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WO2005082865A1 - Dérivé de pyrimidine bicyclique fondu - Google Patents

Dérivé de pyrimidine bicyclique fondu Download PDF

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Publication number
WO2005082865A1
WO2005082865A1 PCT/JP2005/003207 JP2005003207W WO2005082865A1 WO 2005082865 A1 WO2005082865 A1 WO 2005082865A1 JP 2005003207 W JP2005003207 W JP 2005003207W WO 2005082865 A1 WO2005082865 A1 WO 2005082865A1
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reference example
chloro
compound
amino
lower alkyl
Prior art date
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PCT/JP2005/003207
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English (en)
Japanese (ja)
Inventor
Noriyuki Kawano
Susumu Igarashi
Yohei Koganemaru
Shingo Yamasaki
Kazuyuki Hattori
Naoyuki Masuda
Noriko Ishikawa
Takahiro Miyazaki
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Astellas Pharma Inc
Yamanouchi Pharmaceutical Co Ltd
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Astellas Pharma Inc
Yamanouchi Pharmaceutical Co Ltd
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Priority claimed from JP2004053121A external-priority patent/JP2007210886A/ja
Priority claimed from JP2004183083A external-priority patent/JP2007210887A/ja
Application filed by Astellas Pharma Inc, Yamanouchi Pharmaceutical Co Ltd filed Critical Astellas Pharma Inc
Publication of WO2005082865A1 publication Critical patent/WO2005082865A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel fused bicyclic pyrimidine derivative, and a medicament containing the same as an active ingredient, particularly a therapeutic agent for inflammatory diseases.
  • Chemokines which are cell chemotactic factors, are broadly classified into two types, CXCZ chemokines and CCZ iS chemokines, depending on their structural characteristics.
  • these chemokine receptors belong to the family of seven transmembrane G-protein coupled receptors, and are composed of CXC chemokine receptor and CC chemokine receptor (Pharmacological Reviews, 52, 145, 2000).
  • CCR4 CC chemokine receptor 4
  • Thymus and activation-regulated chemoine (I'ARC) and macrophage-derived chemokine (MDC) are specific ligands for CCR4 (CCJ chemokines) (Journal of Biological Chemistry, 272, 1503 ⁇ , 1997, Journal of Biological chemistry, 273, 1764, 1998).
  • TARC was found as a T cell chemotactic factor (Journal of Biological Chemistry, 271, 21514, 1996), and MDC was discovered as a chemotactic factor for monocytes' macrophages and ⁇ cells (Journal of Experimental Medicine, 185, 1595, 1997).
  • Chemokines are also known to have the characteristics of both inflammatory chemokines and homeostatic chemokines. Today, 20, 254, 1999).
  • CCR4 and its ligands are involved in various diseases such as inflammatory diseases, allergic diseases, and autoimmune diseases.
  • diseases such as asthma, The Journal of Clinical Investigation, 107, 1357, 2001
  • atopic dermatitis Journal of Investigative Dermatology, 115, 640, 2000
  • psoriasis Laboratory dermatitis
  • CCR4 function modulators are expected as agents for preventing or treating these diseases and the like.
  • Various drugs such as steroids are used as prophylactic or therapeutic agents for the above-mentioned inflammatory diseases, allergic diseases, autoimmune diseases, etc. There is a strong need for the development of drugs based on this.
  • Patent Document 1 the compound represented by the following general formula has a function of regulating the function of TARC or MDC.
  • N represents 0-4, R 1 represents halogen, -CN, etc., R 2 represents heterocyclyl containing at least one hetero atom, R 3 represents halogen, -CN, etc., R 4 And R 5 represents H or a ring formed together, and R 1Q represents H, alkyl or the like. See the gazette for details. )
  • R 1 and R 2 are H, optionally substituted alkyl, optionally substituted alkoxy, halogen, etc., and R 3 and R 4 are H, substituted And R 5 represents an alkyl which may be substituted, a heterocyclic group which may be substituted, an arylcarbyl which may be substituted, and the like.
  • R 1 and R 2 are H, optionally substituted alkyl, optionally substituted alkoxy, halogen, etc.
  • R 3 and R 4 are H
  • substituted And R 5 represents an alkyl which may be substituted, a heterocyclic group which may be substituted, an arylcarbyl which may be substituted, and the like.
  • a quinazoline derivative having a Rho-kinase inhibitory activity (Patent Document 4), a 1H-pyrazo- [3,4-d] pyrimidine derivative having a p38 kinase inhibitory activity (Patent Document 5), and a phosphoesterase inhibitory activity.
  • Fused pyrimidine derivative (Patent Document 6), quinazoline derivative having EGF receptor inhibitory activity (Non-Patent Document 1), quinazoline derivative having cytostatic activity (Patent Documents 7 and 8), tumor cells against antitumor drugs And quinazoline derivatives having a sensitizing effect (Patent Document 9).
  • These documents do not disclose any fused bicyclic quinazoline conjugate having a piperidino or piperazino group at the 2-position to which a saturated ring is bonded. There is no disclosure or suggestion of a CCR4 function-modulating effect.
  • Patent Document 1 International Publication No. 03Z104230 pamphlet
  • Patent Document 2 US Patent Application Publication No. 2004Z0048865
  • Patent document 3 JP-A-2000-281660
  • Patent Document 4 WO 02Z076976 pamphlet
  • Patent Document 5 International Publication No. 03Z099820 pamphlet
  • Patent Document 6 U.S. Pat.No. 6,331,543
  • Patent Document 7 US Patent No. 6262059
  • Patent Document 8 U.S. Patent Application Publication No. 2001Z0031760
  • Patent Document 9 International Publication No. 92Z007844 pamphlet
  • Non-Patent Document l Bioorganic and Medicinal Chemistry, 1996, Vol. 4, No. 8, p. 1203-1207
  • the present inventors provide a pharmaceutical composition useful for the prevention and treatment of inflammatory diseases, allergic diseases, autoimmune diseases and the like based on the function-regulating action of CCR4, and further include those.
  • the research was conducted for the purpose of providing a drug having the same.
  • the present inventors have diligently studied compounds having a CCR4 function regulating action. As a result, it has a piperidino or piperazino group with a saturated ring attached at the 2-position and a substituted amino at the 4-position.
  • the present inventors have found that a fused bicyclic pyrimidine derivative having an amino group is useful as a CCR4 function regulator, and completed the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a novel fused bicyclic pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
  • a pharmaceutical composition effective as a prophylactic / therapeutic agent for asthma, atopic dermatitis, rheumatoid arthritis and the like.
  • A: substituted !, may! /, Aryl, substituted !, may, cycloalkyl or substituted, may be, monocyclic 6 membered heteroaryl,
  • R a H, substituted !, may, lower alkyl, substituted !, may, cycloalkyl, substituted, may, phenyl, substituted !,
  • R 1 the same or different, -OH, -CN, halogen, optionally substituted lower alkyl, -0- (optionally substituted lower alkyl), -S- (optionally substituted optionally substituted lower ⁇ alkyl), -SO - (substituted lower alkyl), -NO, - N (R 8) (R 9), - CO- R. ,
  • bicyclic heterocyclic group or -CO- substituted or a monocyclic or bicyclic heterocyclic group
  • R ° lower alkyl or phenol
  • R 2 same or different from each other, - R °, halogen, halogeno-lower alkyl, - E-0H, - E- 0- R °, - E- N (R 8) (R 9), - E- CN, — E—N (R 8 ) —CO—R °, — E—N (R 8 ) —SO—R. ,
  • R 3 and R 4 the same or different, H, lower alkyl or CN,
  • R 8 and R 9 the same or different, H or lower alkyl
  • R 5 and R 6 the same or different, the groups described in H or R 2 or R 5 and R 6 are
  • R 7 H, lower alkyl, halogeno lower alkyl, -R °° -0H, -CON (R 8 ) (R 9 ), -R °° -0-R. , -R. . - N (R 8) (R 9), - R. . -CN ⁇ -R. . - N (R 8) - CO- R. , -R. . - N (R 8) - SO - R. , -R. . -0- CO- R 0
  • n 0, 1, 2, or 3
  • the fused bicyclic pyrimidine derivative of the present invention has a function to regulate the functions of CCR4 or TARC and Z or MDC, various inflammatory diseases, allergic diseases, autoimmune diseases and the like (eg, asthma, allergy) Rhinitis, allergic conjunctivitis, hay fever, dermatitis (atopic dermatitis, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), during organ transplantation Rejection, cancer, inflammatory bowel disease (ulcerative colitis, Crohn's disease), interstitial cystitis, sepsis, pain].
  • IDDM insulin-dependent diabetes mellitus
  • it can be expected as a therapeutic agent for preventing asthma, atopic dermatitis or rheumatoid arthritis.
  • alkyl and “alkylene” mean a straight or branched hydrocarbon chain.
  • “Lower alkyl” is preferably an alkyl having 116 carbon atoms (hereinafter abbreviated as C).
  • a alkyl group more preferably C alkyl, still more preferably methyl and ethyl.
  • “Lower alkylene” means a divalent group (C alkylene) obtained by removing one arbitrary hydrogen atom from the above “lower alkyl”, preferably C alkylene, more preferably methylene
  • Halogen refers to F, Cl, Br and I.
  • Halogeno lower alkyl preferably means C alkyl substituted with one or more halogen, more preferably one or more F
  • Cycloalkyl is preferably C 4 cycloalkyl, which may be bridged
  • Aryl means an aromatic hydrocarbon group of C and is “cycloalkyl”.
  • Alkyl and a fused ring.
  • Preferred are phenyl and naphthyl, and more preferred is phenyl.
  • a “monocyclic heterocyclic group” is a monocyclic 3- to 8-membered, preferably 5- to 7-membered ring group containing 1 to 4 heteroatoms selected from 0, S and N forces,
  • the monocyclic heteroaryl which is an unsaturated ring, the monocyclic heterocycloalkyl which is a saturated ring, and the monocyclic heteroaryl Includes partially hydrogenated ring groups.
  • the monocyclic heteroaryl preferably a pyridyl, pyrazur, pyrimidyl, pyridazyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxoxazolyl, thiadiazolyl, oxaziazolyl group Is mentioned.
  • the monocyclic heterocycloalkyl or the ring group in which the heteroaryl group is partially hydrogenated is preferably a piperidyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydrovinyl, morpholinyl, thiomorpholinyl group.
  • the “bicyclic heterocyclic group” is a ring group in which the above-mentioned monocyclic heterocycles are condensed with each other, or a benzene ring and a monocyclic heterocycle are condensed, and preferably, indolyl, isoindolyl, benzofuranyl, benzoche Benzyl, indazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, dihydrobenzofuranyl, tetrahydroquinolyl, and indoleyl groups.
  • S or N as a ring atom may be oxidized to form an oxoxide-dioxide.
  • an arbitrary carbon atom may be substituted with an oxo group.
  • May be substituted means “unsubstituted” or “having 115 identical or different substituents”.
  • Substituents in “substituted or may be aryl”, “substituted or may be cycloalkyl” and “optionally substituted monocyclic or bicyclic heterocyclic group” are preferable. Is halogen, optionally substituted lower alkyl, -OH, -0- (optionally substituted lower alkyl), -CN, -S-lower alkyl, NO alkyl.
  • halogen lower alkyl, -OH, -0-lower alkyl, -CN, and even more preferably, halogen, -CN.
  • the substituent in the "optionally substituted lower alkyl” is preferably halogen, -OH, -0-lower alkyl, phenyl, -COH, -CO-lower alkyl, cycloalkyl,
  • -CN more preferably halogen, -0-lower alkyl, and phenyl.
  • B is a group that forms a quinazoline ring or a 1H-pyrazo [3,4-d] pyrimidine ring together with a condensed pyrimidine ring.
  • B is a group forming a quinazoline ring, more preferably, it has 122 R 1 as a substituent, and R 1 is lower alkyl, halogeno lower alkyl, halogen, -CN or 0-lower alkyl.
  • B is 1H-Pyrazo mouth
  • R 1 has one lower alkyl and Ra is H, lower alkyl, halogeno lower alkyl or substituted.
  • R 2 is halogeno lower alkyl, -R °° -OH, -R °° -0-R ° or -CON (R 8 ) (R 9 ), more preferably -R °° -OH or A compound which is -CON (R 8 ) (R 9 ), still more preferably -R °° -OH.
  • V A compound wherein k is 0 or 1, more preferably a compound wherein k is 1.
  • the compound (I) of the present invention may have a geometrical isomer or a tautomer depending on the type of the substituent.
  • the present invention includes a separated form or a mixture of these isomers. Is done.
  • the compound (I) may have an asymmetric carbon atom, and an (R) -form or (S) -form optical isomer based on this may exist.
  • the present invention includes all of the optical isomers as a mixture or an isolated one.
  • the compound (I) also includes a pharmacologically acceptable prodrug.
  • a pharmacologically acceptable prodrug is defined as the NH4 of the present invention by solvolysis or under physiological conditions.
  • the compound (I) may form an acid addition salt or a salt with a base depending on the type of the substituent.
  • the strong salt is a pharmaceutically acceptable salt, specifically, hydrochloric acid, bromide Inorganic acids such as hydroic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, and citric acid Acid addition salts with organic acids such as methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; methylamine, ethylamine, ethanolamine, lysine, ortin And the like, salts with organic bases such as and the like, and ammonium salts.
  • the present invention also includes various hydrates, solvates, and polymorphic substances of compound (I) and salts thereof.
  • Compound (I) which is an active ingredient of the present invention, and pharmaceutically acceptable salts thereof are produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the type of substituent. can do.
  • Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like, and their protecting groups are described, for example, in Protective Groups in Organic Synthesis (Third Edition) by Green (TW Greene) and Utz (PGM Wuts). , 1999) ", which may be appropriately selected and used according to the reaction conditions.
  • a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group or converting it to a desired group as necessary.
  • the prodrug of the compound (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate or by carrying out a reaction using the obtained compound (I) as in the case of the above-mentioned protective group.
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • This production method is a method for producing a compound (I) of the present invention by ipso-substituting a cyclic amine compound (III) with a quinazoline derivative ( ⁇ ) having a leaving group at the 2-position.
  • Examples of the leaving group represented by L include a halogen, an alkylsulfiel group, an alkylsulfol
  • reaction is carried out by subjecting compound (II) to a solvent inert to the reaction, in the presence or absence of a base or acid (preferably hydrogen chloride), using an equivalent or excess amount of (III) under cooling and heating under reflux. Usually one hour and five days.
  • a base or acid preferably hydrogen chloride
  • the solvent is not particularly limited as long as it is inert to the reaction, but, for example, aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy Ethers such as ethane and 1,2-diethoxytan, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, ⁇ , ⁇ -dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like.
  • aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy Ethers such as e
  • bases examples include organic bases such as triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-pandacene (DBU), 2,6-lutidine, sodium carbonate, and potassium carbonate.
  • bases such as sodium hydride, potassium hydride and potassium tert-butoxide.
  • This production method is a method for producing the compound (I) of the present invention by substituting the quinazoline derivative (IV) having a cyclo group at the 4-position with the amyloid conjugate (V) by ipso.
  • the reaction can be performed under the same conditions as described in the first production method.
  • the present compound having a carboxyl group By hydrolyzing the carboxylic acid ester, the present compound having a carboxyl group can be produced.
  • a conventional method of hydrolysis can be used, and for example, a method described in the above-mentioned “Protective Groups in Organic Synthesis (3rd edition)” for the deprotection reaction of a carboxyl group can be applied.
  • various amide compounds or esterified compounds can be produced.
  • the reaction is carried out with a condensing agent (eg, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-carbylbis- 1H-imidazole (CDI), etc., and in some cases, further additives (eg, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP), etc.) It can be carried out.
  • a condensing agent eg, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-carbylbis-
  • an acid peroxide an acid anhydride, an active ester and the like
  • the reaction can also be carried out, for example, by the method described in “Experimental Chemistry Lecture (4th edition)”, edited by The Chemical Society of Japan, Vol. 22 (1992) (Maruzen).
  • the compound of the present invention having a cyano group By dehydrating the compound of the present invention having a carboxamide group, the compound of the present invention having a cyano group can be produced.
  • the reaction can be carried out by a conventional method of dehydration reaction.
  • the reaction is carried out by the method described in Nihon Dani Kaikai, “Experimental Chemistry Course (4th edition)”, Vol. 20 (1992) (Maruzen). I can.
  • the compound of the present invention having an NH group can be obtained by starting from a compound having a nitro group,
  • It can be produced by a catalytic reduction method in which a reaction is carried out in a hydrogen atmosphere in the presence of a catalyst such as sulfur, or a reduction reaction using an equivalent or excessive amount of a metal reagent such as iron powder, zinc, or tin.
  • a catalytic reduction method in which a reaction is carried out in a hydrogen atmosphere in the presence of a catalyst such as sulfur, or a reduction reaction using an equivalent or excessive amount of a metal reagent such as iron powder, zinc, or tin.
  • the method can be carried out according to the method described in “Experimental Science Course (4th Edition)”, edited by The Chemical Society of Japan, Vol. 26 (1992) (Maruzen).
  • the compound of the present invention having an NH group can be produced from a compound having a phthalimide group.
  • the compound of the present invention having a carboxyl group or the compound of the present invention having an N-methyl-N-methoxycarboxamide group, which is a reactive intermediate thereof is used as a starting material for the reaction with an organic metal reagent such as an alkyl lithium reagent or an alkyl Grignard reagent.
  • an organic metal reagent such as an alkyl lithium reagent or an alkyl Grignard reagent.
  • the compound of the present invention having an alkyl-CO- group can be produced by the bond formation reaction.
  • a conventional method of carbon-carbon bond forming reaction using an organic metal reagent can be used, and is described in, for example, “Experimental Science Lecture (4th edition)” edited by Nippon Dani Gakkai, Vol. 25 (1992) (Maruzen). This can be done in the following manner.
  • the starting compound (II) can be produced by subjecting a compound (1) having a chloro group at the 4-position to an amide compound (V) by an ipso substitution reaction.
  • the same conditions as in the first production method can be applied to the reaction.
  • the starting compound (IV) can be produced by reacting the quinazolin-4-one derivative (3) with an equivalent excess of a chlorinating agent in a solvent inert to the reaction or without a solvent.
  • a chlorinating agent for example, phosphorus oxychloride, phosphorus pentachloride, chloride salt, or the like can be used alone or as a mixture thereof.
  • the solvent aromatic hydrocarbons, ethers, halogenated hydrocarbons, ⁇ , ⁇ -dimethylaline and the like can be used alone or as a mixture thereof.
  • the quinazolin-4-one derivative (3) can be produced by subjecting a 2-clonal quinazolin-4-one derivative (2) to an ipamine substitution reaction with an amine represented by the general formula (III). The same conditions as in the first production method can be applied to the reaction.
  • the compound (la) wherein the ring B is a pyrazole ring can be produced by the method represented by the above formula.
  • the cyanation reaction may be carried out in the presence of a base such as sodium carbonate or potassium carbonate in a solvent inert to the reaction of halogenated hydrocarbons or the like.
  • the hydrazonedani reaction between cyanohydrazine (5) and compound (6) was
  • the cyclization reaction that can be carried out in a solvent at room temperature and under heating may be carried out in a solvent such as an alcohol in the presence or absence of a base such as sodium alkoxide and sodium hydroxide.
  • the reaction between compound (8) and urea (9) may be performed without solvent and at room temperature and with heating.
  • the same conditions as those for chlorination using compound (3) can be applied.
  • the cyclic amine conjugates (Ilia) and (Illb) can be produced by the method shown in the above formula.
  • the conversion of compound (11) to (15a) and the conversion of (13) to (15b) can be performed by a conventional method of reductive alkylation. Edition) ”, Vol. 20 (1992) (Maruzen).
  • the method described in the above-mentioned “Protective Groups in Organic Synthesis (3rd edition)” for the deprotection reaction of the amino group and the like can be applied.
  • cyclic amine conjugates (IIIc) and (Illd) can be produced by the method shown in the above formula.
  • various cyclic amine conjugates (III) can be prepared by, for example, converting a compound having a hydroxyl group to an alkyl ether group by an alkylation or Mitsunobu reaction with an alkylating agent (such as an alkyl halide sulfonic acid alkyl ester).
  • the compound can be converted to a compound having a phthalimide group by a Mfluorinating reaction with a fluorinating agent (eg, fluorinated sulfur or morpholino sulfur trifluoride). In this case, it is preferable to protect the cyclic amino group.
  • reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate.
  • the salt can be produced by subjecting it to a usual salt-forming treatment.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between the isomers.
  • the optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography.
  • the optical isomer can be produced from an appropriate optically active starting compound.
  • a vector (containing a neomycin resistance gene) having the human CCR4 gene inserted downstream of the EF-1a promoter was prepared, and transfected into mouse pre B cell line B300-19 cells by electoporation. These cells were cultured in a medium supplemented with G418, and a single cell line that constantly and stably expresses human CCR4 was obtained by the limiting dilution method.
  • Test compounds were prepared at 20 mM Hepes pH 7.05, 100 mM NaCl, 5 mM MgCl,
  • the following example compounds showed more than 50% inhibitory activity at a concentration of 100 nM: Examples 1, 3-13, 17-19, 22-24, 26-28, 31, 32, 34, 35, 37, 39—43, 4 5—56, 58—67, 69—72, 75—78, 81—88, 89, 91—93, 97, 99—101, 104, 106—107, 110—114, 118 — 123, 125, 129, 131—132, 135, 139, 144—146, 150—152, 157—158, 160—163, 165—166, 175, 182 and 187—188.
  • the comparative compound: 2- (4-benzylpiperazyl) -4-phenethylaminoquinazoline exerted no inhibitory activity at a concentration of 1 ⁇ M.
  • the inhibitory activity values (IC [nM]) of the main example compounds are shown.
  • Inhibition rate (swelling of control group swelling of test drug administration group) xl00 / (swelling of control group-swelling of normal group)
  • the following example compounds showed significant inhibitory activity at 30 mg / kg oral dose: Examples 1, 22, 24, 83, 85, 88, 91, 99, 104, 107, 109, 111, 113, 116, 118, 121, 123, 125, 128—129, 131, 135, 139, 145—146, 151, 153, 161, 165—166, and 187—188.
  • the comparative compound: 2- (4-benzylpiperazyl) -4-phenethylaminoquinazoline shows no inhibitory activity at 100 mg / kg oral administration.
  • the compound of the present invention has a function of regulating CCR4, TARC, Z or MDC, and is therefore useful as a preventive / therapeutic agent for various inflammatory diseases, allergic diseases, autoimmune diseases, etc. It is clear.
  • a preparation containing one or more of compound (I) or a salt thereof as an active ingredient is prepared using a carrier, an excipient, and other additives that are usually used for formulation.
  • parenteral administration may be in the form of injections such as intravenous injection and intramuscular injection, suppositories, transdermal preparations, nasal preparations, or inhalants.
  • the dose is determined as appropriate depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration subject.However, for oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per day for an adult. This should be given once or in 2-4 doses.
  • intravenous administration depending on the symptoms, the dose is usually in the range of 0.0001 mg / kg to 10 mg / kg per adult once or more times a day.
  • the dose is usually in the range of 0.0001 mg / kg to 1 mg / kg for an adult once or more times a day.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substance (s) at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, or a solubilizer according to a conventional method.
  • Tablets or pills may be coated with sugar coating or a gastric or enteric coating agent, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including.
  • the composition may contain, in addition to the inert solvent, auxiliaries such as solubilizers, wetting agents and suspending agents, sweeteners, flavoring agents, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solvents include, for example, distilled water for injection and physiological saline.
  • non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (pharmacopoeia name).
  • Such compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizing agent, and a solubilizing agent.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods.
  • an excipient and as Ratatosu Ya starch furthermore, P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate.
  • P H adjusting agent a preservative
  • a surfactant e.g., a lubricant, a stabilizing agent, a thickening agent, or the like
  • a thickening agent e.g., a thickening agent, or the like
  • an appropriate inhalation or insufflation device can be used for administration. Solutions or suspensions of the compounds, alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier, using known devices or nebulizers, such as metered dose inhalers.
  • Can be administered as A dry powder inhaler or the like can utilize a dry powder or a powder-containing capsule that can be used for single or multiple doses.
  • a dry powder or a powder-containing capsule that can be used for single or multiple doses.
  • it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or diacid carbon, etc. .
  • External preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments and the like. It contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like.
  • ointment or lotion bases include polyethylene glycol, carboxyvul polymer, white petrolatum, salami beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl anore konore, cetyl alcohol, lauromacrogol, sonorebitan sesquioleate, and the like. No.
  • NMR2 ⁇ (ppm) of characteristic peak in 1 H NMR in DMSO-d, MP: melting point (° C), EA : Elemental analysis value (%) (Cal: calculated value; Fnd: measured value)), Sal: salt and contained solvent (HC1: hydrochloride, not described: free form, the number before the component is, for example, 2HC1 is dihydrochloride) ), Str: Structural formula, Syn: Production method (numerals indicate the example numbers produced in the same manner), Me: methyl, Et: ethyl, Ms: methanesulfonyl, tBu: t-butyl, Boc: t- Butoxycarbonyl, Ph: phenyl, Bn: benzyl, A acetinole.
  • the 2-chloro-5- (trifluoromethyl) benzo-tolyl was reacted with sodium azide in DMF at 100 ° C for 1 hour.
  • the residue obtained by evaporating the solvent was reacted with triphenylphosphine in toluene at room temperature for 2 hours.
  • the residue obtained by distilling off the solvent was treated with 1M hydrochloric acid in THF at room temperature for 19 hours, followed by post-treatment and purification by a conventional method to give 2-cyano-4- (trifluoromethyl) a-phosphorin.
  • Methyl 5-fluoroanthrolate was reacted with potassium cyanate in acetic acid at 100 ° C for 18 hours to obtain 6-fluoroquinazoline-2,4- (1 ⁇ , 3 ⁇ ) _dione. F: 181.
  • Acetic acid is added to an aqueous solution of 2-amino-6-fluorobenzoic acid, and then an aqueous solution of potassium cyanate is added dropwise at 35 ° C at 35 ° C and reacted to give 5-fluoroquinazoline-2,4. -(1 ⁇ , 3 ⁇ ) -dione is obtained.
  • Methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate is reacted with thiourea in ethanol in the presence of sodium methoxide to give 6,6-dimethyl-2-thioxo-2,3,5,6, 7,8-Hexahydroquinazolin-4 (1H) -one was obtained.
  • N- (4-chlorophenol) -6,6-dimethyl-2- (methylsulfur) -5,6,7,8-tetrahydroxy Nazolin-4-amine is treated with m-chlorobenzoic acid in dichloromethane under ice-cooling to give N- (4-chlorophenyl) -6,6-dimethyl-2- (methylsulfinyl) -5, 6,7,8-Tetrahydroquinazolin-4-amine was obtained.
  • Titanium tetraisopropoxide was added to a mixture of benzyl 4-oxopiperidine-1-carboxylate and piperidin-3-ylmethanol, and the mixture was stirred at 80 ° C. Then, ethanol and sodium borohydride were added under ice cooling and reacted at room temperature to obtain benzyl 3- (hydroxymethyl) -1,4′-bipiperidine-1′-carboxylate.
  • ES 333.
  • a THF solution of tert-butyl (3S) -3-ethoxycarbol-1,4'-bipiperidine-1'-carboxylate was added dropwise to a suspension of lithium boron hydroxide in THF under ice-cooling. Then, the mixture was stirred with heating under reflux to obtain tert-butyl (3S) -3- (hydroxymethyl) -1,4′-bipiperidine-1′-carboxylate.
  • ES 299.
  • tert-Butyl 3- (hydroxymethyl) -1,4'-bipiperidine-1'-carboxylate is treated with sodium hydride in THF and then reacted with methane to give tert-butyl 3- (methoxymethyl)- 1,4′-Bipiperidine-1′-carboxylate was obtained.
  • Reference Example 37 The same operation as in Reference Example 22 was performed using 1-benzyl-3-methoxymethylpyrrolidine to give crude tert-butyl 4- (3-methoxypyrrolidine-1-yl) piperidine-1-carboxylate Was obtained. The same operation as in Reference Example 30 was performed using this compound to obtain 4- (3-methoxypyrrolidine-1-yl) piperidine dihydrochloride. F: 185.
  • the compound of Reference Example 38 was treated in the same manner as in Reference Example 3, the compound of Reference Example 39 was treated in the same manner as in Reference Example 7, and the compound of Reference Example 40-44 was treated in the same manner as in Reference Example 8.
  • the compound of Reference Example 45 was obtained in the same manner as in Reference Example 9
  • the compound of Reference Example 46 was obtained in the same manner as in Reference Example 11
  • the compound of Reference Examples 47-49 was obtained in the same manner as in Reference Example 14.
  • N-Bromosuccinimide was added to a dichloromethane solution of 2-amino-3-methoxybenzoic acid, and the mixture was stirred at room temperature for 2 hours to obtain 2-amino-3-bromobenzoic acid.
  • ES 246, 248.
  • Methyl 6-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate is reacted with phosphorus oxychloride in toluene in the presence of tripropylamine at 100 ° C for 3 days to give methyl 2 , 4-Dichloro-6-methoxyquinazoline-7-carboxylate was obtained.
  • 2,4-dichloro-7- (methylsulfol) quinazoline was obtained in the same manner as in Reference Example 8 using 7- (methylsulfol) quinazoline-2,4 (1H, 3H) -dione.
  • LDA Lithium diisopropylamide
  • tert-Butyl 4-aminopiperidine-1-carboxylate is reacted with vinyl sulfone in ethanol at 0 ° C to room temperature for 18 hours to obtain tert-butyl 4- (1,1-dioxidethiomorpholine-4-yl ) Piperidine-1-carboxylate was obtained. F: 319.
  • tert-Butyl 4- (1,1-dioxidethiomorpholine-4-yl) piperidine-1-carboxylate is reacted with LDA in THF at -78 ° C for 10 minutes, and then ethyl formate is added. And -78 ° C to 5 ° C for 5 hours to obtain tert-butyl 4- (2-formyl-1,1-dioxidethiomorpholin-4-yl) piperidine-1-carboxylate .
  • FN 345.
  • the compound of Reference Example 182 the compound of Reference Example 183 in the same manner as in the method of Reference Example 138, the compound of Reference Example 184-186 in the same manner as in the method of Reference Example 171, In the same manner as in the method of Reference Example 3, the compound of Reference Examples 187-193 was used.
  • the compound of Reference Example 202 was treated in the same manner as in Reference Example 147, and the compound of Reference Examples 203 to 207 was treated in the same manner as in Reference Example 149.
  • the compounds of Reference Examples 213 to 215 and the compound of Reference Example 216 (the base is DIPEA) were prepared in the same manner as in the method of Reference Example 162, using the compounds of 208 to 212 in the same manner as in Reference Example 144.
  • the compound of Reference Example 222 and the compound of Reference Example 223 (excluding the solvent 1,2-dichloroethane) and Reference Example 2
  • the compound of 24-225 (the solvent was THF-acetonitrile) was used in the same manner as in the method of Reference Example 127 to obtain a compound of Reference Examples 226-228 and 256-261.
  • the compound of Reference Example 264 was prepared in the same manner as in the method of Reference Example 163, and the compound of Reference Examples 265-266 was prepared in the same manner as in the method of Reference Example 22.
  • the compound of Reference Example 271 was produced in the same manner as in the method of Reference Example 29, using the corresponding starting materials. Table 7-14 shows the structures and physical data of the compounds of Reference Examples 182-272.
  • Example 1 2-chloro-N- (4-chloro mouth) -6-fluoroquinazoline-4-amine
  • a solution of 1.20 g of dioxane in 50 ml of (3S) -1,4, -bipiperidin-3-ylmethanol 2 1.10 g of hydrochloride and 1.82 ml of DBU were sequentially added, and the mixture was stirred at 90 ° C for 3 days.
  • the reaction solution was cooled to room temperature, the solvent was distilled off, and a saturated aqueous solution of sodium hydrogen carbonate was added to the obtained residue, followed by extraction with chloroform.
  • the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Example 1 was prepared using 300 mg of N- (4-chlorophenol) -6,6-dimethyl-2- (methylsulfuryl) -5,6,7,8-tetrahydroquinazoline-4-amine. (However, the reaction was carried out at 140 ° C. for 1.5 days using 10 ml of 1,2-dietoxetane as a solvent), and the reaction was carried out using (1 ′- ⁇ 4-[(4-chloromouth phenol)). [Amino] -6,6-dimethyl-5,6,7,8-tetrahydroquinazoline-2-yl ⁇ -1,4'-bipiperidin-3-yl) methanol dihydrochloride 38 mg as light brown crystals Obtained.
  • Example 9 The same operation as in Reference Example 17 was performed using 518 mg of 2,4-dichloro-6,7-dimethoxyquinazoline and 294 mg of 2,4,6-trifluorofluorinline to obtain 2-chloro-N- (2, 400 mg of crude crystals of 4,6-trifluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride were obtained.
  • This compound was dissolved in 5 ml of dichloromethane, 102 mg of acetic anhydride and 79 mg of pyridine were added, and then 1 ml of pyridine was added and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 2 hours, and extracted with chloroform.
  • Example 20 (1 and ⁇ 4-[(4-chlorophenol) amino] -6-troquinazoline-2-yl ⁇ -1,4'-bipiperazine-3-yl) methanol 3.16 g of methanol 200 ml To the solution, 300 mg of 10% palladium-carbon was added under an argon atmosphere, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 3 hours. After completion of the reaction, the reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. 200 ml of getyl ether was added to the obtained residue, and the precipitate was collected by filtration.
  • Methyl 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiberidin-1'-yl] quinazoline-7-carboxylate 152 0.43 ml of a 1M aqueous sodium hydroxide solution was added to 1.5 ml of a methanol solution of mg, and the mixture was stirred at room temperature for 2 hours. Further, 1.5 ml of THF, 2 ml of chloroform, 1.5 ml of methanol and 1.4 ml of 1M aqueous sodium hydroxide solution were added in several portions, and the mixture was stirred at room temperature overnight.
  • the reaction solution was made basic by adding a 1M aqueous sodium hydroxide solution, and then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (form: form / methanol / 28% aqueous ammonia) to give 4-[(4-form-2-fluorophenyl) amino] -2- [3- ( 451 mg of hydroxymethyl) -1,4′-bipiperidine-1 [yl] quinazoline-7-carbo-tolyl were obtained as crystals.
  • Example 105 In the same manner as in Example 105, the compounds of Examples 106 to 107 shown in Table 24 below were produced using the corresponding starting materials.
  • reaction solution was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (form: methanol-28% aqueous ammonia) to give (1,- ⁇ 4-[(4-chloro-2-fluorophenol) amino] -6. 1,7-Dimethylpteridine-2-yl ⁇ -1,4'-bipiperidin-3-yl) methanol was obtained in an amount of 130 mg.
  • Ethyl 1,- ⁇ 4-[(4-chloro-2-fluorophenyl) amino] -7-cyanoquinazoline-2-yl ⁇ -1,4, -bipiperidine-3-carboxylate 941 mg of ethanol 3.50 ml of a 1 M aqueous sodium hydroxide solution was added to the 10 ml solution, and the mixture was stirred at room temperature for 8 hours.
  • Example 181 shown in Table 29 below was produced using the corresponding starting materials.
  • Example 103 In the same manner as in Example 103, the compounds of Examples 182 to 188 shown in Tables 27 to 33 described below were produced using the corresponding raw materials.
  • Table 11-34 shows the structure and physicochemical data of the compound of Example 11-188.
  • Tables 35-37 show the structures of other compounds of the present invention. These can be easily synthesized by using the methods described in the above-mentioned production methods and Examples and methods obvious to those skilled in the art, or modified methods thereof.
  • F 470; EA: Cal (C> 5 H 2V C1FN 5 0.2HC1.
  • the fused bicyclic pyrimidine derivative of the present invention has a function to regulate the function of CCR4 or TARC and Z or MDC, various inflammatory diseases, allergic diseases, autoimmune diseases and the like (for example, asthma, allergic rhinitis, Allergic conjunctivitis, hay fever, dermatitis (atopic dermatitis, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), organ transplant rejection , Cancer, inflammatory bowel disease (ulcerative colitis, Crohn's disease), interstitial cystitis, sepsis, pain].
  • inflammatory diseases for example, asthma, allergic rhinitis, Allergic conjunctivitis, hay fever, dermatitis (atopic dermatitis, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus

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Abstract

[PROBLÈMES] Fournir un composé utile en tant qu'agent de prévention ou remède des maladies inflammatoires, des maladies allergiques, des maladies auto-immunes et autres dans lesquelles participe le récepteur de chimiokines CC (CCR4). [MOYENS DE RÉSOUDRE LES PROBLÈMES] Il est prouvé qu’un dérivé de pyrimidine bicyclique fondu comprenant en 2ème position un groupe pipéridine ou pipérazine, auquel un anneau saturé est accroché en 4ème position, et un groupe amino substitué en 4ème position, a une action favorable en tant qu'action de contrôle de la fonction CCR4. De plus, il est prouvé que ce dérivé est particulièrement utile en tant que remède contre les maladies inflammatoires comme la dermite.
PCT/JP2005/003207 2004-02-27 2005-02-25 Dérivé de pyrimidine bicyclique fondu Ceased WO2005082865A1 (fr)

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