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WO2004002948A1 - Compose amide et utilisation medicinale de ce compose - Google Patents

Compose amide et utilisation medicinale de ce compose Download PDF

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Publication number
WO2004002948A1
WO2004002948A1 PCT/JP2002/006606 JP0206606W WO2004002948A1 WO 2004002948 A1 WO2004002948 A1 WO 2004002948A1 JP 0206606 W JP0206606 W JP 0206606W WO 2004002948 A1 WO2004002948 A1 WO 2004002948A1
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Prior art keywords
alkyl
phenyl
cyano
group
pharmaceutically acceptable
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English (en)
Japanese (ja)
Inventor
Youichiro Naito
Hiroyuki Ushio
Yukio Hoshino
Masahiko Kagoshima
Kouichi Oshita
Hirotoshi Kataoka
Kenji Chiba
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Pharma Corp
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Priority to JP2001146915A priority Critical patent/JP2002338537A/ja
Application filed by Mitsubishi Pharma Corp filed Critical Mitsubishi Pharma Corp
Priority to AU2002313309A priority patent/AU2002313309A1/en
Priority to PCT/JP2002/006606 priority patent/WO2004002948A1/fr
Publication of WO2004002948A1 publication Critical patent/WO2004002948A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to interticin 4 (hereinafter, referred to as Th2 site), which is produced by a T cell sensitized with an exogenous antigen or an autoantigen, particularly a type 2 helper T cell (hereinafter abbreviated as a Th2 cell).
  • Th2 site interticin 4
  • the present invention relates to a novel amide derivative which has an action of selectively suppressing the production of IL-4) and is useful for prevention and treatment of allergy (4 diseases), a pharmaceutically acceptable salt thereof, and a use thereof as a medicament.
  • Antigen-specific helper T cells sensitized by exogenous or autoantigens produce a variety of biologically active cytokins that promote the proliferation and differentiation of effector ⁇ cells and ⁇ cells, Induces a specific immune response to the antigen.
  • Unsensitized helper ⁇ cells are usually sensitized with ⁇ and then transformed into type 0 helper ⁇ cells (ThO cells) capable of producing interleukin 2 (hereinafter, IL-2). It is known to differentiate into two types of helper T cells that produce different cytokins, namely, type 1 helper T cells (Thl cells) or type 2 helper T cells (Th2 cells).
  • Thl cells in addition to IL-2, produce cytokins such as interferon-gamma (hereafter, IFN- ⁇ ) and myocardial death gene (hereafter, TNF- ⁇ ). Promote epidemics.
  • Th2 cells produce cytokins such as IL-4, IL-5, IL-6, IL-10 and IL-13, and mainly promote humoral immunity, that is, antibody production.
  • the immune response is regulated by the balance between Th1 and Th2 cells, and IFN- ⁇ produced by Th1 cells promotes the differentiation of ThO cells into ⁇ h1 cells, and promotes the differentiation into Th2 cells.
  • Inhibit. IL-14 produced by Th2 cells promotes differentiation of Th0 cells into Th2 cells and inhibits differentiation into Th1 cells.
  • Th2 cells are used in allergic H disease and systemic autoimmune diseases. It has been reported that Th1 cells are predominant in ⁇ -specific autoimmune diseases.
  • IL-14 is immunoglobulin E (I It has effects such as class switch to gE) and induction of differentiation into Th 2 cells, and it has been suggested that it is deeply involved in allergic pathogenesis. In fact, it has been reported that IL-4 is high in the alveolar lavage fluid of asthmatics, and that the expression of IL-4 mRNA is enhanced in the rash of atopic dermatitis. It is considered that hyperactivity of Th2 cells plays an important role in the onset and progression of these diseases (Am. J. Respir. Cell Mo 1. Biol., Vol. 12. p p. 477-487, 1995, J. Immunol 1., Vol. 158, 3539-3544 and J. E. Med., Vol. 173, p. 775-778, 1991) 0
  • IL-4 gene-deficient mice are less susceptible to various allergies, they are deeply involved in the induction of Th-4 cells that produce IL-4. (Nature, Vol. 362, .245-247, 1993 and J. Exp. Med., Vol. 183, .195-201, 1996).
  • a drug that selectively suppresses IL-14 production from Th2 cells and suppresses the immune response involving Th2 cells in patients with allergic diseases is a useful antiallergic drug. It may be a drug.
  • steroids are widely available as therapeutic drugs for allergic diseases, and have shown high efficacy.
  • Steroids have potent anti-inflammatory effects and, in addition, have an inhibitory effect on lymphocyte proliferation, an inhibitory effect on the production of cytodynamics, and an inhibitory effect on the production of mediators such as leukotriene.
  • steroids are known to produce untoward side effects such as large Jii epithelium necrosis due to long-term use or large doses due to their wide-ranging effects.
  • the recently developed sublatast tosilate (IPD-1151T) has the effect of selectively inhibiting the production of IL-4 and IL-15 from Th2 cells, and has an effect on asthmatic diabetic dermatitis.
  • WO 00/475558 discloses a lymphocyte proliferation inhibitory effect, in particular, IL-2, IL-14, IL-7, IL-19, IL-13 or IL-1.
  • IL-2, IL-14, IL-7, IL-19, IL-13 or IL-1 Disclosed are compounds such as virazole-4-carboxamide derivatives which have 5-dependent inhibitory action on lymphocyte proliferation and are useful as preventive and remedy drugs for various visual diseases.
  • Th2 cytokines such as IL-4 from Th2 cells
  • Th1-Th2 Th2 cytokines
  • Compounds that selectively inhibit tocaine production can suppress the enhancement of Th2-cell-related immune responses in allergic patients and improve the bias of Th1-Th2 balance. It is expected that it can be a useful drug for the prevention and treatment of allergic diseases such as atopic H dermatitis, bronchial asthma, and allergic rhinitis, which require less use than drugs.
  • an object of the present invention is to provide a drug which selectively inhibits the production of IL-4, which is deeply involved in the pathogenesis and progression of allergic diseases, among cytokins produced from Th2 cells. It is to be.
  • the present invention focuses on IL-4, which is produced from Th2 cells sensitized with an antigen and also promotes the induction of differentiation into Th2 cells.
  • An object of the present invention is to provide a synthetic low-molecular compound having an action of selectively suppressing production.
  • the selective suppression of IL-4 production depends on the pathways involving NFAT, c-Maf, NIP45, GATA-3, and JunB, which are transcription factors that regulate IL-4 transcription. Restrain Is also included.
  • the present invention suppresses the proliferation and differentiation induction of Th2 cells through suppression of IL-14 production, and improves the bias of Th2 cells toward an immune response involving Th.
  • it also suppresses the production of Th2 site-like proteins such as IL-15, IL-16, and IL-13 produced from Th2 cells.
  • the purpose is also to provide the compound.
  • the present inventors have conducted intensive studies in view of the above situation, and found that an amide compound represented by the following general formula or a pharmaceutically acceptable salt thereof selectively inhibits IL-4 production. And completed the present invention.
  • the present invention is as follows.
  • R 1 is halogen, alkyl, anoreoxy, nitro, amino which may have a substituent, hydroxy, aryl which may have a substituent, or phenyl which may have a substituent.
  • Reel alkyl, optionally substituted heteroaryl, unsubstituted heteroaryl, non-substituted heteroalkyl, substituted or unsubstituted alkyl or substituted alkyl The cycloalkenyl which may have a group is shown.
  • Ring Q is benzene which may have a substituent, cyclohexane which may have a substituent, or pyridine, pyrazine, pyridazine, furan, thiophene, or oxazole which may have a substituent. And a heteroaromatic ring selected from thiazole and imidazole.
  • R 2 represents hydrogen, alkyl, hydroxyanolequinole, acyloxyalkyl, optionally substituted aminoamino, hydroxycarbonylalkyl or alkoxycarbonylalkyl.
  • Z represents CH or N.
  • R 3 represents halogen, cyano, nitro, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl, carbamoyl, alkenyl, anorekinyl or haloanoralkyl.
  • R represents hydrogen, halogen, cyano or nitro.
  • Aminoalkyl optionally having a substituent
  • Het is a saturated group containing one or two heteroatoms selected from an oxygen atom or a nitrogen atom in the ring which may have a substituent and which is powerful.
  • R 6 and R 7 are the same or different and each represents hydrogen, alkyl, hydroxyalkyl or an aminoalkyl which may have a substituent ⁇ or R 6 and R 7 may have a substituent together with the nitrogen atom to form a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in the ring.
  • a cyclic amine which may be contained is formed.
  • R 8 represents hydrogen, halogen, alkyl, ⁇ / recoxy, nitro, amino or hydroxy.
  • X represents ethylene-ketalized or propylene-ketalized methylene; n represents 0, 1 or 2 Shown.
  • Ring Q is the following formula
  • R 11 represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxyl or alkoxycarbonyl.
  • R 12 represents hydrogen, alkyl, alkoxycarbonylalkyl, hydroxycarbonylalkyl, acyloxyalkyl And the other symbol is as described in the above [1].]
  • Z represents CH, R 4 represents hydrogen, and R 3 position in the formula (I) at which the nitrogen atom of the carpamoyl group connecting the phenyl group and the ring Q is bonded to the phenyl group. Based on the halogen, cyano, nitro or halo substituted at the 3-position of the phenyl group
  • R 11 represents hydrogen, halogen, alkyl, alkoxy, nitro, amino, hydroxy, carboxy or alkoxyl.
  • Z represents CH
  • R 2 represents hydrogen or alkyl
  • R 3 represents a force linking the phenyl group in formula (I) with ring Q.
  • R 4 is hydrogen;
  • the force R 5 is the position at which the nitrogen atom of the carpamoyl group connecting the 0.7 enyl group and the ring Q in the formula (I) is bonded to the phenyl group. Is substituted at the 4-position of the fuel group based on
  • R 11 represents hydrogen, halogen, alkynole, alkoxy, nitro, amino, hydroxy, propyloxyl or alkoxy propylon.
  • Z represents CH
  • R 2 represents hydrogen or alkyl
  • R 3 represents a nitrogen atom of a carpamoyl group connecting the phenyl group and the ring Q in the formula (I) to the phenyl group.
  • R 4 is hydrogen
  • R 5 is a force connecting the phenyl group and the ring Q in the formula (I) / the molybdenum atom of the levamoyl group is bonded to the phenyl group. Substitution at the 4-position of the phenyl group based on the position,
  • R 8a represents hydrogen, halogen, alkyl, alkoxy, nitro, amino or hydroxy.
  • Y represents CH 2 , CH-R 9 , or N—R 10.
  • m represents 0, 1 or 2.
  • R 9 represents hydroxy, alkyl, hydroxyalkyl, 4-piperidinyl or morpholino
  • R 10 represents hydrogen, alkyl, hydroxyalkynole, 4-piperidyl or 3,4,5,6-tetrahydro- 1H-pyran —Indicates 4 columns.
  • a pharmaceutical composition comprising the amide compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof.
  • composition according to the above [8] comprising the amide compound according to the above [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a selective inhibitor for the production of interleukin-4 from type 2 helper T cells comprising the amide compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof.
  • An agent for preventing or treating allergic diseases comprising the amide compound according to [1] or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for atopic dermatitis, asthma, or allergic rhinitis comprising the amide compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof.
  • Steroids are prednisolone, methylprednisolone, dexamethasone, hydrocortisone, clobetasone, fuoremethasone, triamcino acetonide, alclomethasone, phnoreno cinosaunacetonide, beclomethasone, betamethasone, deprodone, halcinonide, halcinonide [14]
  • the medicament according to the above [14] which is selected from deflu, diflucortron, budesudo, difluperednate, diflorazone, clobetasol and fatty acid esters thereof.
  • Antiallergic agents include sodium cromoglycate, tranilast, amlexanox, revilinast, ibudilast, tazanolast, pemirolast, ozagrel, splatast, pranlukast, ketotifen, azelastine, oxatomid, mequitazin, terfesmezine And the medicament of the above-mentioned [14], which is selected from various antihistamines.
  • the substituent represented by each symbol in the present specification will be described in detail below.
  • Halogen in R 1 represents fluorine, chlorine, bromine, or iodine.
  • Alkyl in R 1 is linear or branched alkyl having 1 to 4 carbon atoms (hereinafter referred to as “C 4 alkyl”), specifically, methyl, ethyl, propyl, isopropyl, Examples include butyl, isoptyl, tertiary butyl and the like, preferably methyl.
  • Alkoxy in R 1 is a linear or branched alkoxy having 1 to 4 carbon atoms (hereinafter referred to as C i- 4 alkoxy), specifically, methoxy, ethoxy, propoxy, Isopropoxy, butoxy, tertiary butoxy and the like.
  • “Amino optionally having substituent (s)” for R 1 includes, as substituents, 0 to 4 phenylalkyl, 1 to 4 carbon atoms (formyl, acetyl, propionyl, etc .; hereinafter, referred to as C 4 acetyl) and Amino which may be mono- or di-substituted by a substituent selected from benzoyl, specifically, amino, methylamino, dimethylamino, ethyl / reamino, jetinoleamino, formylamino, acetylamino, propioninoleamino, and benzoylamino. can give.
  • the “aryl” of the “aryl which may have a substituent” in R 1 specifically represents phenyl, naphthyl and the like.
  • the aryl is, as a substituent, halogen
  • Trialkyl (methyl, ethyl, propyl, isopropyl, butynole, etc.), C ⁇ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), cyano, nitro, canolepoxy, C 1-4 straight or branched chain Alkylenedioxy (methylenedioxy, ethylenedioxy, propylenedioxy, 1,1-dimethyethylenedioxy, etc .; hereinafter referred to as alkylenedioxy) of a branched chain and haloalkynoles whose alkyl moiety is C-alkyl (methanolene at phenolic mouth, chloromethyl (Hereinafter referred to as halo C4 alkyl) such as trimethylol, methyl, 2,2,2-trifluoroethyl, and the like.
  • substituents are halogen, alkyl, alkoxy, and haloalkyl.
  • Anorexylenedioxy and It is a two-door opening.
  • Specific examples of aryl having a substituent include 4-chloro phenol, 3-chloro phenol, 2-chloro phenol, 3,4 dicyclo phenol, and 4-fluoro.
  • arylalkyl of the “arylalkyl optionally having substituent (s)” for R 1 is a group in which 4 alkyls have been substituted by aryls (phenyl, naphthyl, etc.) (hereinafter referred to as arylalkyls). Examples thereof include furmethyl, 2-phenylenoethyl, 1-phenylethyl, 3-phenylpropynole, and 4-phenylinoleptyl. Examples of the substituent of Ariru portion of the Ariru C 4 alkyl, the same groups as the substituents mentioned in ⁇ "optionally substituted Ari 7 re" and the like.
  • heteroaryl of the “optionally substituted heteroarylene” in 1 is a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • the heteroaryl may have, as a substituent, 4- alkyl, halogen (fluorine, chlorine, bromine, iodine) and the like.
  • Heteroarylalkyl optionally having substituent (s)” for R 1 is a C i-4 alkyl containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • a 6-membered heteroaryl-substituted group hereinafter referred to as "heteroaryl 4- alkyl"
  • the substituent of the heteroaryl part of the heteroaryl C 1 ⁇ alkyl is described in “Heteroaryl” Substituents similar to the substituents can be mentioned.
  • Cycloalkyl in “optionally having a substituent Shikuroarukinore” in R 3 is six cycloalkyl from 3 carbon atoms (hereinafter, C 3 6 will leave cycloalkyl), and for example Shikuropuropinore, Shikuropuchi / , Cyclopentinole, cyclohexyl and the like.
  • C 3 _ 6 cycloalkyl substituent, wherein the same substituents mentioned in "also good I Ariru substituted” substituent group.
  • Cycloalkenyl of “cycloalkenyl optionally having substituent (s)” for R 1 is cycloalkenyl having 3 to 6 carbon atoms (hereinafter, referred to as C 3 _ 6 cycloa / recenyl). Nil, cyclobutenyl, cyclopentyl, cyclohexenyl and the like.
  • the heteroaromatic ring in the ring Q is pyridine, pyrazine, pyridazine, furan, thiophene, thixazole, thiazonole, imidazo / re, and pyridine, furan and thiophene are preferred.
  • the heteroaromatic ring may have a substituent, and examples of such a substituent include halogen, alkyl, alkoxy, nitro, amino, hydroxy, alkoxycarbonylalkyl, hydroxycarponylalkyl, asinoleoxyalkyl, Examples include hydroxyalkyl, carboxyl, and alkoxycarbonyl.
  • the “substituent” of the benzene, cyclohexane and heteroaromatic ring in the ring Q is a substituent defined separately from R 1 , which is also a substituent on the ring Q. Should. Therefore, both R 1 and the substituent of ring Q may be the same substituent. For example, there can be ⁇ where R 1 is halogen and the substituents on the ring Q are also halogens.
  • Alkyl in R 2 is alkyl and includes methyl, ethynole, propyl, isopropyl, butyl, isoptyl and the like. Chill.
  • “Hydroxyalkyl” in R 2 is a group in which alkyl is substituted with water (hereinafter referred to as “hydroxyalkyl”), and examples thereof include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 4-hydroxypropyl. And hydroxypuchinole.
  • Alkoxyalkyl in R 2 and 12 is a group in which the alkyl is substituted with an alkoxy group having 1 to 4 carbon atoms (formyloxy, acetyloxy, propioninoloxy, petyryloxy, etc.) (hereinafter referred to as “C 4 alkoxyoxy”).
  • a C 4 intends alkyl and Rere), specifically, formyl O carboxymethyl, 2-formyl O key shell chill, ⁇ cetyl O carboxymethyl, 2- ⁇ cetyl O key shell chill, 3 over ⁇ cetyl O carboxymethyl prop , 4-acetyloxypuchil, propinol ninole, ximethinole, etc., and preferably 2-acetyloxyxetil.
  • aminoalkyl in “aminoalkyl optionally having substituent (s)” for R 2 is a group in which alkyl is substituted with amino (hereinafter referred to as amino C ⁇ 4 alkyl), and the amino is , C i-4 alkyl, mono- or di-substituted by C _ 4 substituent and the like Ru is selected Ashiru may record, be.
  • aminoalkyl which may have a substituent include, for example, aminomethyl, aminoethyl, dimethylaminomethyl, getylaminomethyl and the like.
  • “Hydroxycarbonylalkyl” in R 2 and R 12 is: A group in which 4- alkyl is substituted with hydroxycarbonyl (hereinafter referred to as hydroxycarbonylalkyl), for example, hydroxycanoleponylmethyl, 2-hydroxycanoleponylethyl, 3-hydroxycanoleponinolepropyl, 4-hydroxydrenocanoleponyl, and the like, with preference given to hydroxycarbonylmethyl and 3-hydroxycarbonylpropyl.
  • hydroxycarbonylalkyl for example, hydroxycanoleponylmethyl, 2-hydroxycanoleponylethyl, 3-hydroxycanoleponinolepropyl, 4-hydroxydrenocanoleponyl, and the like, with preference given to hydroxycarbonylmethyl and 3-hydroxycarbonylpropyl.
  • R 12 is, C i-4 alkyl, a group alkoxy portion is substituted with an alkoxycarbonyl alkoxy - a (hereinafter, alkoxy one carbonitrile as Le Ji 4 alkyl)
  • alkoxycarbonylmethyl methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, propoxycarbonyl And methoxycarbonylmethyl, and preferably ethoxycarbonylmethyl.
  • Halogen in R 3 represents fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
  • Alkyl in R 3, six 1 -C straight or branched chain alkyl Le - A (hereinafter, C]. 6 alkyl and refers), for example, methyl, Echiru, propyl Le, isopropyl, butyl, Isopuchiru, tertiary heptyl, pentyl, Isopenchi Le, neopentyl, etc. hexyl can be mentioned to, 1 to 3 carbon atoms straight or branched chain alkyl (hereinafter, referred to. 3 alkyl) are Preferred, especially methyl.
  • “Anorecoxy” in R 3 is a straight-chain or branched alkoxy having 1 to 6 carbon atoms (hereinafter referred to as “C- 6 alkoxy”), for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy. Tertiary butoxy, pentyloxy, isopenti / reoxy, neopentyloxy, hexyloxy and the like. Among them, straight or branched alkoxy having 1 to 3 carbon atoms (hereinafter referred to as alkoxy) ) Is preferred.
  • Arukeniru in R 3,. 2 to 4 carbon atoms or a straight-chain or branched Aruke sulfonyl (hereinafter, C 2 - 4 as alkenyl) A, for example Eteyuru, 1-propenyl Honoré, 1 Butyr, etc., and particularly preferred is ether.
  • Haloalkyl in R, a halo one 4 alkyl, for example Furuo port Mechinore, chloromethyl, Promo methyl, triflusulfuron Ruo Russia, 2- Funoreo port E Chi le, 2- Kuroromechinore, 2, 2, 2-triflate Oloethyl and the like, and particularly preferred is trifluoromethyl.
  • alkoxycarbonyl in R 3, alkoxycarbonyl alkoxy part is C 1 _ 4 Anorekokishi (hereinafter, C 3 - 4 alkoxy that one carbonyl) shall apply, for example methoxy Cal Poni Le, ethoxycarbonyl, propoxycarbonyl, I isopropoxy Examples include carbonyl, butoxycarponyl, and tertiary butoxycarpoel.
  • Alkyl in R 3 is a linear or branched alkyl having 1 to 4 carbon atoms.
  • Sulfonyl hereinafter, C 3 - of 4 alkynyl
  • Echiniru for example Echiniru, 1 Puropini Le, 1 one Petit - such as Le and the like, particularly Echeru is preferred.
  • Halogen in 4 represents fluorine, chlorine, bromine, and iodine, and is preferably chlorine.
  • Alkynole in R 5 is alkyl, for example, methyl, ethyl, propizole, isopropyl, butyl, isobutynole, tertiary butyl, pentyl, isopentyl, neopentyl / re, hexyl, isohexyl, such as cyclohexyl Neo like et be, inter alia carbon number 4-6 straight-chain or branched alkyl (hereinafter, C 4 - that 6 Al kill) is preferred.
  • Haldroxyalkyl in R 5 is a hydroxyalkyl, in example embodiment, hydroxymethyl Honoré, 2-hydroxy E chill, 3-hydroxypropyl Honoré, such as 4-hydroxybutyl and the like.
  • Hydroxycarboxylic Poni Le alkyl in 5, a hydroxycarbonyl C i-4 alkyl, for example, hydroxycarboxylic Poni methyl, 2-hydroxycarboxylic Bo two / Reechinore, 3-hydroxycarbonyl-propyl, and 4-hydroxy local Poni Lube chill like Can be
  • aminoanoreki Le J of an amino Anore Keno also be substituted “in 5 is an Amino alkyl, the amino, C i-4 alkyl, selected from. ⁇ ⁇ sill and downy Nzoiru
  • the amino-4 alkyl which may have a substituent may be, for example, aminomethyl, 2-aminoethyl, dimethylaminomethyl, 2-ge. Examples thereof include tylaminomethyl, honoleminoleaminomethinole, acetylaminomethyl, 2-formylaminoethyl, 2-acetylaminoethyl, and benzoylaminomethyl.
  • the amino is di-substituted with the above substituent: ⁇ , the substituent may have a substituent together with the nitrogen atom of the amino, and an oxygen atom and a sulfur atom are present in the ring.
  • a cyclic amine which may contain one or two heteroatoms selected from nitrogen atoms may be formed. Examples of such cyclic amines include, for example, pyrrolidine, optionally substituted piperidine, homopirididine, substituted or unsubstituted piperazine, optionally substituted Homopyrazine, morpholine and thiol And morpholine.
  • aminoalkyl which may have a substituent of this ⁇ include, specifically, piperidinomethyl, 2-piberidinoethyl, morpholinomethyl, 2-monorefolinetinole, chiomo / refolinomethyl, piperazinomethyl, (4-morpholinomethyl) Piperidine-11-methyl) and the like.
  • Alkoxy in R 5 is: 6 Alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexoxy, isohexynoleoxy, neohexyl such as talent carboxymethyl and the like, mosquito ⁇ but C 4 - 6 ⁇ alkoxy are preferred.
  • Haloalkoxy for R 5 is: 4 halogen alkoxy (fluorine, chlorine, bromine, iodine) is obtained by substituting (hereinafter, referred to as halo alkoxy) shall apply, for example Furuorometokishi, chloromethoxy, 2-Furuoroetokin, 2, 2, 2-triflate Ruo Roe butoxy, etc. And preferably 2,2,2-trifluoroethoxy.
  • aryloxy for R 5 includes, for example, phenyloxy, naphthyloxy and the like, with phenyloxy being preferred.
  • “Cycloalkyloxy” for R 5 is C 3 _ 6 cycloalkyloxy, for example, cyclopentyloxy, cyclohexyl / reoxy, etc., preferably cyclohexyloxy.
  • “Hydroxyalkoxy” in R 5 is, C 3 one 6 alkoxy is substitution with a hydroxy group (hereinafter, hydroxy C 3 - 6 that alkoxy) A, such as 3-hydroxycarboxylic propoxy, 1- Mechinore 1- Examples include hydroxyethoxy, 4-hydroxybutoxy, 5-hydroxypentynoleoxy, 6-hydroxyhexynoleoxy, 2,2-dimethyl-3-hydroxypropoxy and the like.
  • “Hydroxycarbonyl alkoxy” in R 5 is (: 4 alkoxy hydrate Rokishikarubo - substituted group Le (hereinafter, a hydroxycarboxylic Poni Le C i_ 4 an alkoxy), for example, hydroxycarbonyl methoxy, 2-hydroxycarboxylic Poni Le Etokishi, 3-hydroxycarbonylpropoxy and 4-hydroxycanoleponylptoxy.
  • the “aminoalkoxy” of the “aminoalkoxy optionally having substituent (s)” for R 5 is: 6 is a group in which an alkoxy is substituted with an amino (hereinafter, referred to as an amino or an alkoxy). It may be mono- or di-substituted by a group selected from alkyl, acryl and benzyl.
  • the amino is di-substituted with the above substituent, and the substituent may have a substituent together with the nitrogen atom of the amino, and an oxygen atom or a sulfur atom may be present in the ring. It may contain one or two heteroatoms selected from nitrogen atoms, and may form a cyclic amine.
  • cyclic amines include, for example, pyrrolidine, optionally substituted piperidine, homopirididine, optionally substituted piperazine, and optionally substituted Homopyrazine, morpholine and morpholine.
  • amino alkoxy which may have a substituent as described above include aminomethoxy, aminoethoxy, aminopropoxy, methylaminomethoxy, dimethylaminomethoxy, 2-dimethylaminoethoxy, formylaminomethoxy, Acetinole aminomethoxy, propioninole aminomethoxy, benzoinoleamino methoxy, morpholinomethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2,2-dimethyl-13-morpholinopropoxy, 4-morpholinoboxy, 5-morpholino Pentyloxy, 6-morpholinohexyloxy, thiomorpholinomethoxy, 2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy, 2,2-dimethyl-13-thiomorpholinopropoxy, 4-thiomorpholinopoxy 5-thiomorpholinopentinoleoxy, 6-thiomorpholinohexyloxy, piperidinomethoxy, 2-piberidinoethoxy, 3-
  • “Hydroxyalkylthio” in R 5 is hydroxyalkylthio, specifically, hydroxymethylthio, 2-hydroxyethylthio, 3-hydroxypropylthio, 4-hydroxybutylthio, 5-hydroxypentyl And 6-hydroxyhexylthio.
  • “Hydroxycarbonylalkylthio” in R 5 is hydroxycarbonylalkylthio, specifically, hydroxycarbonylmethylthio, 2-hydroxycarbonylethylthio, 3-hydroxycarbonylpropino! ⁇ O, 4-hydroxycarbonylbutyltylthio Is raised.
  • aminoalkylthio of “aminoalkylthio optionally having substituent (s)” for R 5 is a group in which —6alkylthio is substituted by amino (hereinafter referred to as aminoCi-ealkylthio), amino, C 3 _ 4 alkyl. With a substituent selected from Preparative 4 Ashiru Contact Yopi Benzoiru it may be mono- or di-substituted.
  • the substituent in which the amino is replaced with the above substituent may have a substituent together with the nitrogen atom of the amino, and may have an oxygen atom, a sulfur atom and a sulfur atom in the ring.
  • a cyclic amine which may contain one or two heteroatoms selected from nitrogen atoms may be formed.
  • Such cyclic amines include, for example, pyrrolidine, piperidine optionally having gm ⁇ , homopiridine, piperazine optionally having a substituent, homopidine optionally having a substituent Razine, morpholine and thiomorpholine.
  • amino alkylthio which may have a substituent as described above include aminomethinorethio, 2-aminoethylthio, 3-aminopropinorethio, 4-aminobutylthio, and dimethylamino.
  • Methylthio acetylaminomethylthio, 2-dimethylaminoethylthio, 3-dimethylaminopropylthio, 4-dimethylaminobutylthio, formylaminomethylthio, 2-formylaminoethylthio, acetinoleamino Methylthio, 2-acetylaminoethylthio, benzoinoleaminome Tylthio, 2-benzoylaminoethylthio, morpholinomethylthio, 2-morpholinoethylthio, 3-morpholinopropylthio, 4-morpholinoptylthio, 5-morpholinopentylthio, 6-morpholinohexylthio, thiomorpholinomethylthio, 2 —Thiomorpholinoethylthio, 3-thiomorpholinopropylthio, 4-thiomorpholinoptylthio, 5-thiomorpholinopentylthi
  • the “force connecting the phenyl group and the ring Q in the formula (I) / the position where the nitrogen atom of the levamoyl group is bonded to the phenyl group” in R 3 and R 5 means, for example, the following position (a): In R 3 , the “position 3 of the phenyl group” based on the position (a) means the following position (b). Moreover, the:. ⁇ , In R 5, and the position (a) as a reference "4-position of the phenyl group", that means the position of the following (c).
  • Alkyl j in R 6 and R 7 is alkyl. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isopti / re, and tertiary butyl, and preferably ethyl.
  • Hydroxyalkyl in R 6 and R 7, hydroxy ⁇ - a 4 alkyl, for example, hydroxymethyl, 2-hydroxyethyl E chill, 3-hydroxy-flop port pills, and 4-hydroxybutyrate Honoré the like, preferably Is 2-hydroxyethyl.
  • “Aminoalkyl” in R 6 and R 7 is a group in which Ci- 4 alkyl is substituted by amino, and the amino is mono- or di-substituted by a group selected from alkyl, acyl and benzoyl. Is also good. Specific examples of such an amino C4 alkyl include aminomethyl, aminoethyl, dimethylaminomethyl, getylaminomethyl, formylaminomethyl, 2-honoleminoleaminoethyl, acetinoleaminomethylino, 2 —Acetylaminoethyl, benzoy7-reaminomethyl and the like.
  • R 6 and R 7 may be combined with a difficult nitrogen atom to form a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring.
  • a cyclic amine which may contain two or more.
  • Such cyclic amines include, for example, pyrrolidine, optionally substituted piperidine, homopyridine, optionally substituted piperazine, and substituted And cyclic amines selected from homopiperazine, morpholine and thiomorpholine.
  • Examples of the cat in the above-mentioned "optionally substituted piperidine” include: hydroxy; carboxy; Ci- 4 alkoxy-monocarbonyl; and hydroxy. 4 alkyl Le; alkoxy C i-4 alkoxy (methoxymethoxy, ethoxymethoxy, Provo alkoxy methoxy, butoxymethoxy, 2 'methoxyethoxy, 3-Metokishipu port epoxy, 4-methoxy script alkoxy, etc.); carboxy C 4 alkyl one Karuponiru Oxy (carboxymethylcarbonyloxy, 2-carboxyethylcarboyl Carboxymethyl, etc.); C 3 - 4 Ashinoreokishi; Benzoiruokishi; phenyl; Ji ⁇ alkylene Njiokishi (Mechirenjiokishi, etc.
  • piperidine which may have a substituent examples include piberidine-11-yl, 4-hydroxypiperidine-11-inole, 4-hydroxypropyloxyperidine-11-yl, 4-methoxycarbonylpiperidine-11-yl, 4-ethoxycarboxy-rubiperidine-1-1-yl, 4-((2-carboxyethyl) carbonyloxy) piperidine-1-1-yl, 4-benzoinoleoxy Piperidine 11-yl, 4-piperidino-piperidine 11-yl, 4-morpholinopiperidine 11-yl, 4-thiomorpholinopiperidine 11-yl, 4- (N-oxidemorpholino ) Pyridine-11-yl, 4,4-Ethylenedioxypiperidine-1-1-yl, 4-oxopiperidine-1-1-yl, 4-aminopiperidine-1-inole, 4-Dimethi A "Aminopiperidine 1 1 4— (N— (2-hydroxyethyno
  • Substituents of the "pin may have a substituent Bae Rajin" described above, ⁇ _ 4 Al kills; carboxy alkyl (carboxymethyl, etc. Karubokishechiru); hydroxyalkyl; C 3 - 4 alkoxy alkyl; hydroxy ⁇ alkoxy d _ 4 alkyl (hydroxy methoxymethyl, etc.
  • pidazine which may have a substituent include piperazin-1-inole, 4-methinolebiperazine-11-inole, and 4-ethinorebiperazine-11-ii.
  • C DOO 4 ⁇ alkyl may have a hydroxyalkyl, specifically Homopiperaji on as a substituent, 4 one (hydroxymethyl Honoré ) Homopiperazine-11-yl, 4- (2-hydroxyethyl) homopiperazine-11-yl, 4-methinole homopiperazine-11-yl and the like.
  • the "saturated ring" of the “saturated heterocyclic ring which may have a substituent and contains one or two heteroatoms selected from an oxygen atom and a nitrogen atom in the ring,” is 5 or It is a 6-membered heterocyclic ring, and its substituents include alkyl, arylalkyl and the like.
  • Such a saturated heterocyclic ring include piperidine-1-4-inole, 1-methinolepiperidine-1-4-inole, 1-ethylpiperidine-4-inole, 1-benzylpiperidine-1-4-yl 1,3-pyrrolidine-1,3-yl, 1-methinolepyrrolidine-1,3-yl, 1-ethylpyrrolidine-13-yl, 1_benzinolepyrrolidine-1,3-yl, 3,4,5,6- Tetrahydro-1H-pyran-1-yl and 2,3,4,5-tetrahydrofuran-3-yl.
  • R 8, R 8 a, R 9, R 1 (), R ", alkyl of R 1 2 is, C - a 4 alkyl, methyl, Echiru, propyl, isopropyl, Petit / Les, Isopuchiru, tertiary Butyl, preferably methyl.
  • X represents an ethylene ketalized or propylene ketalized methylene, preferably an ethylene ketalized methylene.
  • Halogen in R 8 , R 8a , and R 11 represents fluorine, chlorine, bromine, or iodine.
  • R 8, R 8 a "Anorekokishi" in R 1 1, a Anorekokishi, methemoglobin carboxymethyl, ethoxy, Purobokishi, Isopurobokishi, butoxy, tertiary butoxy and the like.
  • “Hydroxyalkyl” in R 9 and R 12 is hydroxyalkyl, for example, hydroxymethinole, 2-hydroxyethynole, 3-hydroxypropyl, 4-hydroxybutyl, and the like. It is methyl.
  • alkoxyl alkoxyl in R 11 is an alkoxyl alkoxyl, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxyl alkoxyl, butoxycarbonyl, tertiary butoxycarbonyl and the like.
  • Pharmaceutically acceptable salts of the compound of the present invention include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate, or acetate, propionate, succinate, Contains salts with organic acids such as maleate, fumarate, benzoate, citrate, malate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or contains a carboxyl group ⁇ ⁇ Is a metal salt such as a sodium salt, a potassium salt, a calcium salt, an aluminum salt or a magnesium salt; a salt with an amine such as triethylamine; or a salt with a di-amino acid such as lysine.
  • the compounds of the present invention also include hydrates (such as monohydrate, 1Z dihydrate, tri-tetrahydrate, and tetrahydrate), and hydrates. Further, the compound of the present invention includes an N-year
  • the compound of the present invention has a geometric isomer ⁇ 8 ⁇ Is also a mixture of those ⁇ -f. Further, in the present invention, when one or more asymmetric centers are present in the molecule, various optical isomers are present therefrom.
  • the present invention includes optical isomers, racemates, diastereoisomers, and mixtures thereof.
  • the compound of the present invention can be produced by the following method.
  • Method 1 The compound (I) of the present invention can be produced by the following method.
  • the condensation reaction between compound (VI) and compound (VI I) can be carried out by the following methods (1), (2) and (3).
  • Compound (VI) is converted to an acid halide by a conventional method using a halogenating agent for thionino chloride, and then ⁇ (triethylamine, pyridine) in an appropriate salt (e.g., dichloromethane, dichloroethane, chlorophoronelem). , Sodium methoxide, sodium methoxide, sodium hydroxide, potassium heptaoxide, sodium acetate, etc.) and condensate with compound (VI I) at a reflux temperature of 20 ° C to Nada for 30 minutes to 12 hours. ) Is obtained.
  • the above donkey may also serve as a nada, and in that case, a solvent may not be used (for example, when the base is triethynoleamine, pyridine or the like).
  • Compound (I) can be produced by condensation with I). Is usually 0 ° C to 100 ° C, and the reaction time is usually 30 minutes to 24 hours. The use of the condensing agent can be carried out under 1-hydroxybenztriazole or the like, if necessary.
  • the compound (VI) is converted into a mixture of 7 compounds.
  • M triethylamine, pyridine, sodium methoxide, sodium methoxide, water
  • isopropyl alcohol butanol / butane, ethylene glycol / etre, tetrahydrofuran, tonolene, nitrobenzene or a mixture thereof (From sodium oxide, potassium hydroxide, etc.) for 1 to 24 hours at room temperature
  • Compound (I) can be obtained by condensation with (VI I).
  • Method 3 The compound of the present invention is subjected to a condensation reaction commonly used in the field of synthetic organic chemistry with a ⁇ ⁇ carboxylic acid compound, an acid halide compound or an acid anhydride compound having water fiber. The corresponding ester compound can be produced.
  • the compound of the present invention has a carboxylic acid group: ⁇ , an alcohol compound or a phenol compound and an ester compound corresponding to a condensate S commonly used in the field of organic synthetic chemistry can be produced. it can.
  • the compound of the present invention has an ester group: ⁇ , an acid (hydrochloric acid, sulfuric acid, etc.) or a donkey (sodium hydroxide, hydroxylating power, etc.) and a corresponding carboxylic acid compound by carohydrate water by a conventional method. Can be manufactured.
  • the compound of the present invention can be N-alkylated or N-acylated by an ordinary method using an alkyl halide or an acyl halide in the presence of ⁇ having an amino group (such as triethylamine or pyridine).
  • Method 4 Compound I ⁇ wherein R 2 is hydrogen (VII) (VI 1 - 1 ) may be prepared by the following way. .
  • the compound (X) is subjected to a reduction method usually used in the field of synthetic organic chemistry [for example, in an appropriate (water, methanol, ethanol, propanol, butanol, ethylene glycol or a mixture thereof ⁇ ) iron powder Treatment with dilute hydrochloric acid or a catalytic amount of ammonium chloride as a catalyst, or a parasite reduction method in which hydrogenation is performed in the presence of a catalyst such as Eckel, palladium, or platinum, a method using iron chloride and hydrazine, or liquid ammonia. , (Birch) reduction method using an alkali metal such as sodium or lithium] to obtain compound (VI1-1) power S.
  • the reaction is usually from room temperature to reflux in the sea, and the time is usually from 1 hour to 24 hours.
  • Method 5 The compound (V I I-1) can also be produced by the following method.
  • the compound (XII) is converted to a suitable compound (water, methanol, ethanol, propanol, butanol, tertiary butyl alcohol, ethylene glycol, benzene, tonolene, xylene, preferably benzene) using the Schmidt reaction.
  • a suitable compound water, methanol, ethanol, propanol, butanol, tertiary butyl alcohol, ethylene glycol, benzene, tonolene, xylene, preferably benzene
  • R 5 is ⁇ / rekoxy, / peranorekoxy, aryloxy, cycloalkyloxy, hydroxya / rekoxy, hydroxycanolepo 2 7 ureanorekoxy, optionally substituted amino alkoxy, alkylthio, hydroxy alkylthio, hydroxycarboxylic Poni Le alkyl thio substituents to have optionally may ⁇ be amino alkyl thio or a group N (6) (R 7), compound (X- 1) is to be produced by the following method Can be.
  • Y is alkoxy, haloalkoxy, aryloxy, cycloalkyloxy, hydroxyalkoxy, hydroxycarbonylalkoxy, optionally substituted aminoalkoxy, alkylthio, hydroxyalkylthio, hydroxycarbonylalkylthio, substituent Represents an aminoalkylthio or a group N (R 6 ) (R 7 ) which may have the other symbols as defined above.)
  • the compound (XIII) is mixed with or without an appropriate solvent (eg, formaldehyde, acetonitrile, water, methanol, ethanol, tetrahydrofuran, ethinoleate / dimethylmethonolemamide, dimethylsulfoxide, or a mixture thereof). Under a base (sodium heptaoxide, sodium methoxide, sodium ethoxide, sodium hydride, petit / relithium, etc.) at a temperature of 120 ° C. to 100 ° C. After reacting for 1 to 24 hours, compound (X-1) is obtained.
  • Method 7 Compound (XV II) can be produced by the following method c
  • Method 8 Compound (XIX) can be produced by the following method.
  • Compound (XIX) can be obtained by allowing compound (IX) in a solution (such as tetrahydrofuran, dimethyl ether, dimethylformamide, or dimethylsulfoxide) at room temperature to 60 ° C. for 1 to 24 hours.
  • a solution such as tetrahydrofuran, dimethyl ether, dimethylformamide, or dimethylsulfoxide
  • R ′′ is an aryl which may have a substituent or a heteroaryl which may have a substituent, and other symbols are as defined above.
  • the compound (VII) is condensed with a halogen-substituted benzene or a compound having a heteroaromatic ring having a 7-reponic acid (XX) by the method of Method 1 to obtain an amide (XXI).
  • the obtained amide compound (XXI) is prepared by reacting an aryl boran or a heteroaryl borane [R "-B (OH) 3 , R 1 'with the same meaning as described above in the presence of a palladium insect medium such as tetrakistriphenylphosphine z radium.
  • Suitable solvents such as ice, methanol, ethanol, propanol, butanol, tertiary butyl alcohol, ethylene glycol, benzene, toluene, xylene, dimethylformamide, etc.), sodium carbonate or carbonated water, etc.
  • the compound (1,) can be obtained by the Suzuki coupling method in which the mixture is treated at room temperature for 1 hour for 24 hours at room temperature with the use of ⁇ ; or the obtained amide (XXI ) With tetrakistriphenylphosphine paradigm, etc.
  • alkyl tin such as, suitable ⁇ (water, methanol, ethanol, propanol, butanol, tertiary Butyl alcohol, ethylene glycol, benzene, toluene, xylene, dimethylformamide, etc.
  • the instant compounds can be converted, if necessary, to pharmaceutically acceptable salts.
  • the compound of the present invention is dissolved in an appropriate solvent (water, methanol, ethanol, propanol, isopropyl alcohol, dimethyl ether, tetrahydrofuran, dioxane, etc.) in an acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Treatment with an inorganic acid such as nitric acid, or an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesnoleic acid, benzenesulfonic acid, etc. can do.
  • an appropriate solvent water, methanol, ethanol, propanol, isopropyl alcohol, dimethyl ether, tetrahydrofuran, dioxane, etc.
  • an acid hydroochloric acid, hydrobromic acid, sulfuric acid, phospho
  • the compound of the present invention containing a carboxyl group can be converted into a corresponding metal salt by treating with sodium hydroxide, potassium hydroxide, calcium heptaoxide, aluminum hydroxide, magnesium hydroxide, sodium alcoholate and the like.
  • the corresponding amino acid salt can be obtained by treating with a suitable amino acid such as triethylamine or a diamino acid such as lysine.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is a crystalline anhydride, treated with water, water-containing »or other to obtain 7j hydrate (monohydrate, 1 / 2zK hydrate, 3 ⁇ 4 water). Japanese) or Japanese.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be converted to an N-oxide compound by treating the compound with an oxidizing agent such as hydrogen peroxide, metaclo ii ⁇ benzoic acid in a conventional manner. Monkey
  • the thus-obtained compound of the present invention or a salt thereof, and a hydrate or a Nadaoxide N-oxide compound thereof can be obtained by a method in the field of synthetic chemistry such as recrystallization and column chromatography. Can be isolated and purified. Also, the obtained product is a racemic form, for example, by a fractional crystallization method using a photoacid or a salt with; ⁇ 3 ⁇ 4, or by passing through a column packed with a photocarrier. Thereby, it can be divided into a desired light emitting substance. Alternatively, the photoreceptor can be produced by using a photoreactive compound as the raw material in the above-mentioned method.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an action of selectively suppressing IL-4 production from Th2 cells activated by an antigen or the like, it is possible to improve the immunity involved in Th2 cells. It is effective as a selective inhibitor of response as a preventive or therapeutic agent for various allergic diseases.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease caused by abnormal proliferation or hyperfunction of Th2 cells, for example, systemic erythematosus, nephrotic syndrome lupus, Hashimoto's thyroid, It can be used to prevent sclerosis, m rn dysfunction, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, allergy's inflammation, and glomerulonephritis.
  • inflammatory, proliferative and hyperproliferative skin diseases, and immune-mediated diseases on the skin such as psoriasis, psoriatic arthritis, atopic eczema (atopic dermatitis), dermatitis, and even eczema dermatitis , Seborrheic dermatitis, lichen planus, pemphigus, 7 effervescence ⁇ epidermolysis bullosa, urticaria, vascular edema, vasculitis, erythema, dermatitis, acne, round hair loss It can also be used for the treatment of diseases, eosinophilic fasciitis and atherosclerosis.
  • the compounds of the present invention may be used for respiratory diseases such as sarcoidosis, pulmonary fibrosis, see interstitial pneumonia and reversible obstruction airway diseases such as bronchial asthma, pediatric asthma, allergic asthma, endogenous asthma, extrinsic asthma and dusty asthma
  • respiratory diseases such as sarcoidosis, pulmonary fibrosis, see interstitial pneumonia and reversible obstruction airway diseases
  • bronchial asthma pediatric asthma, allergic asthma, endogenous asthma, extrinsic asthma and dusty asthma
  • the present invention is applicable to the treatment of symptoms such as asthma including chronic or refractory asthma (eg, asthma and airway hypersensitivity), bronchitis and the like.
  • the compounds of the invention may also be of use in the treatment of liver damage associated with ischemia.
  • the compound of the present invention may be used for a specific eye disease such as allergic keratitis, keratoconjunctivitis, keratitis, spring catarrh, uveitis associated with Behcet's disease, herpes keratitis, keratoconus, corneal epithelial degeneration, It is also effective against corneal vitiligo, pemphigus peso, Mohren's ulcer, scleritis, Graves' eye disease, and severe intraocular inflammation.
  • a specific eye disease such as allergic keratitis, keratoconjunctivitis, keratitis, spring catarrh, uveitis associated with Behcet's disease, herpes keratitis, keratoconus, corneal epithelial degeneration, It is also effective against corneal vitiligo, pemphigus peso, Mohren's ulcer, scleritis, Graves' eye disease, and
  • Kidney diseases such as maternal toxicity syndrome and urinary nephropathy; neuropathy selected from polymyositis, Guillain-Paray syndrome, Meniere's disease and root disease; hyperthyroidism and Passeow's disease Endocrine disorders such as; sarcoidosis, pulmonary «disease and ⁇ Skin diseases such as dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; Cardiovascular diseases such as scleroderma, collagen disease such as Pellner's granulomas and siedaren syndrome; steatosis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; hemolytic uremic syndrome; and muscular dystrophy It can also be used in the treatment or prevention of The compounds of the present invention are characterized
  • the gastrointestinal tract is also suitable for the prevention or treatment of migraine, rhinitis and eczema, which exhibit directly related symptoms.
  • the compound of the present invention has an immunogenic disease (for example, autoimmune depression, or a citrus juice) because it has a liver regeneration activity and / or an activity of promoting hepatocyte hypertrophy and hyperplasia. Used in the treatment of chronic autoimmune cirrhosis including cholangitis, chronic autoimmune 'fighting disease', B type virus' 14f inflammation, non-A type Z non ⁇ inflammation and liver disease such as cirrhosis it can.
  • the present invention also provides Shy-Drager syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ophthalmopathy, progressive systemic sclerosis, mixed ⁇ yarn!
  • ⁇ Disease Aorticitis Syndrome, Zegener's Granulation I Heavy, Active Activity '[»Inflammation, Evans Syndrome, Pollen, Hypoparathyroidism, Addison's Disease (Autoimmune Adrenalitis), Autoimmune Testicleitis, Autoimmunity Ovarian inflammation, cold hemocytosis, seizure-associated cold hemoglobinuria, anemia, adult T-cell leukemia, autoimmune atrophic gastritis, lupus hepatitis, tubulointerstitial nephritis, membranous nephritis, It can be used for the prevention or treatment of amyotrophic lateral sclerosis, rheumatic fever, post-myocardial infarction syndrome, and gross inflammation.
  • the present promiscuous compound or a pharmaceutically acceptable salt thereof may contain other immunosuppressants (such as tactile limus hydrate, ascomycin, FTY720), steroids (prednisolone, methylprednisozoe). Mouth, dexamethasone, hydrocortisone, clobetasone, flumethasone, triamcinolone acetonide, alclomethasone, fluocino acetonide, beclomethasone, betamethasone, deprodone, ⁇ resinide, amshinonide, fluocidonide, diflucordone difludonide , Diflorazone, clobetazonole or their fatty acid esters), antiallergic agents (sodium cromoglycate, tranilast, amlexano) Can be used in combination with e.g. .
  • immunosuppressants such as tactile limus hydrate, ascomycin, FTY720
  • steroids prednisolone, methylpre
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has a novel mechanism of action for selectively suppressing IL-4 production from Th2 cells. This is a different mechanism of action than existing immunosuppressants, steroids or antiallergic drugs used to treat various allergic or autoimmune diseases. Therefore, by using the compound of the present invention or a pharmaceutically acceptable salt thereof as a concomitant drug in combination with such an existing drug, the dose of the existing drug can be reduced from the conventional dose. Even in such cases, excellent pharmacological effects can be exhibited. As a result, it is possible to provide a medicament having fewer side effects and excellent pharmacological effects as compared with conventional medicament.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicine ⁇ , a pharmaceutically acceptable carrier of the compound of the present invention (excipients, binders, disintegrating pastes, odor correctors, lactating agents, Diluents, solubilizing agents, etc.) and medically difficult compounds or preparations (tablets, pills, capsules, granules, dusts, syrups, emulsions, elixirs, suspensions, etc.) It can be administered orally or parenterally in the form of a night mist, m, drops, eye drops, eye ointments, suppositories, ointments or lotions.
  • the pharmaceutical composition of the present invention can be formulated according to a usual method.
  • Preparations such as sterile aqueous or oily preparations or suspensions, are prepared in a manner known in the art using suitable solvents, dispersants, wetting or suspending agents. can do.
  • the orchid preparation is a sterile injectable solution or suspension obtained by dissolving or suspending the compound of the present invention in a parenterally administrable diluent or solvent (eg, water).
  • parenterally administrable diluent or solvent eg, water.
  • parenteral administration in the present specification means a method of administration including subcutaneous administration, intravenous administration, intramuscular administration, internal administration, instillation, ophthalmic administration, and the like.
  • acceptable vehicles or solvents that can be used in the above preparations include water, Ringer's solution, and the like.
  • aseptic non-volatile oil can also be used.
  • This non-volatile oil examples include natural, synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides.
  • the preparation for viewing may be used in combination with an appropriate suspending agent, a nonionic surfactant, a melting agent and the like, if necessary.
  • Suppositories for aggressive administration include compounds of the present invention and suitable nonirritating excipients (eg, cocoa putters and polyethylene glycols) which are solid at room temperature but liquid at intestinal tract and rectal. It can be manufactured by mixing it with a substance that releases drugs.
  • suitable nonirritating excipients eg, cocoa putters and polyethylene glycols
  • Solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like.
  • the active ingredient according to the present invention may be used in combination with at least one additive (eg, sucrose, lactose, cellulose, mannitol, maltitol, dextran, starches, agar, alginate, chitin, Mix with chitosans, pectins, gum tragacanth, gum arabic, gelatins, collagens, casein, anorepmin, synthetic or semi-synthetic polymers or glycerides.
  • the medicinal compositions of the present invention having these dosage forms may generally contain additional carotenoids.
  • Further adjuvants include, for example, inert diluents; lubricants such as magnesium stearate. Preservatives such as parabens and sorbins; antioxidants such as ascorbic acid, ⁇ -tocopherol and cysteine; disintegrants; binders; thickeners; buffers; sweeteners; Agents and the like.
  • inert diluents such as magnesium stearate.
  • Preservatives such as parabens and sorbins
  • antioxidants such as ascorbic acid, ⁇ -tocopherol and cysteine
  • disintegrants binders; thickeners; buffers; sweeteners; Agents and the like.
  • tablets and pills may further be provided with an enteric coating.
  • Liquid dosage forms for oral administration include emulsions, syrups, elixirs, suspensions, and night-time preparations. These may contain inert diluents commonly used in the art, such as water.
  • the compound of the present invention is used as an ophthalmic solution: ⁇ is used in the form of an aqueous solution or water, particularly preferably in the form of sterile water intense night.
  • Various additives such as a buffering agent, a tonicity agent, a solubilizing agent, a preservative, an agent, a chelating agent, a ⁇ adjuster, and a fragrance may be appropriately added to the ophthalmic solution.
  • the compound of the present invention is used as an ointment.
  • An ointment can be obtained by mixing a soluble base, a suspending base and the like, and appropriately mixing a dissolution / increase promoter.
  • the compound of the present invention is used as a lotion by dispersing or partially dissolving the compound of the present invention in a liquid medium, and appropriately mixing an emulsifier, a dissolution absorption promoter, a thickening agent and a stabilizing agent. Can be obtained.
  • the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof can be used in combination with an existing drug such as an immunosuppressant, a steroid or an antiallergic drug. (Concomitant drug), an excellent therapeutic effect can be expected.
  • “combination” in the above concomitant drug means ( ⁇ ) the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof and ( ⁇ ) an immunosuppressant, a steroid or an antiallergic drug. It means that it is used in combination with one agent, and the form of use is not particularly limited.
  • compositions in which both preparations are mixed and used as a single composition after being made into separate preparations using excipients, etc., or both preparations are not mixed, Or a combination of two types of preparations (with a time difference so that the period of use of both preparations partially overlaps).
  • the combination preparation include, for example, a set, a kit, a pack, and the like in which both preparations are packaged in one container.
  • the administration route of the concomitant drug of the present invention may be either oral administration or parenteral administration, similarly to the administration route already described for the pharmaceutical preparation containing the compound of the present invention.
  • the administration route is determined in consideration of the disease site to be treated as ⁇ ⁇ ⁇ ⁇ .
  • the contained preparations may be administered to the same subject at the same time or different times, simultaneously, separately or partially simultaneously.
  • the concomitant drug of the present invention may have any of the dosage forms already described for the pharmaceutical composition containing the compound of the present invention.
  • the dosage form may be an administration route, an administration fiber, or the like. It is decided in consideration of.
  • each preparation contained in the combination preparation may have the same dosage form or may have different dosage forms.
  • the dosage depends on age, weight, general health, gender, diet, time of administration, mode of administration, release, combination of drugs, and the severity of the condition the patient is treating at the time. , Or other factors.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be safely used with low toxicity, and the daily dose depends on the condition and weight of the patient, the type of the compound, the administration route, and the like. Different, but parenterally, for example, subcutaneously, intravenously, intramuscularly, or urn, about
  • OmgZ persons Z days preferably 0.01 to 5 OmgZ persons Z days, and orally about 0.01 to 100 Omg / person Z days, preferably 0.01 to 50 It is preferred that the OmgZ person be administered Z days.
  • Diisopropylethynoleamine (22 mL) was added to 2-dimethyl-5-nitropyridine (10 g) and 4-hydroxypiperidine (7.7 g) in dimethylformamide (5 OmL). The mixture was stirred at C for 2 hours. After cooling the reaction mixture with ice, water was added, and the precipitated solid was collected by filtration. A suspension of the obtained solid, methanol (20 OmL), hydrazine 'monohydrate (7.2 g), anhydrous ferrous chloride (0.2 g) and carbonaceous carbon (2 g) The mixture was stirred at ° C for 2 hours. After the reaction, the suspension was filtered through celite, and the filtrate was concentrated to remove the solvent.
  • the shelf layer was cooled with ice, and the ⁇ of the strong night was set to 10 with a 10% carbon dioxide rich water, and then the aqueous layer was separated.
  • the 7_ layer was washed with ethyl acetate, cooled again, and then the pH of the aqueous layer was adjusted to 2 with 4N hydrochloric acid, and the precipitated solid was collected by filtration. Recrystallization from acetone water gave pale yellow crystals.
  • Phosphorous oxychloride (6.2 mL) was added to a solution of N- (4'-monoclonal phenacyl) oxamic acid ethyl ester (3.6 g) in benzene (20 mL), and the mixture was heated for 5 hours. Distilled off. The residue was extracted with ether, and the organic layer was washed with water and a saturated diet, and dried over magnesium sulfate. After the solvent was removed by concentration, the residue was recrystallized from ether / hexane to obtain pale red crystals.
  • Trifluoromethanesulfonic anhydride (8.8 mL) was added dropwise to ice-cooled dimethyl 5-hydroxyisophthalate (10 g) in pyridine (10 OmL) intense night, and the mixture was stirred for 1 hour. The residue was extracted with ethyl acetate. Wash the column with water, saturated food 3 ⁇ 4 ⁇ , dry over magnesium sulfate, and then concentrate to a light brown oil
  • the organic layer was washed with water and a saturated diet; dried with magnesium sulfate, dried over magnesium sulfate, dried, and then subjected to silica gel column chromatography (formaldehyde methanol). Yellow crystals were obtained (0.18 g).
  • White crystals were obtained by performing the same operation as in Difficult Example 1 using 5-amino-2- (2,2-dimethinole 3-hydroxypropoxy) benzonitrinole and 4-odobenzoic acid.
  • Example 2 The same procedure as in Example 1 was performed using 5-amino-2- (2,2-dimethinole-1-hydroxypropoxy) benzonitrinole and 3-odobenzoic acid to obtain pale yellow crystals.
  • Example 7 The same operation as in Example 2 was carried out using the compound obtained in Example 7 and 4-chlorophenolic acid to obtain pale yellow crystals.
  • Example 2 The same operation as in Example 1 was carried out using 5-amino-2- (4-hydroxypiperidine-11-inole) benzonitrile and 5- (4-chloropheninole) furan-2-force olevonic acid. As a result, pale yellow crystals were obtained.
  • Example 1 using 5-amino-2- (4-hydroxypiperidine-11-yl) pyridine and 5- (4-chloroporous furan) furan-2-carboxylic acid obtained in Primitive Example 1. By performing the same operation as in above, pale yellow crystals were obtained.
  • Example 2 The same operation as in Example 1 was carried out using 5-amino-2- (4-bromo-7-refolinopyridine-1-yl) benzobutryl and 5- (4-chlorophenyl) furan-2-canoleponic acid. As a result, pale yellow crystals were obtained.
  • Example 13 5- (4-chlorophenyl) -N- [3-cyano-14- [4- (3,4,5,6-tetrahydro-1H-pyran-1-inole) pidazine-1 1- ⁇ ] ⁇ 2 / ⁇ ] 1-furan 2-force ⁇ / poxamide
  • Fiber Example 18 5— (4, 1-mouth) Xipiperidine-1 1-yl) fueni / re] thiophene 1-carboxamide
  • Example 20 4- (4-chlorophenol) 1 N— [3-cyano 4-1 (4-hydroxypiperidine-11-yl) phenyl] thiazole 1-2-ca ⁇ boxamide
  • Example 23 3- (4-chloroporous phenyl) -1-5-[[3-cyano-14- (4-hydric xypiperidine-1-11yl) phenyl] aminocarbyl ⁇ benzoic acid
  • Example 2 The same procedure as in Example 2 was carried out using the compound obtained in Example 24 and 4-chlorophenylphenolic acid.
  • the obtained crude product was converted into hydrochloride by adding 4N dioxane hydrochloride and purified by crystallization from N-methyl-12-pyrrolidone / ether / water to obtain pale yellow crystals.
  • Example 2 The same operation as in Example 2 was carried out using the compound obtained in Example 26 and 4-monophenylenoboronic acid to obtain a pale yellow amorphus.
  • a white crystal was obtained by performing the same operation as in Example 1 using 5-amino-2- (4-hydroxypiperidine-11-inole) benzonitrile and 4- (11-pyromouth) benzoic acid.
  • 30 g of the compound of the present invention, 328.8 g of lactose and 82.2 g of crystal cell mouth are mixed.
  • the mixture is compression-molded using a roller compactor to obtain flakes.
  • a hammer mill pulverize the flakes and crushed material, and crush the flakes to 20 mesh Sieve using a sieve.
  • To the sieved product were added 4.5 g of light anhydrous silicic acid and 4.5 g of magnesium stearate, and mixed.
  • the mixture is tableted using a 7.5 mm diameter die and punch to obtain 3000 tablets weighing 150 mg per tablet.
  • Mouse spleen ⁇ cells are cultured under the compound of the present invention, and IL-4 and I produced in the culture supernatant when activated by the addition of colonnavalin A (Con A) as a mitogen.
  • colonnavalin A Con A
  • Spleens were aseptically removed from 6-12 week old male BALBZc mice and tweezers were used in RPMI 1640 medium (Sigma mane: fc) supplemented with 10% heat-inactivated fetal serum (FCS). After removing erythrocytes by deflocculation and hypotonic treatment, a single cell suspension night of spleen cells was prepared by three times with RPMI 1640 medium. The FCS used was previously heat-inactivated at 56 ° C for 30 minutes, and RPMI 1640 medium contained 'iOmmolZL's 2- [4- (2-hid-mouth).
  • IL-14 and IFN- ⁇ in the culture supernatant were quantified by the following method.
  • 1 ⁇ g ZniL of rat anti-mouse IL-4 monoclonal antibody (farmindiene ⁇ ) or rat anti-mouse IFN- ⁇ Mouth-Nanore antibody (Pharmingenne: fc3 ⁇ 4) was added at 50 LZ well, and the whole was allowed to stand at 4 ° C.
  • Block Ace Dainippon Shikikai Kai; fc
  • the concentration of IL-4 or IFN- ⁇ in each culture supernatant was quantified from the standard curve using the standard curve.
  • the 50% inhibitory concentration (IC 50 ) was determined by non-linear regression based on the * ®S curve.As a result, the compound of the present invention showed a decrease in IL-4 production from 0.0001 to 0.01 / imo.
  • the inhibitory effect on IFN- y production was as weak as 1Z10 to 1/1000 of the inhibitory effect on IL-14 production. — It was found to show a selective inhibitory effect on the production of 4.
  • mice were immunized intraperitoneally twice at two-week intervals. One week later, mice were challenged with 10 ⁇ g of egg white anolebumin subcutaneously in the auricle of mice, resulting in biphasic ear edema with bimodal edema 1 and 24 hours after challenge. Triggered.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is suspended or dissolved in 0.5% hydrated xypropylmethylcellulose to give an oral probe at a dose of 0.01 to 100 mg / kg body weight.
  • the thickness of the pinna of the mouse was measured using a dial gauge and used as an index of ear edema.
  • the group administered with the vehicle alone was used as a control and compared with the Dunnett method. When the value was less than 0.05, it was judged to be significant.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof was subjected to repeated oral administrations of 0.1 to 10 Omg / kg body weight in an immediate phase 1 hour after the challenge and a delayed phase 24 hours after the challenge. It was suggested that the induction of edema in both phases was significantly and dose-dependently suppressed, as compared to the control group to which vehicle alone was administered, and that allergic Si3 ⁇ 4 associated with Th 2 cells was suppressed.
  • the compound of Example 25 significantly inhibited the induction of both edemas by repeated oral administration of 3 mg / kg body weight.
  • the compound of the present invention 10 Omg / kg, was repeatedly orally administered to male SD rats and male BALBZc mice for 14 days, and no deaths were found.
  • the compound of the present invention selectively inhibits the production of IL-14 from Th2 cells sensitized with an antigen, and thus is useful for preventing or preventing allergic H3 ⁇ 4 disease.
  • the compounds of the present invention are also useful as preventive or therapeutic agents for various autoimmune diseases.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be prepared by using an existing immunosuppressant, By preparing a drug in combination with a drug such as a loid drug or an antiallergic drug, an excellent pharmacological effect can be exerted even when the dose of the existing drug is reduced from the conventional dose. Therefore, according to the present invention, it is possible to provide a medicament having less side effects than the conventional medicament and having an excellent pharmacological effect.

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Abstract

Cette invention se rapporte à un composé amide représenté par la formule générale (I) ou à un sel pharmaceutiquement acceptable de ce composé; et à un médicament comprenant ce composé. Dans ladite formule, R1 représente halogéno, alkyle, alkoxy, etc.; le cycle Q représente un cycle aromatique hétérocyclique ou un benzène éventuellement substitué, etc.; R2 représente hydrogène, alkyle, etc.; Z représente CH ou azote; R3 représente halogéno, cyano, nitro ou amino; et R5 représente alkyle, un groupe représenté par -N(R6)(R7) (où R6 et R7, qui sont identiques ou différents, représentent chacun hydrogène, alkyle, etc. ou R6 et R7 forment une amine cyclique associée à l'atome d'azote adjacent), etc. Ce composé est très efficace pour inhiber la production d'interleukine-4 dans les lymphocytes T auxiliaires de type 2 et il est utile comme agent prophylactique ou thérapeutique contre les allergies.
PCT/JP2002/006606 2001-05-16 2002-06-28 Compose amide et utilisation medicinale de ce compose Ceased WO2004002948A1 (fr)

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