent is not particularly limited. Further, when two or more substituents are present, they may be the same or different.
  • the “substituent” of the “heteroarene optionally having a substituent in addition to the group represented by the formula OA and the formula X—E” in the definition of the ring Z is preferably a halogen atom. A child.
  • the "aryl group" of the "aryl group” in the definition of E includes the same group as the "aryl group” in the definition of the "hydrocarbon group”.
  • C to C aryl groups such as phenyl group, 1 naphthyl group, and 2-naphthyl group,
  • a phenyl group is preferred.
  • the “substituent” of the “aryl group” in the definition of E above is the “substituent” in the definition of “having a substituent.” A similar group.
  • the substitution position on the aryl group of the substituent is not particularly limited, and when two or more substituents are present, they may be the same or different! /.
  • aryl group in the definition of E above is “a phenyl group which may have a substituent”, it is preferably a “mono-substituted file”.
  • the “aryl group optionally having substituent (s)” in the definition of E above is “2,5-disubstituted phenyl group”, more preferably, “2,5-disubstituted phenyl group (provided that the At least one of the substituents is a trifluoromethyl group) ”, particularly preferably a group selected from the following“ substituent group ⁇ -3e ”, most preferably 2, 5 Bis (trifluoromethyl) phenol group.
  • the above “optionally substituted aryl group” is a "3,5 disubstituted phenol group", more preferably, a "3,5 disubstituted phenol group ( Provided that at least one of the substituents is a trifluoromethyl group) ”, particularly preferably a group selected from the following“ substituent group ⁇ -5e ”, most preferably 3, 5-bis (trifluoromethyl) phenol group.
  • aryl group in the definition of E above is “a phenyl group having three or more substituents”
  • suitable groups include the following “substituents” And groups represented by group ⁇ -7ej.
  • heteroaryl group of the “having a substituent, which may have a substituent,” in the definition of E is the “monocyclic heteroaryl group” and the “condensed polycyclic ring” in the definition of the above “heterocyclic group”. Examples thereof include the same groups as those in the formula “heteroaryl group”. Preferably, it is a 5- to 13-membered heteroaryl group. Specific examples of suitable groups include a chael group, a pyrazolyl group, an oxazolyl group, a 1,3,4 thiadiazolyl group, a pyridyl group, and a pyrimidinyl group. Group, indolyl group, quinolyl group, carbazolyl group, thiazolyl group, and pyrajur group.
  • heteroaryl group of the “having a substituent, which may have a substituent” in the definition of E is more preferably a 5-membered heteroaryl group, and particularly preferably a phenyl group.
  • the "substituent" of "having a substituent may be a heteroaryl group" in the above definition of E is the same as in the definition of "having a substituent”.
  • the same groups as “substituent” are listed.
  • the substitution position of the substituent on the heteroaryl group is not particularly limited, and when two or more substituents are present, they may be the same or different.
  • “having a substituent, may be a heteroaryl group” is “a substituent.
  • “optionally having thiazolyl group” it is preferably “optionally substituted thiazole-2-yl group”, and more preferably “monosubstituted thiazol-2-yl”.
  • the compound represented by the general formula (I) can form a salt.
  • a metal salt such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, or ammonium salt
  • Ammonium salts such as methyl ammonium salt, dimethyl ammonium salt, trimethyl ammonium salt, dicyclohexyl ammonium salt, etc.
  • mineral salts such as hydrochloride, odorate, sulfate, nitrate, phosphate, etc., or methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate, propion Organic acid salts such as acid salts, tartrate salts, fumarate salts, maleates, malates, oxalates, succinates, succinates, benzoates, mandelate, kainate, lactate Can be raised. It may form a salt with an amino acid such as glycine.
  • a pharmaceutically acceptable salt can also be suitably used as the active ingredient of the medicament of the present invention.
  • the compound represented by the general formula (I) or a salt thereof may exist as a hydrate or a solvate. Any of the above substances may be used as the active ingredient of the medicament of the present invention. Further, the compound represented by the general formula (I) may have one or more asymmetric carbons and may exist as a stereoisomer such as an optically active diastereomer. As an active ingredient of the medicine of the present invention, a stereoisomer in a pure form, an optical enantiomer or an arbitrary mixture of diastereomers, a racemate and the like may be used.
  • the compound represented by the general formula (I) has, for example, a 2-hydroxypyridine structure, it may exist as a 2-pyridone structure which is a tautomer thereof.
  • a pure tautomer or a mixture thereof may be used.
  • the configuration may be either the Z configuration or the E configuration as an active ingredient of the medicament of the present invention! Alternatively, geometrical isomers of any arrangement or mixtures thereof may be used.
  • the compounds included in the general formula (I) are exemplified below as the active ingredients of the medicament of the present invention.
  • the active ingredients of the medicament of the present invention are not limited to the following compounds.
  • surface is as follows.
  • the compound represented by the general formula (I) has a COX inhibitory action, preferably a COX-2 selective inhibitory action, as an active ingredient of a medicine for antipyretic, analgesic, anti-inflammatory and cancer treatment.
  • a COX inhibitory action preferably a COX-2 selective inhibitory action
  • the mechanism of action of the above drugs in cancer treatment is thought to be due to the anti-angiogenic effect of tumors, which is highly effective in cancers that highly express COX-2, and also that the sensitivity of conventional anticancer agents is enhanced. (See Non-Patent Document 1).
  • the above medicaments are diseases that can be treated by inhibiting COX-2, more specifically, for example, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout attacks, shoulder joint arthritis, Acute otitis media, symptomatic neuralgia, cystitis, prostatitis, toothache, temporomandibular disorders, alveolar periosteitis, polymorphic exudative erythema, erythema nodosum, palmoplantar pustulosis, endometriosis, etc., analgesia, anti-inflammatory Useful for.
  • COX-2 more specifically, for example, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout attacks, shoulder joint arthritis, Acute otitis media, symptomatic neuralgia, cystitis, prostatitis, toothache, temporomandibular disorders, alveolar periosteitis, polymorphic ex
  • NF- ⁇ B inhibitory activity since the above-mentioned medicine also has NF- ⁇ B inhibitory activity (see Patent Documents 6 and 7), furthermore, diseases involving NF- ⁇ B, more specifically chronic Rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, systemic scleroderma, polymyositis, Siedalen syndrome, vasculitis syndrome, antiphospholipid syndrome, Still's disease, Behcet's disease, nodular artery Autoimmune diseases such as peripheral inflammation, ulcerative colitis, Crohn's disease, active chronic hepatitis, glomerulonephritis, chronic nephritis, chronic splenitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, intimal thickening , Psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, epilepsy, hay fever, allergic diseases, asthma, bronchi
  • Hyperlipidemia diseases with abnormal vascular proliferation such as retinopathy, pneumonia, Alzheimer's disease, encephalomyelitis, epilepsy, acute hepatitis, chronic hepatitis, drug-addictive hepatopathy, alcoholic hepatitis, viral hepatitis , Jaundice, cirrhosis, liver failure, atrial mucus Tumor, Castleman syndrome, mesangial proliferative nephritis, kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer, knee cancer, other solid cancers, sarcoma, osteosarcoma, metastatic infiltration of cancer, canceration of inflammatory lesions, cancerous worse From liquid quality, cancer metastasis, leukemia such as acute myeloblastic leukemia, multiple myeloma, rennel trypanoma, malignant lymphoma, cancer resistance to cancer, canceration of lesions such as viral hepatitis and cirrhosis, from colon polyp
  • the medicament of the present invention is suitable for metabolic bone diseases such as osteoporosis and bone cancer pain.
  • the active ingredient of the medicament of the present invention is selected from the group consisting of the compound represented by the general formula (I) and pharmacologically acceptable salts thereof, and hydrates and solvates thereof.
  • One kind or two or more kinds of substances can be used.
  • the medicament of the present invention The substance described above may be used, but preferably, the medicament of the present invention is a pharmaceutical composition comprising the above-mentioned substance, which is an active ingredient, and one or more pharmaceutically acceptable pharmaceutical additives. Provided in form. In the above pharmaceutical composition, the ratio of the active ingredient to the pharmaceutical additive is about 1% to 90% by weight.
  • the medicament of the present invention is administered as a pharmaceutical composition for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids.
  • a pharmaceutical composition for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids.
  • injections for intravenous, intramuscular or subcutaneous administration drops, suppositories, transdermal absorption agents, transmucosal absorption agents, nasal drops, ear drops, eye drops, inhalation
  • It can also be administered as a pharmaceutical composition for parenteral administration such as an agent.
  • a preparation prepared as a pharmaceutical composition in the form of a powder may be dissolved at the time of use and used as an injection or infusion.
  • Solid or liquid pharmaceutical additives can be used for the production of the pharmaceutical composition.
  • the pharmaceutical additive may be either an organic substance or an inorganic substance. That is, when producing an oral solid preparation, after adding excipients, further binders, disintegrants, lubricants, coloring agents, flavoring agents and the like to the main drug as necessary, tablets, Formulations in the form of coated tablets, granules, powders, capsules and the like can be prepared.
  • excipients include lactose, sucrose, sucrose, glucose, corn starch, starch, talc, sorbite, crystalline cellulose, dextrin, kaolin, calcium carbonate, silicon dioxide and the like.
  • binder examples include polybulal alcohol, polybutylether, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, and pectin. Can do.
  • lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hardened oil. Any colorant can be used as long as it is normally allowed to be added to pharmaceutical products.
  • a flavoring agent cocoa powder, pine bran, aromatic acid, bonito oil, dragon brain, cinnamon powder and the like can be used. These tablets and granules can be appropriately coated with sugar coating, gelatin coating, etc. if necessary.
  • preservative, antioxidant, etc. can be added as needed.
  • liquid preparations for oral administration such as emulsions, syrups, suspensions, solutions
  • inert diluents such as water or vegetable oils
  • this preparation may contain adjuvants such as wetting agents, suspending aids, sweeteners, fragrances, coloring agents or preservatives.
  • solvents or suspensions used in the manufacture of preparations for parenteral administration such as injections or suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin.
  • Examples of the base used for producing the suppository include cocoa butter, emulsified cocoa butter, laurin butter, and witetbuzole.
  • the preparation method of the preparation is not particularly limited, and any method widely used in the art can be used.
  • the carrier is, for example, water, ethyl alcohol, macrogol, propylene glycol, citrate, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide.
  • Diluents such as sodium citrate, sodium acetate and sodium phosphate pH adjusters and buffers; sodium pyrosulfite, ethylenediamine tetraacetic acid, thioglycolic acid and thiolactic acid and other stabilizers can be used.
  • a normal solubilizer, soothing agent or local anesthetic that may contain a sufficient amount of sodium chloride, glucose, mannitol or glycerin in the preparation to prepare an isotonic solution. It can be done by using agents.
  • ointments such as pastes, creams and gels
  • bases for example, white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite and the like
  • preservative methyl noroxybenzoate, ethyl oxycarboxylate, propyl paraoxybenzoate and the like
  • the above-mentioned ointment, cream, gel, paste or the like can be applied to an ordinary support by a conventional method.
  • the dose of the medicament of the present invention is not particularly limited, but in the case of oral administration, the weight of the substance as an active ingredient per day for an adult is usually 0.01-5, OOOmg. It is preferable to increase or decrease the dose according to the patient's age, condition and symptoms.
  • the daily dose may be administered once a day, or divided into 2-3 times a day at an appropriate interval, or may be administered intermittently every several days.
  • the weight of the substance, which is an active ingredient per day for adults is about 0.001 to 100 mg.
  • prostaglandin H2 generated from arachidonic acid by COX-1 derived from human platelets was converted to prostaglandin E2, and quantified by enzyme immunoassay method to inhibit COX-1 of the compound of the present invention The effect was measured.
  • COX inhibitory activity is expressed as IC value M) or inhibition rate (%) in 1 ⁇ test compound.
  • the medicament of the present invention has a COX inhibitory action, preferably a COX-2 selective inhibitory action, and is useful as a medicament for prevention and Z or treatment of diseases involving COX and COX-2. .

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Abstract

L'invention concerne les médicaments possédant une activité d'inhibition de la cyclooxygénase, de préférence une activité d'inhibition sélective de la cyclooxygénase 2, et qui contiennent comme ingrédients actifs des composés de formule générale (I) ou les sels correspondants : (I) dans laquelle X est un groupement de liaison, optionnellement substitué, dont la chaîne principale est composée de 2 à 5 atomes; A est l'hydrogène ou l'acétyle; E est un aryle optionnellement substitué ou un hétéroaryle optionnellement substitué; et Z est une arène qui contient un substituant en plus des groups ayant la formule générale : -O-A et -X-E ou une hétéroarène qui peut avoir un substituant en plus des groupes de formules générales : -O-A et -X-E.
PCT/JP2005/014172 2004-08-05 2005-08-03 Médicaments possédant une activité d'inhibition de la cyclooxygénase Ceased WO2006013873A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015037659A1 (fr) 2013-09-13 2015-03-19 株式会社医薬分子設計研究所 Préparation de solution aqueuse et son procédé de fabrication

Citations (5)

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Publication number Priority date Publication date Assignee Title
JPH04217916A (ja) * 1990-06-21 1992-08-07 Japan Tobacco Inc 抗炎症剤
WO2002049632A1 (fr) * 2000-12-18 2002-06-27 Institute Of Medicinal Molecular Design. Inc. Inhibiteurs de production et de liberation de cytokines inflammatoires
WO2003103658A1 (fr) * 2002-06-05 2003-12-18 株式会社医薬分子設計研究所 Inhibiteurs de proteines-kinases en relation a l'immunite
WO2003103655A1 (fr) * 2002-06-10 2003-12-18 株式会社医薬分子設計研究所 Agent therapeutique pour soigner le cancer
WO2003103665A1 (fr) * 2002-06-06 2003-12-18 株式会社医薬分子設計研究所 Anti-allergique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04217916A (ja) * 1990-06-21 1992-08-07 Japan Tobacco Inc 抗炎症剤
WO2002049632A1 (fr) * 2000-12-18 2002-06-27 Institute Of Medicinal Molecular Design. Inc. Inhibiteurs de production et de liberation de cytokines inflammatoires
WO2003103658A1 (fr) * 2002-06-05 2003-12-18 株式会社医薬分子設計研究所 Inhibiteurs de proteines-kinases en relation a l'immunite
WO2003103665A1 (fr) * 2002-06-06 2003-12-18 株式会社医薬分子設計研究所 Anti-allergique
WO2003103655A1 (fr) * 2002-06-10 2003-12-18 株式会社医薬分子設計研究所 Agent therapeutique pour soigner le cancer

Non-Patent Citations (1)

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Title
VERMA P. ET AL: "On the role of polarizability in QSAR", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 13, no. 1, 2004, pages 237 - 255, XP004668290 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015037659A1 (fr) 2013-09-13 2015-03-19 株式会社医薬分子設計研究所 Préparation de solution aqueuse et son procédé de fabrication
US9974860B2 (en) 2013-09-13 2018-05-22 Akiko Itai Aqueous solution formulation and method for manufacturing same

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