WO2005094805A1 - Dérivé imine et dérivé amide - Google Patents

Dérivé imine et dérivé amide Download PDF

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Publication number
WO2005094805A1
WO2005094805A1 PCT/JP2005/006464 JP2005006464W WO2005094805A1 WO 2005094805 A1 WO2005094805 A1 WO 2005094805A1 JP 2005006464 W JP2005006464 W JP 2005006464W WO 2005094805 A1 WO2005094805 A1 WO 2005094805A1
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Prior art keywords
group
substituent
hydroxy
hydroxypyrazole
compound
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PCT/JP2005/006464
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English (en)
Japanese (ja)
Inventor
Rika Tanaka
Hirohisa Kitagawa
Masao Sasaki
Susumu Muto
Akiko Itai
Ryukou Tokuyama
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Institute Of Medicinal Molecular Design. Inc.
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Publication of WO2005094805A1 publication Critical patent/WO2005094805A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P25/00—Drugs for disorders of the nervous 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
    • A61P25/04—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P37/08—Antiallergic agents
    • 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 relates to a production inhibitory effect of prostaglandin D2 (PGD2) and Z or hematopoietic type.
  • the present invention relates to a medicament having a PGD2 synthase inhibitory action and having an action such as an anti-allergy, anti-inflammatory, tissue damage-protecting action or anti-asthma.
  • Prostaglandin D2 is a type of arachidonic acid metabolite synthesized using prostaglandin H2 (PGH2) as an intermediate by the cyclooxygenase pathway in the arachidonic acid cascade. It is known that prostaglandin F2a (PGF2 ⁇ ), prostaglandin E2 (PGE2), prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) are synthesized in addition to PGD2 from the synthetic pathway, You.
  • mast cells activated by binding of a complex of antigen and immunoglobulin E (IgE) that are thought to play a central role in allergic reactions Therefore, it is considered that the arachidonic acid metabolic cascade is activated and various inflammatory mediators derived from arachidonic acid are released, which plays an important role in causing allergic symptoms.
  • IgE immunoglobulin E
  • PGD2 is the most inflammatory mediator produced and released, and is detected at high concentrations in bronchoalveolar lavage fluid of asthmatic patients (The Journal of
  • H-PGDS hematopoietic enzymes
  • lipocalin enzymes Lipocalin-type enzymes are mainly distributed in the brain.Since PGD2 is a sleep inducer, it is implicated in inducing sleep, lowering body temperature, suppressing progestin secretion, and regulating pain and odor responses. It is known (Vitamins and hormones, Vol. 58, p. 89--120 (2000); The Journal of Biological Chemistry, Vol. 260, No. 23, p.
  • HQL-79 (4-benzhydryloxy-1- (3- (1H-tetrazol-5-yl)), a benzhydryloxy derivative having a tetrazole skeleton, has been used as an inhibitor of hematopoietic organ enzymes.
  • Propyl ⁇ pyridine is known, and it has been reported that HQL-79 suppresses eosinophil infiltration into the respiratory tract, delayed asthmatic reaction, and irritation of the respiratory tract as an asthma model.
  • Japanese Journal of Pharmacology, Vol. 78, No. l, p. 1-10 (1998); and Japanese Journal of Pharmacology, Vol. 78, No. l, p. 11-22 (1998)
  • its activity Is not enough.
  • a hydroxy-substituted aryl derivative having a pyrazolyl group, a naphthyl group, or the like bonded via a linking group for example, The Journal of Medicinal Chemistry, Vol. 44, No. 22, p. 3730-3745 ( And WO 01/89457 disclose compounds having an agonist effect on thrombopoietin receptors, which may be useful in the treatment of thrombocytopenia and other conditions associated with suppression of platelet production. It is described. However, according to The Journal of Medicinal Chemistry, Vol. 44, No. 22, p. 3730-3745 (2001), among the hydroxy-substituted aryl derivatives, the agonist action of the thrombopoietin receptor was observed.
  • -CH N-, -CONH- and -CHNH- are compounds of the thrombopoietin receptor No second strike activity is observed.
  • the above documents suggest and teach that the hydroxy-substituted aryl derivative has an inhibitory action on PGD2 production and an inhibitory action on Z or hematopoietic PGD2 synthase.
  • antiallergic agents such as ketotifen and terfenadine, antihistamines such as chlorphenamine-maleate, and antiinflammatory steroids are used for allergic diseases, but conventional antiallergic agents and antihistamines are not used. They may have sufficient medicinal properties, may not sufficiently suppress late allergic reactions, and may have central side effects such as drowsiness and sedation. Anti-inflammatory steroids are effective in suppressing late-onset allergic reactions. These drugs are not easy-to-use drugs due to the side effects such as immunosuppression. Therefore, selective and potent inhibitors of hematopoietic enzymes can be expected to be potent therapeutic agents for V, allergic inflammatory diseases, especially allergic asthma, which have fewer side effects than conventional drugs.
  • An object of the present invention is to develop a selective inhibitor of hematopoietic PGD2 synthase, and to provide an allergic inflammatory disease such as allergic rhinitis, which has little side effects and high safety, and particularly allergic asthma. It is to provide a medicament for treatment.
  • Hematopoietic PGD2 synthase is a subtype of Glutathione S-transferase (GST) and is an enzyme requiring Glutathione classified into ⁇ class GST.
  • GST Glutathione S-transferase
  • its three-dimensional structure has been elucidated by X-ray crystallography (see Cell, Vol. 90, ⁇ .6, ⁇ . 1085-1095 (1997)). It was reported that the ⁇ -helix has a short, wide and deep specific Cleft structure.
  • the present inventors used a computer-based molecular design method based on the analyzed three-dimensional structure to design a low-molecular-weight organic compound that could bind to the Cleft structure of hematopoietic PGD2 synthase. Synthesized.
  • the compound represented by the following general formula (I) can be converted into a hematopoietic PGD2 synthase.
  • the present invention provides
  • R 3 and R 4 are each independently a hydrogen atom, a halogen atom, and a C -C alkyl group which may have a substituent.
  • R 5 represents a C -C alkyl group which may have a substituent, or a C -C aryl group which may have a substituent Represents; R is substituted
  • a pharmacologically acceptable salt thereof and a substance selected from the group consisting of hydrates and solvates thereof, as a prostaglandin,
  • A may have a substituent C-C aryl group, may have a substituent 6 or more
  • B may have a substituent C-C aryl group, optionally having a substituent 5 to The medicament according to the above (1), which is a 13-membered heteroaryl group or a substituted or unsubstituted 5- or 10-membered partially saturated heterocyclic group;
  • A is a hydroxy-substituted C-C aryl group (the aryl group is further substituted in addition to the hydroxy group)
  • B has a substituent, and may be a 5- to 13-membered heteroaryl group
  • A is a hydroxy-substituted naphthyl group (the naphthyl group may have a substituent in addition to the hydroxy group);
  • B has a substituent and may be a virazolyl group
  • A is a 1-hydroxy-2-naphthyl group
  • B force is a hydrogen atom at position 1 and may have a substituent.
  • B is a C-C alkyl group optionally substituted at the 1-position,
  • Hydrogen atom optionally substituted C-C alkyl group, or optionally substituted
  • a good C-C aryl group which may have a hydrogen atom or a substituent at the 4-position.
  • B is a C-C atom which may have a hydrogen atom or a substituent at the 1-position.
  • 4-position is hydrogen atom
  • 5-position may have a substituent C-C aryl
  • a 6- to 10-membered heteroaryl group in which A is substituted with a hydroxy group (the heteroaryl The group may further have a substituent in addition to the hydroxy group, or);
  • B has a substituent and may be a 5-membered heteroaryl group
  • A is a hydroxy-substituted quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group);
  • B has a substituent and may be a virazolyl group
  • A is a 4-hydroxy-3-quinolyl group (the quinolyl group may have a substituent in addition to the hydroxy group);
  • B is a C-C alkyl group which may have a substituent at the 1-position, and may have a substituent
  • a C -C aryl group or a C -C aralkyl group which may have a substituent, wherein the 3-position is
  • a force A 9- or 10-membered partially saturated heterocyclic group containing one or two nitrogen atoms as a ring constituent atom (the partially saturated heterocyclic group may have a substituent and Y Is the position of the nitrogen atom which is a ring-constituting atom);
  • B has a substituent and may be a 5-membered heteroaryl group
  • A is a group selected from the following ring group ⁇ -3-1;
  • ⁇ ka N CH—;
  • B is a C-C alkyl group which may have a substituent at the 1-position, and may have a substituent
  • a C -C aryl group or a C -C aralkyl group which may have a substituent, wherein the 3-position is
  • the compound represented by the general formula (I) is a compound selected from the group consisting of the compounds represented by the compound Nos. 1 to 406 described in the present specification. The described medicament is provided.
  • the medicament according to any one of the above (1) to (13), which has one or more actions selected from the group consisting of an antiallergic action, an antiallergic inflammatory action, and an antiasthmatic action;
  • the medicament according to the above (1) which has an action of preventing exacerbation of brain damage and an action of improving the prognosis of brain damage or ⁇ or (13).
  • a compound represented by the above general formula (I), a pharmacologically acceptable salt thereof, and a hydrate thereof for the production of the above medicament are provided. And a solvate; use of the selected substance; a compound represented by the above general formula (I) and a pharmacologically A PGD2 production inhibitor comprising a substance selected from the group consisting of an acceptable salt thereof, and a hydrate and a solvate thereof as an active ingredient; a compound represented by the above general formula (I); A hematopoietic PGD2 synthase inhibitor comprising, as an active ingredient, a substance selected from the group consisting of acceptable salts thereof, and hydrates and solvates thereof; A method of inhibiting the compound selected from the group consisting of the compound represented by the general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate and a solvate thereof.
  • Acceptable salts, and it A method comprising administering to a mammal, including a human, an effective amount of a selected substance; selected from the group consisting of allergic diseases, allergic inflammatory diseases, and asthma
  • a method for preventing and / or treating one or more diseases comprising a compound represented by the above general formula (I), a pharmacologically acceptable salt thereof, and a hydrate and solvate thereof.
  • Group strength a method comprising the step of administering an effective amount of a selected substance to mammals including humans; a method for preventing exacerbation of brain damage, comprising the compound represented by the above general formula (I) and a pharmacologically active substance.
  • a method comprising administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of hydrates and solvates thereof;
  • the general formula (I) A method comprising administering to a mammal, including a human, an effective amount of a selected substance, and a pharmacologically acceptable salt thereof, and a hydrate and solvate thereof.
  • a method for protecting the brain comprising the step of using a compound represented by the above general formula (I) and a pharmacologically acceptable salt thereof, and an effective substance selected from the group consisting of hydrates and solvates thereof.
  • a method comprising the step of administering an amount to a mammal, including a human; and a method for regulating a biological effect selected from the group consisting of estrous cycle, sleep, body temperature, pain sensation, and olfaction. And pharmacologically acceptable salts thereof, and hydrates and solvates thereof.
  • a method comprising the step of administering to a mammal, including a human, an effective amount of the selected substance. Is provided.
  • R 1M , R 2M , R 3M and R 4M are each independently A hydrogen atom, a halogen atom, and a C-C
  • R 5Q1 represents a C-C alkyl group which may have a substituent or a C- which may have a substituent
  • R 1001 represents an amino group which may have a substituent.
  • a 1Q1 is 2-hydroxy - be a 1-naphthyl group; ⁇ ⁇ 2-hydro carboxymethyl-4-sulfonyl -1 -Excluding compounds that are naphthyl groups]
  • a 1Q1 is a hydroxy-substituted naphthyl group (the naphthyl group may further have a substituent in addition to the hydroxy group;);
  • B 1Q1 is an optionally substituted pyrazolyl group, a salt thereof, or a hydrate or solvate thereof;
  • B 1Q1 is a C-C alkyl group optionally substituted at the 1-position,
  • the 4-position is a hydrogen atom, and the 5-position may have a substituent C-C
  • a 1M is a hydroxy-substituted quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group);
  • B 1Q1 is an optionally substituted pyrazolyl group, a salt thereof, or a hydrate or solvate thereof;
  • a 1M is a 4-hydroxy-3-quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group;).
  • B 1Q1 may have a C-C alkyl group optionally having a substituent at the 1-position, or a substituent
  • A1Q1 is a 9- or 10-membered partially saturated heterocyclic group containing 1 or 2 nitrogen atoms as a ring-constituting atom (the partially saturated heterocyclic group may have a substituent
  • the bond position to Y 1Q1 is the position of the nitrogen atom which is a ring-constituting atom);
  • B 1Q1 is an optionally substituted pyrazolyl group, a salt thereof, or a hydrate or solvate thereof;
  • a 1M is a group selected from the following ring group a ⁇ -3-1;
  • B 1Q1 may have a C-C alkyl group optionally having a substituent at the 1-position, or a substituent
  • the compound power represented by the general formula (II) The compound power represented by the compound Nos. 1 to 406 described in the present specification. Or a salt thereof, or a hydrate or solvate thereof, is provided as a novel substance.
  • Another aspect of the present invention is also selected from the group consisting of the compound represented by the above general formula (II), a pharmacologically acceptable salt thereof, and a hydrate and solvate thereof.
  • Containing active substance as an active ingredient; has a prostaglandin D2 (PGD2) production inhibitory action
  • PGD2 prostaglandin D2
  • the above-mentioned medicine having hematopoietic-type PGD2 synthase inhibitory action; the above-mentioned medicine having at least one action selected from the group consisting of antiallergic action, antiallergic inflammatory action and antiasthmatic action;
  • the above-mentioned medicines having a preventive action of exacerbation of brain damage and an improvement action of Z or brain prognosis; the above-mentioned medicines having a brain-protective action; and a sexual cycle controlling action, a sleep controlling action, a body temperature controlling action, an analgesic action, And a drug having at least one action selected from
  • Preventive action of exacerbation of brain injury A drug having an effect of improving the prognosis of Z or brain injury; selected from the group consisting of the compound represented by the above general formula (II) and pharmacologically acceptable salts thereof, and hydrates and solvates thereof.
  • a method for inhibiting the production of PGD2 in mammals including humans comprising a compound represented by the above general formula (II), a pharmaceutically acceptable salt thereof, and a hydrate thereof.
  • a method comprising administering an effective amount of a selected substance to mammals including humans; and a method for inhibiting hematopoietic PGD2 synthase in mammals including humans.
  • a method for improving the prognosis of brain injury comprising the compound represented by the above general formula (II), a pharmacologically acceptable salt thereof, and a hydrate and a solvent thereof.
  • Group strength consisting of Japanese comprising the step of administering to a mammal comprising: a method for protecting the brain, comprising the compound represented by the general formula (II) and a pharmacologically acceptable salt thereof, and a hydrate and a hydrate thereof.
  • a method comprising the step of administering an effective amount of a selected substance to a mammal, including a human; and a living body, wherein a group force consisting of estrous cycle, sleep, body temperature, pain, and smell is also selected.
  • a method of regulating the action comprising a group represented by the compound represented by the general formula (II) and a pharmacologically acceptable salt thereof, and a hydrate and a solvate thereof.
  • Administering an effective amount to a mammal, including a human, is provided.
  • -CH N-
  • -N CH-
  • -CONH- and -NHCO- are each represented by the following formula:
  • H, H O H, and H O are meant.
  • a and B each independently have a substituent, and may represent a hydrocarbon ring group or a substituent and represent a heterocyclic group.
  • the hydrocarbon ring group may be partially saturated, fully saturated, or deviated from an aromatic ring (aryl group). These groups can be bonded at any position on the ring.
  • aryl group examples include a phenyl group, a naphthyl group, an anthryl group, and a phananthryl group.
  • substituents including the aryl moiety (eg, an aralkyl group, an aryloxy group, an arylamino group, etc.).
  • Examples of the partially saturated hydrocarbon ring group include a cyclohexyl group, a cyclohexenyl group, an indenyl group and the like.
  • Examples of the completely saturated hydrocarbon ring group include cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; a bicyclo [3.2.1] octyl group; and an adamantyl group. .
  • heterocyclic group examples include a 3- to 14-membered monocyclic or condensed-ring group containing, as a ring-constituting atom, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. I can do it. If they contain two or more heteroatoms, they may be the same or different.
  • the heterocyclic group may be partially saturated, fully saturated, or an aromatic ring (heteroaryl group). These groups can be attached at any position on the ring.
  • Heteroaryl groups include chel, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, benzothiopropyl, benzofurol, and isobenzothiophene.
  • 1.2.3-Triazolyl group 1,2,4-triazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazuryl group, quinolyl group, isoquinolyl group, phthalazyl group, naphthyridyl group, quinoxalinyl group, quinazolinyl Group, cinnolyl group, pteridinyl group,
  • 1.2.4-Triazyl group 1,3,5-triazyl group, carbazolyl group,
  • Partially saturated heterocyclic groups include a chromal group, an isochromanyl group, an imidazolyl group, a virazolyl group, an indole group, an isoindole group, a 1,2,3,4-tetrahydroquinolyl group, Examples thereof include a methylenedioxyphenyl group.
  • Examples of the fully saturated heterocyclic group include an azetidinyl group, a pyrrolidyl group, an imidazolidyl group, a bilazolidyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, and a quinutalidinyl group.
  • the hydrocarbon ring group and heterocyclic group represented by A or B may have a substituent.
  • a certain functional group when a certain functional group has a “substituent, it may have a substituent” t, in such a case, the type, number, and substitution position of the substituent present in the functional group are as follows. There is no particular limitation. When two or more substituents are present, they may be the same or different.
  • Examples of such a substituent include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be used), an oxo group, a thioxo group, an oxoxide group, a nitro group, a nitroso group, a cyano group, an isocyano group.
  • a halogen atom a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be used
  • an oxo group a thioxo group
  • an oxoxide group a nitro group
  • a nitroso group a cyano group
  • an isocyano group an isocyano group.
  • hydrocarbon group examples include an alkyl group, an alkenyl group, an alkynyl group, an aryl group and an aralkyl group.
  • the alkyl group may be linear, branched, cyclic, or a combination thereof!
  • the cyclic alkyl group may be a monocyclic or condensed ring. More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, tert-butyl -Pentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, adamantyl and the like.
  • alkyl moiety of other substituents containing an alkyl moiety eg, an alkoxy group, an alkylamino group,
  • An alkenyl group may be linear, branched, cyclic, or a combination thereof, unless otherwise specified.
  • the cyclic alkyl group may be a monocyclic or condensed ring.
  • the number and position of double bonds present in the alkyl group are not particularly limited. More specifically, examples include a butyl group, an aryl group, an isopropyl group and an arenyl group.
  • the alkynyl group may be linear, branched or displaced unless otherwise specified.
  • the number and position of triple bonds present in the alkyl group are not particularly limited.
  • the alkenyl group may contain one or more double bonds. More specifically, examples include an ethur group and a propargyl group. The same applies to the alkyl moiety of other substituents containing an alkynyl moiety (for example, an alkyloxy group and the like).
  • the aralkyl group may be linear or branched unless otherwise specified. More specifically, examples thereof include a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a 1-phenethyl group, and a 2-phenethyl group. The same applies to the aralkyl part of other substituents containing an aralkyl part (eg, an aralkyloxy group).
  • acryl group examples include a formyl group; an alkanol group such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a bivaloyl group; Alkyl group such as propioyl group; aroyl group such as benzoyl group, 1-naphthoyl group and 2-naphthoyl group; aralkyl carboxyl group such as benzylcarbon group; piperidinocarbon group; morpholino Heterocyclic carboyl groups such as carboyl group, furoyl group, tenoyl group, nicotinoyl group and isonicotinoyl group; carboxy groups; alkoxycarbonyl groups such as methoxycarbonyl groups; alkeoxy groups such as aryloxycarbonyl groups.
  • -Roxycarbol group propargylo Alkynyloxycarbyl groups such as xycarbonyl groups; aryloxycarbol groups such as phenoxycarbol groups; aralkyloxycarbonyl groups such as benzyloxycarbol groups; 4-piperidyloxycarboxy- A heterocyclic oxycarbyl group such as a benzyl group or a 3-pyridyloxycarbol group; an alkyl group such as a carbamoyl group or a methylcarbamoyl group; a dialkyl group such as a dimethylcarbamoyl group; a fluorcarbamoyl group; Arylalkyl groups such as benzylcarbamoyl group; sulfo groups; alkylsulfol groups such as mesyl group and propanesulfol group; alkenylsulfonyl groups such as arylsulfonyl group; propargylsul
  • substituents may be further substituted by the above-mentioned substituents.
  • substituents include halogenated alkyl groups such as trifluoromethyl group and pentafluoroethyl group; hydroxyalkyl groups such as hydroxymethyl group; carboxyalkyl groups such as carboxymethyl group; Halogenated alkanol groups such as trifluoroacetyl group; halogenated alkylsulfol groups such as trifluoromethanesulfol group; methoxycarbolamino group, tert-butoxycarbylamino group and the like.
  • alkoxysulfo-amino group such as a benzyloxycarbo-amino group; an alkylsulfo-amino group such as a mesylamino group; an arylsulfo-amino group such as a benzenesulfo-amino group.
  • a benzyloxycarbo-amino group an alkylsulfo-amino group such as a mesylamino group
  • an arylsulfo-amino group such as a benzenesulfo-amino group.
  • two or more of the above substituents may form a ring together with the atom to which they are bonded (carbon atom, nitrogen atom, etc.).
  • a ring may contain one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and may have one or more substituents on the ring. May be.
  • the ring may be partially saturated, fully saturated, or a saturated ring, or an aromatic ring.
  • the hydrocarbon ring group which may have a substituent represented by A is preferably a C-C aryl group which may have a substituent, and more preferably a hydroxy-substituted C -C reel
  • the aryl group may further have a substituent in addition to the hydroxy group), particularly preferably a hydroxy-substituted naphthyl group (the naphthyl group is a hydroxy group and a further substituent group). And may be;)).
  • a hydrocarbon ring group having a substituent represented by A or an S-hydroxy-substituted naphthyl group (the naphthyl group may further have a substituent in addition to the hydroxy group;)
  • preferred examples include a group selected from the following ring group ex-1.
  • the hydrocarbon ring group which may have a substituent represented by A, is most preferably a 1-hydroxy-2-naphthyl group.
  • the heterocyclic group having a substituent represented by A may be a 6- or 13-membered heteroaryl group or a substituent. At least a 9- or 10-membered partially saturated heterocyclic group.
  • a heterocyclic group having a substituent represented by A or a heterocyclic group having a substituent is a 6- or 13-membered heteroaryl group, it is preferably hydroxy.
  • a 6- or 10-membered heteroaryl group (the heteroaryl group may further have a substituent in addition to the hydroxy group), more preferably a hydroxy-substituted quinolyl group (the quinolyl group is And further preferably a 4-hydroxy-3-quinolyl group (the quinolyl group further has a substituent in addition to the hydroxy group).
  • the heteroaryl group is preferably a group selected from the group consisting of a quinolyl group, an indolyl group, an indazolyl group, a benzothiazolyl group, a benzoxazolyl group, a carbazolyl group, a pyridyl group, a quinoxalinyl group and a dibenzofural group.
  • the 6- to 10-membered heteroaryl group is preferably a quinolyl group or a pyridyl group.
  • the heterocyclic group may have a substituent represented by A, and the heterocyclic group may be a hydroxy-substituted quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group, ;)), Preferred specific examples include groups selected from the following ring group oc-2-1.
  • the heterocyclic group may have a substituent represented by A, and the heterocyclic group may be a 4-hydroxy-3-quinolyl group (the quinolyl group may have a substituent in addition to the hydroxy group, In addition, when it is;), preferred V, specific examples include groups selected from the following ring group ex-2-2.
  • the heterocyclic group having a substituent represented by A or a heterocyclic group having a substituent is a 9- or 10-membered partially saturated heterocyclic group, More preferably, a 9- or 10-membered partially saturated heterocyclic group containing 1 or 2 nitrogen atoms as a ring-constituting atom (the partially saturated heterocyclic group may be substituted with Y Is the position of a nitrogen atom which is a ring-constituting atom), and is more preferably an isoindoline-2-yl group which may have a substituent, 1,2,3,4-tetrahydroisoquinoline-2-yl group and a substituent 1,2,3,4-tetrahydroquinazoline-3-yl having a 1,2-dihydroisoquinolin-2-yl group and a substituent! It is a group from which both basic power and group power are selected.
  • a substituent represented by A may have a heterocyclic group substituent, may have a substituent, may have an isoindolin-2-yl group, may have a substituent 1 , 2,3,4-tetrahydroisoquinolin-2-yl group, optionally having a substituent, 1,2-dihydroisoquinolin-2-yl group and optionally having a substituent 1,
  • substituent 1 2,3,4-tetrahydroisoquinolin-2-yl group
  • 1,2-dihydroisoquinolin-2-yl group optionally having a substituent 1
  • preferred examples thereof include groups selected from the following ring group ⁇ -3-1.
  • the hydrocarbon ring group which may have a substituent represented by ⁇ , is preferably a C-Caryl group which may have a substituent.
  • the hydrocarbon ring group When the hydrocarbon ring group has a substituent represented by ⁇ , the hydrocarbon ring group may have a substituent, or may be a C / C aryl group. Selected from group 13 -1-1
  • the heterocyclic group may preferably have a substituent, and may be a 5- or 13-membered heteroaryl group or a substituent.
  • a heterocyclic group having a substituent represented by B or a heterocyclic group having a substituent or a 5- or 13-membered heteroaryl group is preferred, it is preferably a 5-membered heteroaryl group.
  • (A) 1-position has a hydrogen atom, a C-C alkyl group which may have a substituent, and a substituent
  • a 9-membered heteroaryl group which may have a substituent; or a C-C alkyl group, which may have a substituent at the 3-position, or may have a substituent.
  • a 4-position is a hydrogen atom or a C-C alkoxycarboyl group which may have a substituent
  • (C) position 1 is a hydrogen atom or a C -C aryl group which may have a substituent; position 4 is water
  • a C-C alkyl group which may have a substituent at the 5-position, having a substituent
  • a heteroaryl group is preferably a pyrazolyl group, a carbazolyl group, an indolyl group, a benzimidazolyl group, a tetrazolyl group, a pyridyl group, a quinolyl group, a thiazolyl group, a benzothiazolyl group, an indazolyl group, a chelyl group, a benzothiopropyl group, or a furyl group. And a benzofural group.
  • the heterocyclic group may be
  • (A) 1-position has a hydrogen atom, a C-C alkyl group which may have a substituent, and a substituent
  • preferred specific examples include groups selected from the following ring group j8-2-1.
  • a 4-position is a hydrogen atom or a C-C alkoxycarboyl group which may have a substituent
  • preferred specific examples include groups selected from the following ring group j8-2-2.
  • (C) position 1 is a hydrogen atom or a C -C aryl group which may have a substituent; position 4 is water A C-C alkyl group which may have a substituent at the 5-position, having a substituent
  • Preferred specific examples include groups selected from the following ring group ⁇ -2-3.
  • heterocyclic group having a substituent represented by the formula (1) or (2) is a 5- or 10-membered partially saturated heterocyclic group having a substituent or a substituent
  • a preferred specific example is As an example, the following ring group j8-3-1 can be mentioned.
  • A may have a substituent C-C aryl group, may have a substituent 6 or more
  • B may have a substituent C-C aryl group, optionally having a substituent 5 to
  • A is hydroxy-substituted c-c aryl group (the aryl group is further substituted in addition to the hydroxy group)
  • a force A 6- to 10-membered heteroaryl group substituted with an S-hydroxy group (the heteroaryl The group may further have a substituent in addition to the hydroxy group, or);
  • A is a 9- or 10-membered partially saturated heterocyclic group containing 1 or 2 nitrogen atoms as ring-constituting atoms (the partially saturated heterocyclic group may have a substituent, and Is bonded to the nitrogen atom which is a ring-constituting atom);
  • A-hydroxy-substituted naphthyl group (the naphthyl group may have a substituent in addition to the hydroxy group);
  • a compound in which B has a substituent and may be a virazolyl group may be a virazolyl group.
  • A is a 1-hydroxy-2-naphthyl group
  • B force is a hydrogen atom at position 1 and may have a substituent.
  • B is a C-C alkyl group optionally substituted at the 1-position,
  • Hydrogen atom optionally substituted C-C alkyl group, or optionally substituted
  • a good C-C aryl group which may have a hydrogen atom or a substituent at the 4-position.
  • B is a C-C atom which may have a hydrogen atom or a substituent at the 1-position.
  • 4-position is hydrogen atom
  • 5-position may have a substituent C-C aryl
  • preferred specific examples of B include a group selected from the following ring group j8-2-1.
  • B include a group selected from the following ring group j8-2-2.
  • [Ring group ⁇ -2-2] 1- (4-methylphenyl) -3-methylvirazol-5-yl group, 1-phenylurazol-5-yl group, 1,3-diphenyl- Rubirazol-5-yl group, 1-phenyl-4- (ethoxycarbyl) pyrazole-5-yl group, 1-phenyl-3-methylpyrazole-5-yl group, 1-ethoxy Carboxyl-3-phenyl-4-azole group, 1-phenyl-3- (tert-butyl) pyrazol-5-yl group, 1- (4-chlorophenol)- 3-methylpyrazole-5-yl group, 1- (4-methoxyphenyl) -3-methylpyrazole-5-yl group, 1-benzyl-3-methylpyrazole-5-yl group, l- ( tert-butyl) -3-phenylpyrazole-5-yl group
  • preferred examples of B include, as specific examples, groups selected from the following ring group j8-2-4.
  • the compound corresponding to the above (0) is particularly preferably a compound selected from the group consisting of a compound represented by the following compound number described in the present specification.
  • A-hydroxy-substituted quinolyl group (the quinolyl group may have a substituent in addition to the hydroxy group);
  • a compound in which B has a substituent and may be a virazolyl group may be a virazolyl group.
  • A is a 4-hydroxy-3-quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group;).
  • B is a C-C alkyl group which may have a substituent at the 1-position, and may have a substituent
  • a C -C aryl group or a C -C aralkyl group which may have a substituent, wherein the 3-position is
  • a preferable example of B is, for example, a group selected from the following ring group j8-2-5.
  • the compound corresponding to the above GO is particularly preferably a compound selected from the group consisting of a compound represented by the following compound number described in the present specification.
  • a compound in which B has a substituent and may be a virazolyl group may be a virazolyl group.
  • a group is a group selected from the following ring group ⁇ -3-1;
  • B is a C-C alkyl group which may have a substituent at the 1-position, and may have a substituent
  • a C -C aryl group or a C -C aralkyl group which may have a substituent, wherein the 3-position is
  • ⁇ include groups selected from the following ring group j8-2-6 Can do.
  • the compound corresponding to the above (iii) is more preferably a compound selected from the group consisting of the following compound numbers described in the present specification.
  • the number of carbon atoms constituting an alkoxycarbonyl group is expressed as the total number of carbon atoms constituting an alkyl moiety and carbon atoms constituting a carbonyl moiety.
  • a C alkoxycarb group represents a methoxycarb group
  • a C alkoxycarb group represents a methoxycarb group
  • the 27 carboxy group represents an n- hexyloxycarbyl group, a (1-methylpentyl) oxycarbol group, a cyclohexyloxycarbol group, a cyclopentylmethoxycarboxy group or the like.
  • R 3 and R 4 are each independently a hydrogen atom, a halogen atom, and a C -C alkyl group which may have a substituent. Or a hydroxy group which may have a substituent;
  • R 5 represents a C -C alkyl group which may have a substituent, or a C -C aryl group which may have a substituent Represents;
  • R is substituted
  • R 3 and R 4 each independently represent a hydrogen atom or an optional substituent;
  • R 5 represents a hydrogen atom or an optional substituent;
  • R represents an amino group which may have a substituent]
  • the compounds represented by are excluded.
  • ⁇ and ⁇ each independently have a substituent, may have a hydrocarbon ring group or a substituent, and may represent a heterocyclic group.
  • the hydrocarbon ring group which may have a substituent represented by ⁇ , is preferably a C -C aryl group which may have a substituent, and is more preferably a hydroxy-substituted group.
  • the aryl group may further have a substituent in addition to the hydroxy group), particularly preferably a hydroxy-substituted naphthyl group (the naphthyl group is a hydroxy group and a further substituent group). And may be;)).
  • the optionally substituted hydrocarbon ring group represented by ⁇ is most preferably a 1-hydroxy-2-naphthyl group.
  • the heterocyclic group is preferably V having a substituent, or 6 or !!, or a 13-membered heteroaryl group, or! Is a 9- or 10-membered partially saturated heterocyclic group having a substituent.
  • heterocyclic group having a substituent represented by 1Q1 or a heterocyclic group having a substituent is a 6- to 13-membered heteroaryl group, it is preferably substituted with a hydroxy group.
  • a 6- or 10-membered heteroaryl group (the heteroaryl group may have a substituent in addition to the hydroxy group), and more preferably a hydroxy-substituted quinolyl group (the quinolyl group is a hydroxy group And further preferably a 4-hydroxy-3-quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group).
  • heterocyclic group has a substituent represented by ⁇ or may be a 6- or 13-membered heteroaryl group having a substituent or may be a 6- or 13-membered heteroaryl group
  • the heteroaryl group is preferably a group selected from the group consisting of quinolyl, indolyl, indazolyl, benzothiazolyl, benzoxazolyl, carbazolyl, pyridyl, quinoxalinyl and dibenzofuranyl groups.
  • a 6- to 10-membered heteroaryl group substituted with an S-hydroxy group having a substituent represented by ⁇ (the heteroaryl group may further have a substituent in addition to the hydroxy group)
  • the 6- to 10-membered heteroaryl group is preferably a quinolyl group or a pyridyl group.
  • preferred specific examples include groups selected from the following ring group ex 1 ex -2-1.
  • the heterocyclic group may have a substituent represented by ⁇ , and the heterocyclic group may be a 4-hydroxy-3-quinolyl group (the quinolyl group may have a substituent in addition to the hydroxy group, Or ;), a specific example is preferably a group selected from the following ring group ex 1 ⁇ - 2-2.
  • a heterocyclic group having a substituent represented by ⁇ or a heterocyclic group having a substituent is a 9- or 10-membered partially saturated heterocyclic group, More preferably, a 9- or 10-membered partially saturated heterocyclic group containing one or two nitrogen atoms as a ring-constituting atom (the partially saturated heterocyclic group may have a substituent Y 1M Is the position of the nitrogen atom which is a ring-constituting atom), and more preferably an isoindoline-2-yl group which may have a substituent, 1,2,3,4-tetrahydroisoquinolin-2-yl group having a substituent!
  • May have a substituent represented by ⁇ may have a heterocyclic group, may have a substituent, may have an isoindoline-2-yl group, may have a substituent 1,2,3,4-tetrahydroisoquinoline 2-yl group, may have a substituent! /, May be 1,2-dihydroisoquinolin-2-yl group and may have a substituent, 1,2,3,4-tetrahydro
  • preferred specific examples include a group selected from the following ring group a 1Q1-3 -l.
  • the hydrocarbon ring group which may have a substituent represented by B1Q1 is preferably a C-Caryl group which may have a substituent.
  • the heterocyclic group having a substituent represented by B 1Q1 or a heterocyclic group is preferably a 5- or 13-membered heteroaryl group, or a substituent.
  • a heterocyclic group having a substituent represented by B 1Q1 or a heterocyclic group having a substituent is a 5- or 13-membered heteroaryl group, preferably 5 Membered heteroaryl group, more preferably a pyrazolyl group optionally having a substituent, particularly preferably (A) hydrogen atom at the 1-position, optionally substituted C- C having an alkyl group and a substituent A C -C aryl group, an optionally substituted C -C aralkyl group, or
  • a 9-membered heteroaryl group which may have a substituent; or a C-C alkyl group, which may have a substituent at the 3-position, or may have a substituent.
  • a 4-position is a hydrogen atom or a C-C alkoxycarboyl group which may have a substituent
  • (C) position 1 is a hydrogen atom or a C -C aryl group which may have a substituent; position 4 is water
  • a C-C alkyl group which may have a substituent at the 5-position, having a substituent
  • a heteroaryl group is preferably a pyrazolyl group, a carbazolyl group, an indolyl group, a benzimidazolyl group, a tetrazolyl group, a pyridyl group, a quinolyl group, a thiazolyl group, a benzothiazolyl group, an indazolyl group, a thienyl group, a benzothiopropyl group, This group is selected from the group consisting of a furyl group and a benzofural group.
  • (A) 1-position has a hydrogen atom, a C-C alkyl group which may have a substituent, and a substituent
  • a 9-membered heteroaryl group which may have a substituent; or a C-C alkyl group, which may have a substituent at the 3-position, or may have a substituent.
  • preferred specific examples include a group selected from the following ring group ⁇ 81 () 1-2-1. [Ring group ⁇ -2-1] 1-phenyl-3-methyl-5-hydroxypyrazole-4-yl group, 1-phenyl
  • the heterocyclic group may be
  • An optionally substituted C-C alkyl group or an optionally substituted C-C aryl group A 4-position is a hydrogen atom or a C-C alkoxycarboyl group which may have a substituent;
  • preferred specific examples include a group selected from the following ring group ⁇ 81 () 1-2-2.
  • the heterocyclic group may be
  • (C) position 1 is a hydrogen atom or a C -C aryl group which may have a substituent; position 4 is water
  • a C-C alkyl group which may have a substituent at the 5-position, having a substituent
  • Preferred specific examples include groups selected from the following ring group ⁇ 1 ⁇ - 2-3.
  • heterocyclic group having a substituent represented by B 1Q1 or a heterocyclic group having a substituent and a 5- or 10-membered partially saturated heterocyclic group are preferred.
  • examples include groups selected from the following ring group j8 1Q1 -3-l.
  • ⁇ ⁇ may have a substituent C-C aryl group, may have a substituent 6 None
  • B 1Q1 may have a substituent, may be a C-C aryl group, may have a substituent, and may have 5 or more.
  • a 13-membered heteroaryl group or a compound having a substituent which may be a 5- or 10-membered partially saturated heterocyclic group.
  • a 1Q1 is a hydroxy-substituted c-c aryl group.
  • B 1Q1 is a compound having a substituent, and may be a 5- to 13-membered heteroaryl group.
  • a 1 () 1 is a 6- or 10-membered heteroaryl group substituted with a hydroxy group (the heteroaryl group may have a substituent in addition to the hydroxy group);
  • B 1Q1 is a 5-membered heteroaryl group having a substituent.
  • (iii) ⁇ is a 9- or 10-membered partially saturated atom containing one or two nitrogen atoms as ring-constituting atoms.
  • a sum heterocyclic group (the partially saturated heterocyclic group may have a substituent! ⁇ , And the bonding position with Y 1Q1 is the position of a ring-constituting nitrogen atom);
  • B 1 () 1 has a substituent and may be a 5-membered heteroaryl group.
  • a 1Q1 is a hydroxy-substituted naphthyl group (the naphthyl group may have a substituent in addition to the hydroxy group);
  • B 1Q1 is a compound having a substituent and possibly a virazolyl group.
  • A1M is a 1-hydroxy-2-naphthyl group
  • B 1 () 1 is a hydrogen atom at the 1-position, which may have a substituent.
  • B 1Q1 is a C 1 -C alkyl group optionally substituted at the 1-position,
  • B 1 (n is a C atom which may have a hydrogen atom or a substituent at the 1-position.
  • the 4-position is a hydrogen atom
  • the 5-position may have a substituent C -C
  • preferred examples of B 1Q1 include, as specific examples, groups selected from the following ring group ⁇ 1Q1-2 -l.
  • B 1Q1 include a group selected from the following ring group j8 ⁇ - 2-2.
  • Te you, the above (c), preferably of beta Omegaiota, as a specific example, can be a group selected from the following ring group j8 ⁇ -2-4.
  • the compound corresponding to the above (0) is particularly preferably a compound selected from the group consisting of a compound represented by the following compound number described in the present specification.
  • the compound corresponding to the above GO is preferably
  • ⁇ is a hydroxy-substituted quinolyl group (the quinolyl group may further have a substituent in addition to the hydroxy group);
  • B 1Q1 is a compound having a substituent and possibly a virazolyl group.
  • a 1M is a 4-hydroxy-3-quinolyl group (the quinolyl group may have a substituent in addition to the hydroxy group;).
  • B 1Q1 may have a C-C alkyl group optionally having a substituent at the 1-position, or a substituent
  • beta Omegaiota leaves in the Rukoto mentioned a group selected from the following ring group ⁇ 1 ⁇ -2-5.
  • the compound corresponding to the above GO is particularly preferably the one described in the present specification.
  • the compound strength represented by the compound number is a compound to be selected.
  • a 1Q1 represents an optionally substituted isoindoline-2- yl group, an optionally substituted 1,2,3,4- tetrahydroisoquinolin-2-yl group, A 1,2-dihydroisoquinolin-2-yl group which may have a group and a 1,2,3,4-tetrahydroquinazoline-3-yl group which may have a substituent A group of choice;
  • B 1Q1 is a compound having a substituent and possibly a virazolyl group.
  • a 1M is a group selected from the following ring group a ⁇ - 3-1;
  • B 1Q1 may have a C-C alkyl group optionally having a substituent at the 1-position, or a substituent
  • beta Omegaiota following ring group
  • the compound corresponding to the above (m) is particularly preferably a compound selected from the group consisting of the following compound numbers described in the present specification.
  • the compound represented by the general formula (II) includes the following general formula (II-1):
  • R 1M , R 2M , R 3M and R 4M are each independently A hydrogen atom, a halogen atom, and a C-C
  • R 5Q1 represents a C-C alkyl group which may have a substituent or a C- which may have a substituent
  • R 1QQ1 represents an amino group which may have a substituent]
  • a 101 is a 2-hydroxy-1-naphthyl group ⁇ excluding compounds in which ⁇ is a 2-hydroxy-4-sulfo-1-naphthyl group.
  • R 1M , R 2M , R 3M and R 4M are each independently Represents a hydrogen atom or an optional substituent;
  • a 1Q1 is A 2-hydroxy-1-naphthyl group; excluding a compound in which ⁇ is a 2-hydroxy-4-sulfo-1-naphthyl group.
  • the compound represented by the above general formula (II) or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, is a novel compound, and The use of the compound based on the substance invention is not particularly limited.
  • the compounds represented by the above general formulas (I) and (II) can form salts.
  • a metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, and a calcium salt, or an ammodimium salt or a methylammonium salt
  • Ammonium salts such as dimethylammonium salt, dimethylammonium salt, trimethylammonium salt, and dicyclohexylammonium salt.
  • a basic group for example, Hydrochloride, bromate, sulfate, nitrate, phosphate, etc., or methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate, propionate, tartrate
  • Organic salts such as fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, silicate, lac
  • the compounds represented by the above general formulas (I) and (II) or salts thereof may exist as hydrates or solvates. Any of the above substances may be used as the active ingredient of the medicament of the present invention. Further, the compounds represented by the general formulas (I) and (II) may have one or more asymmetric carbon atoms and may exist as stereoisomers such as optically active diastereomers. As the active ingredient of the medicament of the present invention, pure mixtures of stereoisomers, any mixture of enantiomers or diastereomers, racemates and the like may be used. Further, the compounds represented by the general formulas (I) and (II) may exist as tautomers depending on the type of the substituent. For example, in the case of the compound of Compound No. 1 described below, a tautomer represented by the following formula can be exemplified.
  • a tautomer in a pure form or a mixture thereof may be used.
  • the configuration may be either Z configuration or E configuration.
  • any configuration of geometric isomers or a mixture thereof may be used.
  • Me methyl group; Et: ethyl group; n- Pr: n-propyl group; n- Bu: n-butyl group; t- Bu: tert-butyl group; OMe: methoxy group; CO Me: methoxycarbol Group; CO Et: ethoxycarbol group;
  • the compound represented by the general formula (I) or (II) can be produced, for example, by the method shown below, but the production method of the compound is not limited to the following method.
  • the target compound (3) can be produced by reacting the aldehyde (1) and the amine (2) in a solvent.
  • the solvent used is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include alcohols such as methanol, ethanol, and isopropanol; halogen solvents such as dichloromethane, dichloroethane, and chloroform; tetrahydrofuran.
  • Ethers such as 1,4-dioxane; aromatic solvents such as benzene, toluene, monochrome benzene, and 0-dichlorobenzene; amide solvents such as ⁇ , ⁇ -dimethylformamide and ⁇ -methylpyrrolidone; acetic acid; Organic acid solvents such as propionic acid; and mixed solvents of these solvents.
  • a catalyst may be used in this reaction. Examples of the catalyst used include salts such as sodium acetate, ammonium acetate, and potassium acetate; acids such as acetic acid and propionic acid; bases such as piperidine and pyrrolidine; and mixtures of these catalysts. be able to.
  • the reaction temperature is not particularly limited, but is usually from 0 ° C to the boiling point of the solvent used, preferably from room temperature to 150 ° C.
  • the reaction time depends on the reaction temperature and is usually 5 minutes to 3 days, preferably 5 minutes to 6 hours.
  • a compound represented by the formula (I), wherein Y is represented by -N CH-, is produced by replacing the combination of the aldehyde (1) and the amine (2) in the above reaction scheme 1. You can do it.
  • the compound in which Y is represented by -CONH- can be produced, for example, according to the method shown in the following reaction scheme 2.
  • the desired compound (5) can be produced by reacting the carboxylic acid (4) with the amine (2) in the presence of a condensing agent in a solvent.
  • a condensing agent examples include, for example, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCHC1); phosphorus trichloride, phosphorus oxychloride, salt chloride, etc. Acid nodogenizing agents.
  • the solvent used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include halogen solvents such as dichloromethane, dichloroethane, and chloroform; ethers such as tetrahydrofuran and 1,4-dioxane; benzene And aromatic solvents such as toluene, monochrome benzene and 0-dichlorobenzene; amide solvents such as ⁇ , ⁇ -dimethylformamide and ⁇ -methylpyrrolidone; and mixed solvents of these solvents.
  • a reagent that promotes the reaction in this reaction may be used. Examples of the reagent used include bases such as triethylamine and pyridine.
  • the reaction temperature is not particularly limited, but is usually from 0 ° C to the boiling point of the solvent used, preferably from room temperature to 150 ° C.
  • the reaction time depends on the reaction temperature, but is usually 5 minutes to 3 days, preferably 5 minutes to 6 hours.
  • an acid nodroside, an acid anhydride or the like corresponding to the carboxylic acid (4) may be used.
  • the compound represented by the general formula (I) wherein Y is -NHCO- can be produced by replacing the combination of the carboxylic acid (4) and the amine (2) in the above reaction scheme 2. .
  • B is a 5-hydroxypyrazole-4-yl group (the group is further substituted in addition to the 5-position hydroxy group).
  • a compound having a group or a 2-hydroxyindole-3-yl group (the group may further have a substituent in addition to the 2-position hydroxy group) For example, it is manufactured by a method similar to “Procedure G” described in Journal of Medicinal Chemistry, Vol. 44, No. 25, p. 4339-4358 (2001).
  • B is a 5-hydroxypyrazol-4-yl group (the group is a 5-hydroxypyroxy group and a substituent other than the 5-position hydroxy group).
  • B is a 5-hydroxypyrazol-4-yl group (the group is a 5-hydroxypyroxy group and a substituent other than the 5-position hydroxy group).
  • the compound represented by the general formulas (I) and (II) may be produced using an optically active raw material.
  • a racemate may be produced and then subjected to optical resolution.
  • a method for optical resolution a method known to those skilled in the art can be used, and for example, high performance liquid chromatography using an optically active column can be used.
  • the compounds represented by the general formulas (I) and (II) produced by the above methods can be prepared by methods known to those skilled in the art, for example, extraction, precipitation, fractional chromatography, fractional crystallization, and suspension washing. It can be isolated and purified by, for example, recrystallization. Also, pharmacologically acceptable salts of the compound of the present invention, hydrates and solvates thereof can be produced by methods known to those skilled in the art.
  • the working examples of the present specification specifically describe methods for preparing representative compounds encompassed by the general formulas (I) and (II). Therefore, those skilled in the art can select appropriate reaction materials, reaction reagents, and reaction conditions while referring to the above description of the general production method and the description of the specific production method in Examples, and if necessary, By appropriately modifying or modifying these methods, any of the compounds included in the general formulas (I) and (II) can be produced. [0082]
  • the compounds represented by the general formulas (I) and (II) have an action of inhibiting PGD2 production and an action of inhibiting Z or hematopoietic PGD2 synthase, and are considered as allergic inflammation inhibitors. Can be suitably used.
  • the above medicament is useful as an active ingredient of a medicament for preventing and / or treating an inflammatory disease caused by an allergic reaction. More specifically, the medicament of the present invention is used for diseases considered to be involved in allergic inflammatory reactions such as contact dermatitis, atopic dermatitis, eczema, hay fever, asthma, and the like.
  • H-PGDS hematopoietic PGD2 synthase
  • DP receptor prostaglandin D receptor
  • H-PDGS inhibitor such as HQL-79 or an antagonist of DP receptor
  • HQL-79 or an antagonist of DP receptor an H-PDGS inhibitor
  • a brain injury model in transgenic mice that overexpresses H-PDGS
  • PGD2 is involved in the exacerbation of brain injury, as the damage is exacerbated. Therefore, a potent inhibitor of H-PDGS is useful as an agent useful for preventing exacerbation of brain injury and improving the prognosis of Z or brain injury, and the medicament of the present invention can also be used for this purpose.
  • the brain injury to which the medicament of the present invention is applied is not particularly limited.
  • traumatic injury due to a traffic accident cerebrovascular disorder such as cerebral infarction or cerebral hemorrhage, cerebral degenerative disease, demyelinating disease, etc. Forces that can exemplify things and the like are not limited to these.
  • PGD2 is known to be involved in the induction of sleep, hypothermia, suppression of luteinizing hormone secretion, and regulation of pain and odor responses (Vitamins and hormones, Vol. 58, p. 89 — 120 (2000); The Journal of Biological Chemistry, Vol. 260, No. 23, p. 12140— 12145 (1985); and Biochimica et Biophysica Acta, Vol. 1482, No. l— 2, p.259-271 (2000)), and the medicament of the present invention has at least one action selected from the group consisting of a sexual cycle control action, a sleep control action, a body temperature control action, an analgesic action, and an olfactory control action. Useful as a medicine.
  • the active ingredients of the medicament of the present invention include compounds represented by the general formulas (I) and (II), pharmacologically acceptable salts thereof, hydrates thereof, and solvates thereof.
  • One or more of the selected substances can be used.
  • the above-mentioned substance itself may be used as the medicament of the present invention, but preferably, the medicament of the present invention is used as an active ingredient and one or more pharmaceutically acceptable additives for pharmaceutical preparations.
  • a pharmaceutical composition comprising: 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 can be administered, for example, 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.
  • 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.
  • a solid or liquid pharmaceutical additive can be used.
  • the pharmaceutical additives may be either organic or inorganic. That is, when an oral solid preparation is produced, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added to the active substance, and then the tablet is prepared in a conventional manner. , Coated tablets, granules, powders, capsules and the like can be prepared.
  • the excipient to be used include lactose, sucrose, sucrose, glucose, corn starch, starch, talc, sorbitol, crystalline cellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide.
  • binder examples include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin, and pectin.
  • Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated spot oil and the like. I can make it. Any coloring agent can be used as long as it is normally permitted to be added to pharmaceutical products.
  • a flavoring agent cocoa powder, heart-shaped brain, aromatic acid, heart-shaped oil, dragon brain, cinnamon powder and the like can be used. These tablets and granules can be sugar-coated, gelatin-coated and optionally coated as needed. Further, if necessary, a preservative, an antioxidant and the like can be added.
  • liquid preparations for oral administration for example, emulsions, syrups, suspensions and liquid preparations
  • inert diluents such as water or vegetable oil
  • this preparation can contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • this preparation After preparing the liquid preparation, it may be filled into capsules of absorbable substance such as gelatin!
  • solvents or suspensions used for preparations for parenteral administration include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin. it can.
  • base used in the production of suppositories for example, cocoa butter, emulsified cocoa butter, laurin fat, and witetbsol can be mentioned.
  • the method for preparing the preparation is not particularly limited, and any method commonly used in the art can be used.
  • a carrier for example, dilution of water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide PH adjusters and buffers such as sodium citrate, sodium acetate and sodium phosphate; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid can be used.
  • a normal solubilizing agent, soothing agent, or local anesthetic which may contain sufficient amounts of salt, glucose, mannitol, or glycerin in the preparation to prepare an isotonic solution It is better to use agents.
  • an ointment for example, a paste, a cream or a gel, commonly used bases, stabilizers, wetting agents, preservatives and the like can be blended as required, and can be prepared by a conventional method.
  • Bases include, for example, white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone Concrete and bentonite can be used.
  • preservative methyl noraoxybenzoate, ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate and the like can be used.
  • the preparation When the preparation is in the form of a patch, the above-mentioned ointment, cream, gel, paste or the like can be applied to a usual support in a conventional manner.
  • a usual support woven or non-woven fabrics made of cotton, swoof and chemical fibers, and films or foam sheets of soft vinyl chloride, polyethylene and polyurethane can be suitably used.
  • the dose of the medicament of the present invention is not particularly limited.
  • the weight of the compound of the present invention per adult day is usually 0.01 to 5,000 mg. It is preferable to increase or decrease this dose appropriately according to the age, disease state and symptoms of the patient.
  • the daily dose may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently every few days.
  • the weight of the compound of the present invention is about 0.001 to 100 mg per adult per day.
  • Example 45 Compound number 45 (General synthesis method B)
  • WL 'WL [ ⁇ ) 8 ⁇ ' (s ⁇ ) ⁇ g :( i a a) WN °% os 3 ⁇ 4 ⁇
  • Example 76 Compound number 76
  • Example 77 Compound number 77
  • Example 87 Compound number 87
  • Example 93 Compound number 93
  • Example 94 Compound number 94

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Abstract

Médicament ayant une activité d'inhibition de la production de la prostaglandine D2 (PGD2) et ayant comme ingrédient actif une substance choisie parmi des composés représentés par la formule générale (I) : A-Y-B {dans laquelle A et B représentent chacun indépendamment un groupe hydrocarboné cyclique ou hétérocyclique facultativement substitué ; et Y représente -CH=N-, -N=CH-, -CONH- ou -NHCO-, à condition que les composés représentés par la formule (I-1) suivante : (I-1) [dans laquelle X représente la formule -N=C(R5)- (dans laquelle la liaison du côté gauche est liée au noyau benzénique et la liaison du côté droit est liée à l'atome d'azote) ou la formule -NH-CH(R5)- (dans laquelle la liaison du côté gauche est liée au noyau benzénique et la liaison du côté droit est liée à l'atome d'azote) ; R1, R2, R3 et R4 représentent chacun indépendamment un hydrogène, un halogéno ou un alkyle en C1-6 facultativement substitué ou un hydroxy ; R5 représente un groupe alkyle en C1-6 ou aryle en C6-10 facultativement substitué ; et R représente un amino facultativement substitué] soient exclus}, des sels, des hydrates et des solvates.
PCT/JP2005/006464 2004-04-01 2005-04-01 Dérivé imine et dérivé amide WO2005094805A1 (fr)

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WO2011044307A1 (fr) 2009-10-08 2011-04-14 Sanofi-Aventis Dérivés de phényloxadiazole en tant qu'inhibiteurs de pgds
US8067589B2 (en) 2007-02-26 2011-11-29 Pfizer Inc Heterocyclic compounds useful in treating diseases and conditions
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CN102584670A (zh) * 2012-01-15 2012-07-18 山东轻工业学院 一种吲哚-3-甲醛缩苯二胺双席夫碱及其制备方法
CN102584671A (zh) * 2012-01-15 2012-07-18 山东轻工业学院 一种吲哚-3-甲醛缩联苯二胺双席夫碱及其制备方法
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WO2013131931A1 (fr) 2012-03-06 2013-09-12 Compound Handling B.V. Pyrazolones aminométhylène à activité thérapeutique
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WO2017103851A1 (fr) 2015-12-17 2017-06-22 Astex Therapeutics Limited Quinoléine-3-carboxamides utilisés comme inhibiteurs de h-pgds
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
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WO2018069863A1 (fr) 2016-10-13 2018-04-19 Glaxosmithkline Intellectual Property Development Limited Dérivés d'azétidine ou de cyclobutane 1,3-disubstitués utilisés comme inhibiteurs de la prostaglandine d synthase hématopoïétique (h-pgds)
WO2018229629A1 (fr) 2017-06-13 2018-12-20 Glaxosmithkline Intellectual Property Development Limited Composés chimiques utilisés en tant qu'inhibiteurs de h-pgds
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WO2019094732A1 (fr) * 2017-11-10 2019-05-16 Academia Sinica Inhibiteurs de protéine de liaison à un élément de réponse d'amp cyclique
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WO2017103851A1 (fr) 2015-12-17 2017-06-22 Astex Therapeutics Limited Quinoléine-3-carboxamides utilisés comme inhibiteurs de h-pgds
WO2018069863A1 (fr) 2016-10-13 2018-04-19 Glaxosmithkline Intellectual Property Development Limited Dérivés d'azétidine ou de cyclobutane 1,3-disubstitués utilisés comme inhibiteurs de la prostaglandine d synthase hématopoïétique (h-pgds)
WO2018229629A1 (fr) 2017-06-13 2018-12-20 Glaxosmithkline Intellectual Property Development Limited Composés chimiques utilisés en tant qu'inhibiteurs de h-pgds
US11149035B2 (en) 2017-06-13 2021-10-19 Glaxosmithkline Intellectual Property Dfvelopment Limited Chemical compounds as H—PGDS inhibitors
JP2020523367A (ja) * 2017-06-13 2020-08-06 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Ｈ−ｐｇｄｓ阻害剤としての化学化合物
CN110753692A (zh) * 2017-06-13 2020-02-04 葛兰素史密斯克莱知识产权发展有限公司 作为h-pgds抑制剂的化学化合物
WO2019094732A1 (fr) * 2017-11-10 2019-05-16 Academia Sinica Inhibiteurs de protéine de liaison à un élément de réponse d'amp cyclique
WO2019116256A1 (fr) 2017-12-13 2019-06-20 Glaxosmithkline Intellectual Property Development Limited Pyridines fusionnées agissant en tant qu'inhibiteurs de h-pgds
WO2020095215A1 (fr) 2018-11-08 2020-05-14 Glaxosmithkline Intellectual Property Development Limited Composés chimiques
WO2021256569A1 (fr) 2020-06-19 2021-12-23 佐藤製薬株式会社 Composés cycliques condensés qui inhibent la h-pgds
KR20230027059A (ko) 2020-06-19 2023-02-27 사토 세이야쿠 가부시키가이샤 H－pgds를 저해하는 축환 화합물

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