WO2005082865A1 - Fused bicyclic pyrimidine derivative - Google Patents

Fused bicyclic pyrimidine derivative 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
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PCT/JP2005/003207
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French (fr)
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.
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Priority claimed from JP2004053121A external-priority patent/JP2007210886A/en
Priority claimed from JP2004183083A external-priority patent/JP2007210887A/en
Application filed by Astellas Pharma Inc. filed Critical Astellas Pharma Inc.
Publication of WO2005082865A1 publication Critical patent/WO2005082865A1/en

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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

Abstract

[PROBLEMS] To provide a compound useful as a preventive or a remedy for inflammatory diseases, allergic diseases, autoimmune diseases and the like in which CC chemokine receptor 4 (CCR4) participates. [MEANS FOR SOLVING PROBLEMS] It is found out that a fused bicyclic pyrimidine derivative having a piperidino or piperazino group, to the 4-position of which a saturated ring is attached, at the 2-position and a substituted amino group at the 4-position has a favorable activity as a CCR4 function-controlling agent. It is further found out that this derivative is particularly useful as a remedy for inflammatory diseases such as dermatitis.

Description

縮合二環性ピリミジン誘導体  Fused bicyclic pyrimidine derivatives
技術分野  Technical field
[0001] 本発明は、新規な縮合二環性ピリミジン誘導体、及びそれを有効成分とする医薬、 特に炎症性疾患治療剤に関する。  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.
背景技術  Background art
[0002] 細胞遊走因子であるケモカインは構造的な特徴により大きく CXCZ ケモカインと CCZ iSケモカインの二種に分類される。また、これらケモカインの受容体は 7回膜貫 通 Gタンパク質共役型受容体ファミリーに属し、 CXCケモカインレセプターと CCケモ 力インレセプターから構成されている（Pharmacological Reviews, 52, 145, 2000)。  [0002] Chemokines, which are cell chemotactic factors, are broadly classified into two types, CXCZ chemokines and CCZ iS chemokines, depending on their structural characteristics. In addition, 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).
CCケモカインレセプター 4 (CCR4)は、 Tリンパ細胞及び胸腺からクローユングされ (Biochemical and Biophysical Research communications, 218, 337, 1996、 European Journal of Immunology, 26, 3021, 1996)、当初、 Th2タイプといわれる T細胞に主に 発現していると報告されていた（Journal of Experimental Medicine, 187, 875, 1998)。 し力し、その後の詳細な解析により CCR4は Thl及び Th2のェフエクタ一'メモリー T細 胞に広く存在することが示された（Journal of Immunology, 166, 103, 2001、 The Journal of Clinical Investigation, 108, 1331, 2001)。更に最近の研究では、 CCR4は ほとんどすべての皮膚指向性の T細胞（Nature, 400, 776, 1999)及び単球'マクロフ ァージ、榭状細胞、 NK細胞に存在することも明らかにされている（Arthritis &  CC chemokine receptor 4 (CCR4) is clawed from T lymphocytes and thymus (Biochemical and Biophysical Research communications, 218, 337, 1996, European Journal of Immunology, 26, 3021, 1996), and is initially referred to as a Th2 type T cell. It was mainly reported to be expressed (Journal of Experimental Medicine, 187, 875, 1998). And subsequent detailed analysis indicated that CCR4 was widely present in ThE and Th2 efecta 'memory T cells (Journal of Immunology, 166, 103, 2001; The Journal of Clinical Investigation, 108 , 1331, 2001). More recent studies have also shown that CCR4 is present on almost all skin-directed T cells (Nature, 400, 776, 1999) and monocyte 'macrophages, dendritic cells, and NK cells ( Arthritis &
Rheumatism, 44, 1022, 2001)。  Rheumatism, 44, 1022, 2001).
CCケモカインで ¾>る Thymus and activation-regulated chemo ine、 I'ARC)と Macrophage- derived chemokine (MDC)は CCR4の特異的なリガンドである（Journal of Biological Chemistry, 272, 1503ο, 1997、 Journal of Biological chemistry, 273, 1764, 1998)。 TARCは T細胞遊走因子として（Journal of Biological Chemistry, 271, 21514, 1996)、また MDCは単球 'マクロファージ ·ΝΚ細胞の遊走因子として発見され (Journal of Experimental Medicine, 185, 1595, 1997)、どちらのケモカインも炎症性 ケモカインと恒常性ケモカインの特徴を併せ持つことが知られて 、る (Immunology Today, 20, 254, 1999)。 Thymus and activation-regulated chemoine (I'ARC) and macrophage-derived chemokine (MDC) are specific ligands for CCR4 (CCJ chemokines) (Journal of Biological Chemistry, 272, 1503ο, 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 ΝΚ 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とそのリガンドである TARC及び MDCは、炎症性疾患、アレルギー疾患、自己 免疫疾患等の様々な疾患に関与することが数多くの報告により示唆されている。例え ば、喘息（The Journal of Clinical Investigation, 107, 1357, 2001)、アトピー性皮膚炎 (Journal of Investigative Dermatology, 115, 640, 2000)、乾癬 (Laboratory  Numerous reports have suggested that CCR4 and its ligands, TARC and MDC, are involved in various diseases such as inflammatory diseases, allergic diseases, and autoimmune diseases. For example, asthma (The Journal of Clinical Investigation, 107, 1357, 2001), atopic dermatitis (Journal of Investigative Dermatology, 115, 640, 2000), psoriasis (Laboratory
Investigation, 81 , 335, 2001)、関節リウマチ（Arthritis & Rheumatism, 44, 2750, 2001)、炎症性腸疾患（Clinical & Experimental Immunology, 132, 332, 2003)等が挙 げられる。従って、 CCR4の機能調節剤はこれらの疾患等の予防又は治療剤として期 待される。上記炎症性疾患、アレルギー疾患、自己免疫疾患等の予防又は治療剤と しては、ステロイド剤等種々の薬剤が使用されているが、その治療効果と副作用の点 から、新たな作用機序に基づく薬剤の開発が切望されている。 Investigation, 81, 335, 2001), rheumatoid arthritis (Arthritis & Rheumatism, 44, 2750, 2001), inflammatory bowel disease (Clinical & Experimental Immunology, 132, 332, 2003) and the like. Therefore, 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.
例えば下記一般式で示される化合物力 TARC又は MDCの機能調節作用を有す ることが報告されて!ヽる (特許文献 1)。  For example, it has been reported that the compound represented by the following general formula has a function of regulating the function of TARC or MDC (Patent Document 1).
[化 3] [Formula 3]
Figure imgf000003_0001
Figure imgf000003_0001
(式中、 m及び nは同一又は異なって 1一 3の整数 [但し m+nは 4以下]を、 R1は- NR4R5 [こ こで R4及び R5は H、置換していてもよいァラルキル等を示す]を、 rは 0— 4の整数を、 s は 0—置換可能な数を、 Gは窒素原子、 CH等を、 qは 0— 2の整数を、 Eは単結合、 -C(C=0)-等を、 R1Qは置換されていてもよい脂環式複素環基等を、 Aは単結合、 -0- 等を、 R3は H、置換されていてもよいアルキル等を示す。詳細は当該公報参照。 ) また、例えば下記一般式で示される化合物が、 CCR4の機能調節作用を有すること が報告されて ヽる (特許文献 2)。 (Wherein m and n are the same or different and are each an integer of 13 [where m + n is 4 or less], R 1 is -NR 4 R 5 [where R 4 and R 5 are H, Represents an aralkyl etc.], r is an integer of 0-4, s is 0-substitutable number, G is a nitrogen atom, CH, etc., q is an integer of 0-2, E is A single bond, -C (C = 0)-, etc., R 1Q represents an optionally substituted alicyclic heterocyclic group, etc., A represents a single bond, -0-, etc., R 3 represents H, substituted And the like may be an alkyl, etc. See the official gazette for details.) Also, for example, it has been reported that a compound represented by the following general formula has a CCR4 function regulating action (Patent Document 2).
[化 4] し [Formula 4] Shi
ノ E No E
Figure imgf000004_0001
Figure imgf000004_0001
(式中、 A、 B、 D、 E、 X及び Yは N又は Cを、 J及び Kは Cを、 Lは 0、 NH又は Sを、 Mは CH又は Nを、 Pは結合又は C=0を、 Zは- (CFG)R2[Fは 0、 H、アルキル等、 Gは 0、 N (Where A, B, D, E, X and Y are N or C, J and K are C, L is 0, NH or S, M is CH or N, P is a bond or C = 0, Z is-(CFG) R 2 (F is 0, H, alkyl, etc., G is 0, N
2  2
又は結合を示す]を、 nは 0— 4を、 R1はハロゲン、 - CN等を、 R2はへテロ原子を最低一 つ含むヘテロシクリルを、 R3はハロゲン、 - CN等を、 R4及び R5は H又は一緒になつて形 成される環を、 R1Qは H、アルキル等を示す。詳細は当該公報参照。 ) 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. )
また、 IgE拮抗活性を有し、アレルギー性疾患や軟骨障害治療剤として有用な下記 一般式で表されるキナゾリン誘導体が報告されて！ヽる (特許文献 3)。しかしながら、 当該文献には、 4位に置換アミノ基を有し、かつ、飽和環が結合したピペリジノ若しく はピペラジノ基を 2位に有する縮合二環性キナゾリンィ匕合物の開示はな 、。また、 CCR4機能調節作用につ 、ては開示も示唆もされて!/、な!/、。  In addition, a quinazoline derivative represented by the following general formula that has IgE antagonistic activity and is useful as a therapeutic agent for allergic diseases and cartilage disorders has been reported! Puru (Patent Document 3). However, the reference does not disclose a fused bicyclic quinazoline conjugate having a substituted amino group at the 4-position and a piperidino or piperazino group bonded to the saturated ring at the 2-position. In addition, CCR4 function regulating action has been disclosed and suggested! /, Na! / ,.
[化 5] [Formula 5]
Figure imgf000004_0002
Figure imgf000004_0002
(式中、 Gは CH又は Nを、 R1及び R2は H、置換されていてもよいアルキル、置換されて いてもよいアルコキシ、ハロゲン等を、 R3及び R4は H、置換されていてもよいァリール 等を、 R5は置換されていてもよいアルキル、置換されていてもよいへテロ環基、置換さ れていてもよいァリールカルボ-ル等を示す。詳細は当該公報参照。 ) [0006] この他、 2位及び 4位にアミノ基を有する縮環ピリミジン誘導体が報告されている。例 えば、 Rho-キナーゼ阻害活性を有するキナゾリン誘導体 (特許文献 4)、 p38キナーゼ の阻害活性を有する 1H-ピラゾ口- [3,4-d]ピリミジン誘導体 (特許文献 5)、ホスホジェ ステラーゼ阻害活性を有する縮環ピリミジン誘導体 (特許文献 6)、 EGF受容体阻害 活性を有するキナゾリン誘導体 (非特許文献 1)、細胞増殖抑制作用を有するキナゾ リン誘導体 (特許文献 7及び 8)、抗腫瘍薬に対する腫瘍細胞増感作用を有するキナ ゾリン誘導体 (特許文献 9)等が挙げられる。これらの文献においても、飽和環が結合 したピペリジノ若しくはピペラジノ基を 2位に有する縮合二環性キナゾリンィ匕合物は何 ら開示されていない。また、 CCR4機能調節作用については開示も示唆もない。 Wherein G is CH or N, 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. [0006] In addition, fused pyrimidine derivatives having amino groups at the 2- and 4-positions have been reported. For example, 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.
[0007] 特許文献 1：国際公開第 03Z104230号パンフレット  [0007] Patent Document 1: International Publication No. 03Z104230 pamphlet
特許文献 2：米国特許出願公開第 2004Z0048865号明細書  Patent Document 2: US Patent Application Publication No. 2004Z0048865
特許文献 3 :特開 2000-281660号公報  Patent document 3: JP-A-2000-281660
特許文献 4:国際公開第 02Z076976号パンフレット  Patent Document 4: WO 02Z076976 pamphlet
特許文献 5：国際公開第 03Z099820号パンフレット  Patent Document 5: International Publication No. 03Z099820 pamphlet
特許文献 6 :米国特許第 6331543号明細書  Patent Document 6: U.S. Pat.No. 6,331,543
特許文献 7：米国特許第 6262059号明細書  Patent Document 7: US Patent No. 6262059
特許文献 8 :米国特許出願公開第 2001Z0031760号明細書  Patent Document 8: U.S. Patent Application Publication No. 2001Z0031760
特許文献 9：国際公開第 92Z007844号パンフレット  Patent Document 9: International Publication No. 92Z007844 pamphlet
非特許文献 l : Bioorganic and Medicinal Chemistry, 1996年，第 4卷，第 8号， p.1203-1207  Non-Patent Document l: Bioorganic and Medicinal Chemistry, 1996, Vol. 4, No. 8, p. 1203-1207
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0008] 本発明者等は、 CCR4の機能調節作用に基づぐ炎症性疾患、アレルギー疾患、自 己免疫疾患等の予防'治療に有用な医薬組成物を提供すること、さらにはこれらを含 有する医薬を提供することを目的として研究を行った。 [0008] 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.
課題を解決するための手段  Means for solving the problem
[0009] 本発明者等は、 CCR4の機能調節作用を有する化合物につき鋭意検討した。その 結果、飽和環の結合したピペリジノ若しくはピペラジノ基を 2位に有し、 4位に置換アミ ノ基を有する縮合二環性ピリミジン誘導体が CCR4の機能調節剤として有用であるこ とを知見し、本発明を完成した。 [0009] 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.
即ち、本発明は、下記一般式 (I)で示される新規な縮合二環性ピリミジン誘導体又 はその製薬学的に許容される塩と製薬学的に許容される担体とからなる医薬組成物 、殊に喘息、アトピー性皮膚炎及び関節リウマチ等の予防 ·治療薬として有効な医薬 組成物に関する。  That is, the present invention provides 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: In particular, it relates to a pharmaceutical composition effective as a prophylactic / therapeutic agent for asthma, atopic dermatitis, rheumatoid arthritis and the like.
[化 6] [Formula 6]
Figure imgf000006_0001
Figure imgf000006_0001
(式中の記号は以下の意味を示す。 (The symbols in the formula have the following meanings.
A：置換されて!、てもよ!/、ァリール、置換されて!、てもよ 、シクロアルキル又は置換さ れて 、てもよ 、単環式 6員へテロァリール、  A: substituted !, may! /, Aryl, substituted !, may, cycloalkyl or substituted, may be, monocyclic 6 membered heteroaryl,
[化 7] [Formula 7]
Figure imgf000006_0002
Figure imgf000006_0002
Ra： H、置換されて!、てもよ 、低級アルキル、置換されて!、てもよ 、シクロアルキル、 置換されて 、てもよ 、フエ-ル、置換されて!、てもよ 、単環若しくは二環式へテロ環 基、 ：じ 又は R a : H, substituted !, may, lower alkyl, substituted !, may, cycloalkyl, substituted, may, phenyl, substituted !, A monocyclic or bicyclic heterocyclic group, : Ji or
Y: CR4又は N、但し、 X力 SCR3のとき Yは Nを、 X力 のとき Yは CR4を示す、 Y: CR 4 or N, where X force SCR 3 Y indicates N, X force Y indicates CR 4 ,
Z: CR5R6、 NR7、 0、 S、 S(0)又は S(0)、 Z: CR 5 R 6 , NR 7 , 0, S, S (0) or S (0),
2  2
R1 :同一又は互いに異なって、 - OH、 - CN、ハロゲン、置換されていてもよい低級ァ ルキル、 -0- (置換されていてもよい低級アルキル)、 -S- (置換されていてもよい低級ァ ルキル)、 -SO -(置換されていてもよい低級アルキル)、 -NO、 - N(R8)(R9)、 - CO- R。、 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. ,
2 2  twenty two
-CO - R。、 - N(R8)C0R。、 - N(R8)C0 R。、 - N(R8)S0 R。、置換されていてもよいフエ-ル、-CO-R. , - N (R 8) C0R . , - N (R 8) C0 R. , - N (R 8) S0 R. , An optionally substituted phenol,
2 2 2 2 2 2
- CO- R°、 -CO H、 - CO- N(R8)(R9)、 - R°°- CO- N(R8)(R9)、置換されていてもよい単環若 - CO- R °, -CO H, - CO- N (R 8) (R 9), - R °° - CO- N (R 8) (R 9), monocyclic young optionally substituted
2  2
しくは二環式へテロ環基又は- CO- (置換されて 、てもよ 、単環若しくは二環式へテロ 環基)、 Or a bicyclic heterocyclic group or -CO- (substituted or a monocyclic or bicyclic heterocyclic group),
R°：低級アルキル又はフエ-ル、  R °: lower alkyl or phenol,
R2 :同一又は互いに異なって、 - R°、ハロゲン、ハロゲノ低級アルキル、 - E-0H、 — E— 0— R°、— E— N(R8)(R9)、— E— CN、— E— N(R8)— CO— R°、— E— N(R8)— SO— R。、 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. ,
2  2
- E- 0- CO- R°、 - E- CO H、 - E- CO - R°、 - E- CON(R8)(R9)又はォキソ、 - E- 0- CO- R °, - E- CO H, - E- CO - R °, - E- CON (R 8) (R 9) or Okiso,
2 2  twenty two
E：結合又は低級アルキレン、  E: bond or lower alkylene,
R3及び R4:同一又は互いに異なって、 H、低級アルキル又は CN、 R 3 and R 4 : the same or different, H, lower alkyl or CN,
R8及び R9 :同一又は互いに異なって、 H又は低級アルキル、 R 8 and R 9 : the same or different, H or lower alkyl,
R5及び R6:同一又は互いに異なって、 H又は R2に記載の基、或いは R5及び R6がー体 となって才キソ、 R 5 and R 6 : the same or different, the groups described in H or R 2 or R 5 and R 6 are
R7: H、低級アルキル、ハロゲノ低級アルキル、 - R°°- 0H、 - CON(R8)(R9)、 - R°°- 0- R。 、 - R。。- N(R8)(R9)、 - R。。- CNゝ - R。。- N(R8)- CO- R。、 - R。。- N(R8)- SO - R。、 - R。。- 0- CO- R0 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 ゝ-R. . - N (R 8) - CO- R. , -R. . - N (R 8) - SO - R. , -R. . -0- CO- R 0
2  2
、 - R°°- CO - R。又は- R°°- CON(R8)(R9)、 , -R °° -CO-R. Or - R °° - CON (R 8 ) (R 9),
2  2
低級アルキレン、  Lower alkylene,
n: 0、 1、 2又は 3、  n: 0, 1, 2, or 3,
m: 0、 1、 2、 3又は 4、  m: 0, 1, 2, 3, or 4,
j: 0、 1、 2又は 3、  j: 0, 1, 2, or 3,
k: 0、 1又は 2。以下同様。 )  k: 0, 1 or 2. The same applies hereinafter. )
発明の効果 [0011] 本発明の縮合二環性ピリミジン誘導体は、 CCR4或いは TARC及び Z又は MDCの 機能調節作用を有することから、種々の炎症性疾患、アレルギー疾患、 自己免疫疾 患等〔例えば、喘息、アレルギー性鼻炎、アレルギー性結膜炎、花粉症、皮膚炎 (アト ピー性皮膚炎、接触性皮膚炎)、乾癬、関節リウマチ、全身性エリテマトーデス、多発 性硬化症、インスリン依存型糖尿病（IDDM)、臓器移植時の拒絶反応、癌、炎症性 腸疾患 (潰瘍性大腸炎、クローン病)、間質性膀胱炎、敗血症、疼痛〕の予防，治療 薬として有用である。特に、喘息、アトピー性皮膚炎又は関節リウマチの予防 '治療 薬として期待できる。 The invention's effect [0011] Since 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]. In particular, it can be expected as a therapeutic agent for preventing asthma, atopic dermatitis or rheumatoid arthritis.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0012] 以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本明細書中、「アルキル」及び「アルキレン」とは、直鎖状又は分枝状の炭化水素鎖 を意味する。「低級アルキル」は、好ましくは炭素数 1一 6個（以下、 C と略す)のアル  In the present specification, “alkyl” and “alkylene” mean a straight or branched hydrocarbon chain. “Lower alkyl” is preferably an alkyl having 116 carbon atoms (hereinafter abbreviated as C).
1-6  1-6
キル基であり、より好ましくは C アルキル、更に好ましくはメチル及びェチルである。  A alkyl group, more preferably C alkyl, still more preferably methyl and ethyl.
1-4  1-4
「低級アルキレン」は、上記「低級アルキル」の任意の水素原子 1個を除去してなる二 価基 (C アルキレン)を意味し、好ましくは C アルキレンであり、より好ましくはメチレ “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
1-6 1-4 1-6 1-4
ン、エチレン及びプロピレンである。  , Ethylene and propylene.
「ハロゲン」は、 F、 Cl、 Br及び Iを示す。「ハロゲノ低級アルキル」とは、好ましくは、 1 個以上のハロゲンで置換された C アルキルを意味し、より好ましくは 1個以上の Fで  “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
1-6  1-6
置換された C アルキルであり、更に好ましくは、フルォロメチル、ジフルォロメチル、  Substituted C alkyl, more preferably fluoromethyl, difluoromethyl,
1-6  1-6
トリフルォロメチル及び 2,2,2-トリフルォロェチルである。  Trifluoromethyl and 2,2,2-trifluoroethyl.
[0013] 「シクロアルキル」は、好ましくは C のシクロアルキルであり、架橋されていてもよい “Cycloalkyl” is preferably C 4 cycloalkyl, which may be bridged
3-10  3-10
。より好ましくはシクロプロピル、シクロペンチル、シクロへキシル、シクロへプチル及 びァダマンチルである。「ァリール」は、 C の芳香族炭化水素基を意味し、「シクロア  . More preferred are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. "Aryl" means an aromatic hydrocarbon group of C and is "cycloalkyl".
6-14  6-14
ルキル」と縮環したフエ-ル基を含む。好ましくはフエ-ル及びナフチルであり、より好 ましくはフエニルである。  Alkyl) and a fused ring. Preferred are phenyl and naphthyl, and more preferred is phenyl.
「単環式へテロ環基」とは、 0、 S及び N力 選択されるへテロ原子を 1一 4個含有す る単環 3— 8員、好ましくは 5— 7員環基であり、不飽和環である単環式へテロァリー ル、飽和環である単環式へテロシクロアルキル、及び前記単環式へテロァリールが部 分的に水素化された環基を含む。単環式へテロァリールとしては、好ましくはピリジル 、ピラジュル、ピリミジ -ル、ピリダジ -ル、イミダゾリル、ピロリル、トリァゾリル、テトラゾ リル、チェニル、フリル、チアゾリル、ピラゾリル、イソチアゾリル、ォキサゾリル、イソォ キサゾリル、チアジアゾリル、ォキサジァゾリル基が挙げられる。単環式へテロシクロア ルキル、又はへテロアリール基が部分的に水素化された環基として好ましくは、ピペリ ジル、ピロリジニル、ピペラジニル、ァゼパニル、ジァゼパニル、テトラヒドロフラニル、 テトラヒドロビラ-ル、モルホリニル、チオモルホリニル基が挙げられる。 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. As 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. Can be
「二環式へテロ環基」は、前記の単環式へテロ環同士、又はベンゼン環と単環式へ テロ環が縮環した環基であり、好ましくは、インドリル、イソインドリル、ベンゾフラニル、 ベンゾチェ-ル、インダゾリル、ベンゾチアゾリル、ベンゾォキサゾリル、キノリル、イソ キノリル、キナゾリル、キノキサリニル、ジヒドロベンゾフラニル、テトラヒドロキノリル、及 びインドリ-ル基が挙げられる。  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.
前記「単環式へテロ環基」及び「二環式へテロ環基」において、環原子である S又は Nが酸化されォキシドゃジォキシドを形成してもよい。また、ヘテロシクロアルキル、及 びへテロァリールが部分的に水素化された環基においては、任意の炭素原子がォキ ソ基で置換されて 、てもよ 、。  In the above “monocyclic heterocyclic group” and “bicyclic heterocyclic group”, S or N as a ring atom may be oxidized to form an oxoxide-dioxide. Further, in the heterocycloalkyl and the ring group in which the heteroaryl is partially hydrogenated, an arbitrary carbon atom may be substituted with an oxo group.
[0014] 「置換されていてもよい」とは、「無置換」あるいは「同一又は異なる置換基を 1一 5個 有していること」を示す。 “May be substituted” means “unsubstituted” or “having 115 identical or different substituents”.
「置換されて 、てもよ 、ァリール」、「置換されて 、てもよ 、シクロアルキル」及び「置 換されていてもよい単環若しくは二環式へテロ環基」における置換基は、好ましくは、 ハロゲン、置換されていてもよい低級アルキル、 - OH、 -0- (置換されていてもよい低 級アルキル)、 - CN、 -S-低級アルキル、 NO ルキルであり、更  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.
2、 -CO H  2, -CO H
2 、 -CO -低級ア  2, -CO -Lower class
2  2
に好ましくは、ハロゲン、低級アルキル、 - OH、 -0-低級アルキル、 - CN、より更に好 ましくは、ハロゲン、 - CNである。  More preferably, they are halogen, lower alkyl, -OH, -0-lower alkyl, -CN, and even more preferably, halogen, -CN.
「置換されていてもよい低級アルキル」における置換基は、好ましくは、ハロゲン、 - OH、 -0-低級アルキル、フエ-ル、 -CO H、 -CO -低級アルキル、シクロアルキル、  The substituent in the "optionally substituted lower alkyl" is preferably halogen, -OH, -0-lower alkyl, phenyl, -COH, -CO-lower alkyl, cycloalkyl,
2 2  twenty two
- CNであり、更に好ましくは、ハロゲン、 -0-低級アルキル、フエ-ルである。  -CN, more preferably halogen, -0-lower alkyl, and phenyl.
[0015] 一般式 (I)に示される本発明化合物の好ましい態様を以下に示す。 i) A力 置換されていてもよいァリールである化合物。 [0015] Preferred embodiments of the compound of the present invention represented by the general formula (I) are shown below. i) A force A compound which is an aryl which may be substituted.
ii) Bが、縮環するピリミジン環と共にキナゾリン環又は 1H-ピラゾ口 [3,4-d]ピリミジン環 を形成する基である化合物。 Bがキナゾリン環を形成する基の場合、より好ましくは、 置換基として 1一 2個の R1を有し、 R1が低級アルキル、ハロゲノ低級アルキル、ハロゲ ン、 -CN又は 0-低級アルキル力も選択される基である化合物。 Bが 1H-ピラゾ口 ii) A compound wherein B is a group that forms a quinazoline ring or a 1H-pyrazo [3,4-d] pyrimidine ring together with a condensed pyrimidine ring. When 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. The compound that is the selected group. B is 1H-Pyrazo mouth
[3,4-d]ピリミジン環を形成する基の場合、より好ましくは、 R1として 1個の低級アルキル を有し、かつ、 Raが H、低級アルキル、ハロゲノ低級アルキル又は置換されていてもよ いフエ-ルである化合物。 In the case of a group forming a [3,4-d] pyrimidine ring, more preferably, R 1 has one lower alkyl and Ra is H, lower alkyl, halogeno lower alkyl or substituted. A compound that is a good fat.
iii) R2がハロゲノ低級アルキル、 - R°°-OH、 - R°°-0- R°又は- CON(R8)(R9)である化合物 、より好ましくは- R°°-OH又は- CON(R8)(R9)、より更に好ましくは- R°°-OHである化合 物。 iii) a compound wherein 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.
iv) jが 0又は 1である化合物、より好ましくは 0である化合物。  iv) Compounds wherein j is 0 or 1, more preferably 0.
V) kが 0又は 1である化合物、より好ましくは 1である化合物。  V) A compound wherein k is 0 or 1, more preferably a compound wherein k is 1.
vi) X力 SCH、かつ Y力 である化合物。  vi) Compounds that have X force SCH and Y force.
vii) Zが CH又は 0である化合物。  vii) Compounds wherein Z is CH or 0.
2  2
[0016] 本発明の化合物 (I)は置換基の種類によっては幾何異性体や互変異性体が存在 する場合がある力 本発明にはこれらの異性体の分離したもの、あるいは混合物が包 含される。  [0016] 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.
また、化合物 (I)は不斉炭素原子を有する場合があり、これに基づく (R)体、 (S)体 の光学異性体が存在しうる。本発明はこれらの光学異性体の混合物や単離されたも のを全て包含する。  Further, 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.
更に、化合物 (I)には、薬理学的に許容されるプロドラッグも含まれる。薬理学的に 許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で本発明の NH  Further, 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.
2 2
、 OH、 CO H等に変換できる基を有する化合物である。プロドラッグを形成する基とし It is a compound having a group that can be converted to OH, COH, and the like. As a base to form a prodrug
2  2
ては、 Prog. Med., 5, 2157-2161 (1985)や「医薬品の開発」（廣川書店、 1990年）第 7 卷 分子設計 163-198に記載の基が挙げられる。  For example, the groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198.
[0017] 化合物 (I)は、酸付加塩又は置換基の種類によっては塩基との塩を形成する場合 もある。力かる塩としては、製薬学的に許容される塩であり、具体的には、塩酸、臭化 水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸、ギ酸、酢酸、プロピオン酸、 シユウ酸、マロン酸、コハク酸、フマル酸、マイレン酸、乳酸、リンゴ酸、酒石酸、クェン 酸、メタンスルホン酸、エタンスルホン酸、ァスパラギン酸、グルタミン酸等の有機酸と の酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機 塩基、メチルァミン、ェチルァミン、エタノールァミン、リジン、オル-チン等の有機塩 基との塩やアンモニゥム塩等が挙げられる。 [0017] 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.
さらに、本発明は、化合物 (I)及びその塩の各種の水和物や溶媒和物及び結晶多 形の物質をも包含する。  Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of compound (I) and salts thereof.
[0018] (製造法）  [0018] (Production method)
本発明の有効成分である化合物 (I)及びその製薬学的に許容される塩は、その基 本骨格あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用 して製造することができる。その際、官能基の種類によっては、当該官能基を原料乃 至中間体の段階で適当な保護基で保護、又は当該官能基に容易に転化可能な基 に置き換えておくことが製造技術上効果的な場合がある。このような官能基としては 例えばアミノ基、水酸基、カルボキシル基等であり、それらの保護基としては例えばグ リーン (T. W. Greene)及びウッツ (P. G. M. Wuts)著、「Protective Groups in Organic Synthesis (第 3版、 1999年)」に記載の保護基を挙げることができ、これらを反応条件 に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反 応を行った後、必要に応じて保護基を除去、あるいは所望の基に転化することにより 、所望の化合物を得ることができる。  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. At that time, depending on the type of the functional group, it is effective in production technology to protect the functional group with an appropriate protecting group at the stage of the raw material or intermediate or to replace it with a group that can be easily converted to the functional group. May be important. 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. In such a method, 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.
また、化合物 (I)のプロドラッグは上記保護基と同様、原料乃至中間体の段階で特 定の基を導入、あるいは得られた化合物 (I)を用い反応を行うことで製造できる。反応 は通常のエステル化、アミド化、脱水等、当業者により公知の方法を適用することによ り行うことができる。  Further, 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.
[0019] 第 1製法 [0019] First manufacturing method
[化 8]
Figure imgf000012_0001
[Formula 8]
Figure imgf000012_0001
(Π) (Π)
[0020] (式中 Lは脱離基を示す。以下同様。 )  (Wherein L represents a leaving group. The same applies hereinafter.)
1  1
本製法は 2位に脱離基を有するキナゾリン誘導体 (Π)に環状アミン化合物 (III)をィ プソ置換させ、本発明化合物 (I)を製造する方法である。  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 (Π) having a leaving group at the 2-position.
Lが示す脱離基としては、ハロゲン、アルキルスルフィエル基、アルキルスルホ-ル Examples of the leaving group represented by L include a halogen, an alkylsulfiel group, an alkylsulfol
1 1
基等が挙げられる。反応は化合物 (II)を反応に不活性な溶媒中、塩基又は酸 (好ま しくは塩化水素）の存在又は非存在下、当量あるいは過剰量の（III)を用いて冷却下 一加熱還流下に通常 1時間一 5日間行なわれる。溶媒としては反応に不活性であれ ば特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素 類、ジェチルエーテル、テトラヒドロフラン (THF)、 1,4-ジォキサン、 1,2-ジメトキシエタ ン、 1,2-ジエトキシェタン等のエーテル類、ジクロロメタン、 1,2-ジクロロエタン、クロ口 ホルム等のハロゲン化炭化水素類、メタノール、エタノール、 2-プロパノール、ブタノ ール等のアルコール類、 Ν,Ν-ジメチルホルムアミド (DMF)、 N-メチルピロリドン (NMP) 、ジメチルスルホキシド (DMSO)等が挙げられる。塩基としては、トリェチルァミン、ジィ ソプロピルェチルァミン (DIPEA)、 1,8-ジァザビシクロ [5.4.0]- 7-ゥンデセン (DBU)、 2,6-ルチジン等の有機塩基、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、水素化 カリウム、 tert-ブトキシカリウム等の塩基が挙げられる。  And the like. The 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. 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, 、, Ν-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like. Examples of bases 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. And bases such as sodium hydride, potassium hydride and potassium tert-butoxide.
[0021] 第 2製法 [0021] Second manufacturing method
[化 9]  [Formula 9]
Figure imgf000012_0002
本製法は 4位にクロ口基を有するキナゾリン誘導体 (IV)にアミンィ匕合物 (V)をィプソ 置換させ、本発明化合物 (I)を製造する方法である。反応は、上記第 1製法に記載と 同様の条件で行うことができる。
Figure imgf000012_0002
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.
第 3製法 Third manufacturing method
一般式 (I)における基 R1又は R2上、或いは環基 A上に種々の置換基を有する化合 物は、本発明化合物 (I)を原料として、当業者にとって自明である反応、又はこれら の変法を用いることにより、容易に合成することができる。例えば以下の反応が適用 できる。 Compounds having various substituents on the group R 1 or R 2 in the general formula (I) or on the ring group A can be obtained by using the compound (I) of the present invention as a raw material, The compound can be easily synthesized by using the modified method. For example, the following reaction can be applied.
(1)加水分解  (1) Hydrolysis
カルボン酸エステル体を加水分解することによって、カルボキシル基を有する本発 明化合物を製造できる。反応は加水分解の常法を用いることができ、例えば、前述の 「Protective Groups in Organic Synthesis (第 3版）」のカルボキシル基の脱保護反応 等に記載の方法を適用することができる。  By hydrolyzing the carboxylic acid ester, the present compound having a carboxyl group can be produced. For the reaction, 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.
(2)アミド化、スルホンアミド化及びエステルイ匕  (2) Amidation, sulfonamidation and esterification
水酸基又はアミノ基を有する本発明化合物を原料とし、カルボン酸若しくはスルホ ン酸化合物又はそれらの反応性誘導体を使用することにより、種々のアミド化合物又 はエステルイ匕合物が製造できる。反応は縮合剤（例えば、ジシクロへキシルカルポジ イミド（DCC)、ジイソプロピルカルボジイミド（DIPC)、 1-ェチル -3- (3-ジメチルアミノプ 口ピル)カルボジイミド (WSC)、 1,1'-カルボ-ルビス- 1H-イミダゾール（CDI)等）、場 合によっては、更に添加剤（例えば、 N-ヒドロキシスクシンイミド（HONSu)、 1-ヒドロキ シベンゾトリアゾール (HOBt)、ジメチルァミノピリジン（DMAP)等）の存在下行うことが できる。カルボン酸若しくはスルホン酸ィ匕合物の反応性誘導体としては、酸ノヽライド、 酸無水物、活性エステル等が使用できる。反応は、例えば日本化学会編「実験化学 講座 (第 4版)」 22卷（1992年）（丸善)等に記載の方法により行うこともできる。  By using the compound of the present invention having a hydroxyl group or an amino group as a raw material and using a carboxylic acid or a sulfonate compound or a reactive derivative thereof, 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. As the reactive derivative of the carboxylic acid or sulfonic acid conjugate, an acid peroxide, an acid anhydride, an active ester and the like can be used. 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).
(3)脱水  (3) Dehydration
カルボキサミド基を有する本発明化合物を脱水することによって、シァノ基を有する 本発明化合物を製造できる。反応は脱水反応の常法を用いることができ、例えば、 日 本ィ匕学会編「実験化学講座 (第 4版)」 20卷 (1992年）（丸善)等に記載の方法により行 うことができる。 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. For example, the reaction is carried out by the method described in Nihon Dani Kaikai, “Experimental Chemistry Course (4th edition)”, Vol. 20 (1992) (Maruzen). I can.
(4)還元  (4) Reduction
NH基を有する本発明化合物は、ニトロ基を有する化合物を原料とし、パラジウム炭 The compound of the present invention having an NH group can be obtained by starting from a compound having a nitro group,
2 2
素等の触媒存在下に水素雰囲気下反応を行う接触還元による方法、或いは、当量 または過剰量の鉄粉、亜鉛、またはスズ等の金属試薬を用いる還元反応により製造 することができる。例えば日本化学会編「実験科学講座 (第 4版)」 26卷 (1992年）（丸 善)等に記載の方法で行なうことができる。 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. For example, 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).
なお、 NH基を有する本発明化合物は、フタルイミド基を有する化合物からも製造で  The compound of the present invention having an NH group can be produced from a compound having a phthalimide group.
2  2
きる。反応は、前述の「Protective Groups in Organic Synthesis (第 3版）」のァミノ基の 脱保護反応等に記載の方法を適用することができる。 Wear. For the reaction, 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.
(5)有機金属試薬による炭素 -炭素結合形成  (5) Carbon-carbon bond formation by organometallic reagents
カルボキシル基を有する本発明化合物またはその反応性中間体である N-メチル -N-メトキシカルボキサミド基を有する本発明化合物を原料とし、アルキルリチウム試 薬、アルキルグリニャール試薬等の有機金属試薬との炭素 炭素結合形成反応によ り、アルキル- CO-基を有する本発明化合物を製造することができる。反応は有機金 属試薬を用いる炭素 炭素結合形成反応の常法を用いることができ、例えば日本ィ匕 学会編「実験科学講座 (第 4版)」 25卷 (1992年）（丸善)等に記載の方法で行なうこと ができる。  Starting from 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. The compound of the present invention having an alkyl-CO- group can be produced by the bond formation reaction. For the 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.
原料合成 Raw material synthesis
[化 10] [Formula 10]
Figure imgf000014_0001
Figure imgf000014_0001
(り  (R
原料化合物（Π)は 4位にクロ口基を有する化合物（1)をァミン化合物 (V)とィプソ置 換反応を行なうことにより製造できる。反応は前記第 1製法と同様の条件が適用でき る。 [0024] [化 11] 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. [0024] [Formula 11]
Figure imgf000015_0001
Figure imgf000015_0001
原料化合物 (IV)はキナゾリン- 4-オン誘導体 (3)を、反応に不活性な溶媒中又は無 溶媒で、当量一大過剰の塩素化剤と反応させることで製造できる。塩素化剤としては 、例えばォキシ塩化リン、五塩化リン、塩ィ匕チォ-ル等を単独で又はそれらを混合し て用いることができる。溶媒としては、芳香族炭化水素類、エーテル類、ハロゲンィ匕 炭化水素類、 Ν,Ν-ジメチルァ-リン等を単独で、又はそれらを混合して用いることが できる。キナゾリン- 4-オン誘導体 (3)は 2-クロ口キナゾリン- 4-オン誘導体 (2)を一般 式 (III)で示されるァミンとィプソ置換反応を行なうことにより製造できる。反応は前記 第 1製法と同様の条件が適用できる。  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. As the chlorinating agent, for example, phosphorus oxychloride, phosphorus pentachloride, chloride salt, or the like can be used alone or as a mixture thereof. As the solvent, aromatic hydrocarbons, ethers, halogenated hydrocarbons, Ν, Ν-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.
[0025] [化 12]  [0025]
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0002
Figure imgf000015_0003
前記式に示した化合物（1)において、特に、 B環がピラゾール環である化合物 (la) は、上記式に示す方法により製造できる。ここで、シァノ化反応は、炭酸ナトリウム、炭 酸カリウム等の塩基の存在下、ハロゲン化炭化水素類等の反応に不活性な溶媒中 で反応させればよい。また、シァノヒドラジン (5)と化合物（6)のヒドラゾンィ匕反応は、無 溶媒下、室温一加熱下で行えばよぐ続く環化反応は、ナトリウムアルコキシド、水酸 化ナトリウム等の塩基存在又は非存在下、アルコール類等の溶媒中で反応させれば よい。また、化合物 (8)と尿素 (9)の反応は、無溶媒下、室温一加熱下で行えばよい。 塩素化は、前記化合物 (3)を用いた場合の塩素化と同様の条件を適用できる。 In the compound (1) represented by the above formula, in particular, the compound (la) wherein the ring B is a pyrazole ring can be produced by the method represented by the above formula. Here, 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. In addition, 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. For chlorination, the same conditions as those for chlorination using compound (3) can be applied.
[0026] [化 13] [0026]
Figure imgf000016_0001
Figure imgf000016_0001
(式中 Pはァミノ基の保護基を示す。以下同様。 )  (In the formula, P represents a protecting group for an amino group. The same applies hereinafter.)
環状アミンィ匕合物（Ilia)及び (Illb)は、上記式に示す方法により製造できる。化合物 (11)の (15a)への変換及び (13)の (15b)への変換は、還元的アルキル化反応の常法を 用いることができ、例えば日本化学会編「実験化学講座 (第 4版)」 20卷（1992年) (丸 善)等に記載の方法が挙げられる。保護基 P及び保護基の除去は、前述の「 Protective Groups in Organic Synthesis (第 3版）」のァミノ基の脱保護反応等に記載 の方法を適用することができる。  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). For the removal of the protecting group P and the protecting group, 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.
[0027] [化 14] [0027] [Formula 14]
(13) + (14) (13) + (14)
Figure imgf000016_0002
Figure imgf000016_0002
環状アミンィ匕合物（IIIc)及び (Illd)は、上記式に示す方法により製造できる。 [0028] その他、種々の環状アミンィ匕合物（III)は、例えば、水酸基を有する化合物より、ァ ルキル化剤（アルキルハライドゃスルホン酸アルキルエステル等）によるアルキルィ匕 又は光延反応によりアルキルエーテル基、フッ素化剤（三フッ化ジェチルァミノ硫黄 や三フッ化モルホリノ硫黄等）によりフルォロ基、フタルイミドとの光延反応によりフタ ルイミド基を有する化合物へと、それぞれ変換できる。この場合、環状アミノ基を保護 しておくことが好ましい。 The cyclic amine conjugates (IIIc) and (Illd) can be produced by the method shown in the above formula. [0028] In addition, 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.
[0029] 上記各製法により得られた反応生成物は、遊離化合物、その塩あるいは水和物な ど各種の溶媒和物として単離され、精製される。塩は通常の造塩処理に付すことによ り製造できる。  [0029] The 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.
単離、精製は、抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー 等通常の化学操作を適用して行われる。  Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
各種異性体は異性体間の物理化学的な性質の差を利用して常法により単離できる 。例えば、光学異性体は一般的な光学分割法、例えば分別結晶化又はクロマトダラ フィ一等により分離できる。また、光学異性体は、適当な光学活性な原料化合物より 製造することちできる。  Various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between the isomers. For example, 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.
[0030] 本発明化合物の薬理活性は以下の試験により確認した。 [0030] The pharmacological activity of the compound of the present invention was confirmed by the following test.
1. CCR4を介した [35S]GTP y S結合試験に対する作用 1. Effects on [ 35 S] GTP y S binding test via CCR4
(1) Human CCR4発現細胞株の取得  (1) Acquisition of human CCR4-expressing cell line
EF-1 aプロモーター下流にヒト CCR4遺伝子を挿入したベクター（ネオマイシン耐性 遺伝子含む）を作製し、マウス pre B細胞株 B300-19細胞にエレクト口ポレーシヨン法 によりトランスフエクシヨンした。これらの細胞を G418添加培地で培養し、限界希釈法 によりヒト CCR4を恒常的かつ安定に発現する単一の細胞株を取得した。  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.
(2) Human CCR4発現細胞株膜画分の調整  (2) Preparation of membrane fraction of human CCR4-expressing cell line
ヒト CCR4発現細胞を回収し PBSで洗浄した後、 Lysis Buffer (10mM Hepes pH 7.5, 2mM EDTA, protainase inhibitor)で懸濁した。懸濁液を氷上に 15分間置いた後、ホ モジェナイザーにより細胞を破砕し遠心した（20000 rpm, 10 min, 4°C) 0さらに上清を 超遠心（22K, 30 min, 4°C)した後、ペレットを PBSに懸濁したものを膜画分として以後 の実験に用いた。 (3) GTP y S結合試験 Human CCR4 expressing cells were collected, washed with PBS, and suspended in Lysis Buffer (10 mM Hepes pH 7.5, 2 mM EDTA, protainase inhibitor). After placing the suspension on ice for 15 minutes, the cells were disrupted with a homogenizer and centrifuged (20000 rpm, 10 min, 4 ° C). 0 The supernatant was ultracentrifuged (22K, 30 min, 4 ° C). Thereafter, the pellet suspended in PBS was used as a membrane fraction in subsequent experiments. (3) GTP y S binding test
試験化合物は、各濃度を 20 mM Hepes pH 7.05、 100 mM NaCl、 5 mM MgCl、  Test compounds were prepared at 20 mM Hepes pH 7.05, 100 mM NaCl, 5 mM MgCl,
2 2
GDP 2 μ Μ, Human MDCゝ [35S]GTP y S 150 pM、 Wheatgerm agglutinin SPA beads 1 mg及び Human CCR4発現細胞株膜画分 1 μ gを含有する反応混合液中で 1時間 30 分、室温で反応させ放射活性を測定した。 GDP 2 μ Human, Human MDC ゝ [ 35 S] GTPyS 150 pM, Wheatgerm agglutinin SPA beads 1 mg and Human CCR4 expressing cell line membrane fraction 1 μg 1 hour 30 minutes at room temperature in a reaction mixture And the radioactivity was measured.
以下の実施例化合物は、 100 nMの濃度で 50%以上の阻害活性を示した： 実施例 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、 91一 93、 97、 99一 101、 104 、 106— 107、 110— 114、 118— 123、 125、 129、 131— 132、 135、 139、 144 一 146、 150— 152、 157— 158、 160— 163、 165— 166、 175、 182及び 187— 188の化合物。  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.
また、比較化合物： 2-(4-ベンジルピペラジ-ル )-4-フエネチルァミノキナゾリン (前 記特許文献 3の実施例 2の化合物）は 1 μ Μの濃度で全く阻害活性を示さな力つた。 なお、主な実施例化合物の阻害活性値 (IC [nM])を示す。  In addition, the comparative compound: 2- (4-benzylpiperazyl) -4-phenethylaminoquinazoline (the compound of Example 2 of Patent Document 3 described above) exerted no inhibitory activity at a concentration of 1 μM. . In addition, the inhibitory activity values (IC [nM]) of the main example compounds are shown.
50  50
実施例 6 : 39  Example 6: 39
実施例 17 : 13  Example 17: 13
実施例 32 : 34  Example 32: 34
実施例 66 : 34  Example 66: 34
実施例 88 : 62  Example 88: 62
実施例 101 : 13  Example 101: 13
実施例 104 : 31  Example 104: 31
実施例 106 : 51  Example 106: 51
実施例 188 : 53  Example 188: 53
2.マウスォキサゾロン誘発接触性皮膚炎に対する作用 2.Effects on mouthoxazolone-induced contact dermatitis
Balb/cマウス（6— 10週齢、雌性、 日本チヤ一ルス'リバ一社）の腹部に 3%ォキサゾロ ン /エタノール溶液 150 1 (シグマアルドリッチジャパン）を塗布により感作した。感作 後 6日目に 1%ォキサゾロン/エタノール溶液 10 1を右耳の両面に塗布した。試験薬 物投与はォキサゾロン溶液の塗布 12時間後に実施し (試験薬物投与群）、コントロー ル群には試験薬物を溶解するのに用いた溶媒のみを投与した。右耳介の厚みは塗 布前と 20時間後にシックネスゲージ (ミツトヨ）を用いて測定し、腫れ (厚み増加分 = 20時間後測定値 塗布前測定値)を算出した。抑制率は感作せずにォキサゾロン溶 液を塗布した群をノーマル群として下式により計算した。なお、上記試験は、一群 5匹 で実施した。 The abdomen of Balb / c mice (6-10 weeks old, female, Nippon Charles' Riva Co., Ltd.) were sensitized by applying a 3% oxazolone / ethanol solution 150 1 (Sigma-Aldrich Japan). Six days after sensitization, a 1% oxazolone / ethanol solution 101 was applied to both sides of the right ear. The test drug was administered 12 hours after application of the oxazolone solution (test drug administration group). Group received only the solvent used to dissolve the test drug. The thickness of the right pinna was measured using a thickness gauge (Mitsutoyo) before and 20 hours after application, and the swelling (thickness increase = measured value 20 hours later, measured value before application) was calculated. The inhibition rate was calculated by the following formula using the group to which the oxazolone solution was applied without sensitization as the normal group. The above test was performed on 5 animals per group.
抑制率 = (コントロール群の腫れ 試験薬物投与群の腫れ )xl00/ (コントロール群の 腫れ—ノーマル群の腫れ）  Inhibition rate = (swelling of control group swelling of test drug administration group) xl00 / (swelling of control group-swelling of normal group)
以下の実施例化合物は、 30 mg/kg経口投与で有意な抑制活性を示した： 実施例 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、 1 65— 166、及び 187— 188のィ匕合物。  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.
一方、比較化合物： 2-(4-ベンジルピペラジ-ル )-4-フエネチルァミノキナゾリン（前 記特許文献 3の実施例 2の化合物）は 100 mg/kg経口投与で全く阻害活性を示さな かった。  On the other hand, the comparative compound: 2- (4-benzylpiperazyl) -4-phenethylaminoquinazoline (the compound of Example 2 of Patent Document 3 described above) shows no inhibitory activity at 100 mg / kg oral administration. Was.
[0032] 3.マウスコラーゲン誘発関節炎に対する作用  [0032] 3. Effect on mouse collagen-induced arthritis
マウスコラーゲン誘発関節炎に対する作用は The Japanese Journal of  Effects on mouse collagen-induced arthritis
Pharmacology, 88, 332 (2002)に記載の方法を用いて評価した。  Evaluation was performed using the method described in Pharmacology, 88, 332 (2002).
上記の各試験例以外にも、例えば Immunology, 98, 345 (1999)に記載のマウス喘息 モデノレ、 Journal of Investigative Dermatorogy, 111, 86 (1998)に記載のォキサゾロン 誘発慢性接触性皮膚炎モデル (アトピー性皮膚炎モデル)等、抗炎症作用を評価す るために一般的に用いられる各種評価モデルにより、本発明化合物の薬理作用を確 認することができる。  In addition to the above test examples, for example, Immunology, 98, 345 (1999) mouse asthma modenole described, Journal of Investigative Dermatorogy, 111, 86 (1998) described oxazolone-induced chronic contact dermatitis model (atopic The pharmacological action of the compound of the present invention can be confirmed by various evaluation models generally used for evaluating an anti-inflammatory action, such as a dermatitis model).
以上の試験結果より、本発明化合物は、 CCR4或いは TARC及び Z又は MDCの機 能調節作用を有することから、種々の炎症性疾患、アレルギー疾患、自己免疫疾患 等の予防 ·治療薬として有用であることは明らかである。  From the above test results, 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.
[0033] 化合物 (I)又はその塩の 1種又は 2種以上を有効成分として含有する製剤は通常 製剤化に用いられる担体ゃ賦形剤、その他の添加剤を用いて調製される。 [0033] 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.
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、あるいは 静注、筋注等の注射剤、坐剤、経皮剤、経鼻剤あるいは吸入剤等による非経口投与 のいずれの形態であってもよい。投与量は症状、投与対象の年齢、性別等を考慮し て個々の場合に応じて適宜決定されるが、通常、経口投与の場合、成人 1日当たり 0.001 mg/kg乃至 100 mg/kg程度であり、これを 1回で、あるいは 2— 4回に分けて投 与する。また、症状によって静脈投与される場合は、通常、成人 1回当たり 0.0001 mg/kg乃至 10 mg/kgの範囲で 1日に 1回乃至複数回投与される。また、吸入の場合 は、通常、成人 1回当たり 0.0001 mg/kg乃至 1 mg/kgの範囲で 1日に 1回乃至複数回 投与される。 For oral administration, tablets, pills, capsules, granules, powders, liquids, etc., or 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. In the case of 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. In the case of inhalation, 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.
本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用 いられる。このような固体組成物においては、一つ又はそれ以上の活性物質力 少な くとも一つの不活性な賦形剤、例えば乳糖、マン-トール、ブドウ糖、ヒドロキシプロピ ルセルロース、微結晶セルロース、デンプン、ポリビュルピロリドン、メタケイ酸アルミン 酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えば ステアリン酸マグネシウム等の滑沢剤やカルボキシメチルスターチナトリウム等の崩壊 剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性 若しくは腸溶性コーティング剤で被膜してもよ 、。  Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, 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.
経口投与のための液体組成物は、薬剤的に許容される乳剤、液剤、懸濁剤、シロッ プ剤、エリキシル剤等を含み、一般的に用いられる不活性な溶剤、例えば精製水、ェ タノールを含む。この組成物は不活性な溶剤以外に可溶化剤、湿潤剤、懸濁化剤の ような補助剤、甘味剤、矯味剤、芳香剤、防腐剤を含有していてもよい。  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.
非経口投与のための注射剤としては、無菌の水性又は非水性の液剤、懸濁剤、乳 剤を含む。水性の溶剤としては、例えば注射用蒸留水及び生理食塩水が含まれる。 非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール、オリー ブ油のような植物油、エタノールのようなアルコール類、ポリソルベート 80 (局方名）等 がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安 定化剤、溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通 す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体 組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解、懸濁して使用す ることちでさる。 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. Examples of the 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. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these produce a sterile solid composition which is dissolved and suspended in sterile water or a sterile solvent for injection before use. Talk about things.
吸入剤や経鼻剤等の経粘膜剤は固体、液体、半固体状のものが用いられ、従来公 知の方法に従って製造することができる。例えば、ラタトースゃ澱粉のような賦形剤や 、更に、 PH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加さ れていてもよい。投与は、適当な吸入又は吹送のためのデバイスを使用することがで きる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化 合物を単独で又は処方された混合物の粉末として、もしくは医薬的に許容し得る担 体と組み合わせて溶液又は懸濁液として投与することができる。乾燥粉末吸入器等 は、単回又は多数回の投与用のものであってもよぐ乾燥粉末又は粉末含有カプセ ルを利用することができる。あるいは、適当な駆出剤、例えば、クロロフルォロアルカ ン、ヒドロフルォロアルカン又は二酸ィ匕炭素等の好適な気体を使用した加圧エアゾー ルスプレー等の形態であってもよ 、。 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. For example, 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. For administration, an appropriate inhalation or insufflation device can be used. 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. Alternatively, 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. .
外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローシ ヨン剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤 、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏又はローション 基剤としては、ポリエチレングリコール、カルボキシビュルポリマー、白色ワセリン、サ ラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリル ァノレコーノレ、セチルアルコール、ラウロマクロゴール、セスキォレイン酸ソノレビタン等 が挙げられる。  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. For example, 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.
実施例 Example
以下、実施例に基づき本発明化合物 (I)の製法を更に詳細に説明する。本発明は 下記実施例に記載の化合物の発明に限定されるものではな 、。また原料化合物の 製法を参考例に示す。  Hereinafter, the production method of the compound (I) of the present invention will be described in more detail with reference to Examples. The present invention is not limited to the compounds described in the following Examples. The production methods of the starting compounds are shown in Reference Examples.
また、参考例及び後記表中以下の略号を用いる。 Ex:実施例番号、 REx:参考例番 号、 No :化合物番号、 Dat :物理化学的データ（F: FAB- MS(M+H)+、 FN :  The following abbreviations are used in Reference Examples and Tables below. Ex: Example number, REx: Reference example number, No: Compound number, Dat: Physicochemical data (F: FAB-MS (M + H) +, FN:
FAB- MS(M- H)―、 ES : ESI- MS(M+H)+、 ESN : ESI- MS(M- H)―、
Figure imgf000021_0001
AP: APCI- MS(M+H)+、 NMR1 : CDC1中の NMRにおける特徴的なピークの δ (ppm FAB-MS (M-H)-, ES: ESI-MS (M + H) +, ESN: ESI-MS (M-H)-,
Figure imgf000021_0001
AP: APCI-MS (M + H) +, NMR1: δ (ppm) of characteristic peak in NMR in CDC1
3 )、 3),
NMR2 : DMSO-d中の1 H NMRにおける特徴的なピークの δ (ppm)、 MP:融点 (°C)、 EA ：元素分析値 (%) (Cal：計算値； Fnd：実測値)）、 Sal：塩及び含有溶媒 (HC1：塩酸塩、 無記載:フリー体、成分の前の数字は例えば 2HC1は 2塩酸塩を示す）、 Str:構造式、 Syn:製造法 (数字は同様に製造した実施例番号を示す）、 Me:メチル、 Et :ェチル、 Ms :メタンスルホニル、 tBu:t-ブチル、 Boc :t-ブトキシカルボニル、 Ph:フエニル、 Bn: ベンジル、 A ァセチノレ。 NMR2: δ (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.
[0036] 参考例 1 Reference Example 1
2-クロ口- 5- (トリフルォロメチル)ベンゾ-トリルを DMF中、アジ化ナトリウムと 100°Cで 1時間反応した。溶媒を留去し得られた残渣を、トルエン中、トリフエニルホスフィンと 室温で 2時間反応した。溶媒を留去し得られた残渣を、 THF中、 1M塩酸で室温下 19 時間処理し、以下常法により後処理、精製して、 2-シァノ -4- (トリフルォロメチル)ァ- リンを得た。 NMR1 : 6.81 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J=8.8, 2.2 Hz), 7.66 (1H, d, J=2.2 Hz)。  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. Got. NMR1: 6.81 (1H, d, J = 8.8 Hz), 7.54 (1H, dd, J = 8.8, 2.2 Hz), 7.66 (1H, d, J = 2.2 Hz).
参考例 2  Reference example 2
2-ァミノ- 4,5-ジフルォロ安息香酸メチルを THF中、ナトリウムメトキシドと、 80°Cで 1.5 時間反応して、 2-ァミノ- 4-メトキシ -5-フルォロ安息香酸メチルを得た。 NMR1 : 6.15 (1H, d, J=7.2 Hz), 3.87 (3H, s), 3.84 (3H, s)。  Methyl 2-amino-4,5-difluorobenzoate was reacted with sodium methoxide in THF at 80 ° C. for 1.5 hours to obtain methyl 2-amino-4-methoxy-5-fluorobenzoate. NMR1: 6.15 (1H, d, J = 7.2 Hz), 3.87 (3H, s), 3.84 (3H, s).
参考例 3  Reference example 3
5-フルォロアントラ-ル酸メチルを酢酸中、シアン酸カリウムと 100°Cで 18時間反応 して、 6-フルォロキナゾリン- 2,4-(1Η,3Η)_ジオンを得た。 F: 181。  Methyl 5-fluoroanthrolate was reacted with potassium cyanate in acetic acid at 100 ° C for 18 hours to obtain 6-fluoroquinazoline-2,4- (1Η, 3Η) _dione. F: 181.
参考例 4  Reference example 4
2-ァミノ- 6-フルォロ安息香酸の水溶液に酢酸をカ卩え、次!、で 35°Cでシアン酸カリ ゥム水溶液を滴下し、反応して、 5-フルォロキナゾリン- 2,4-(1Η,3Η)-ジオンを得た。 ES : 1810 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. -(1Η, 3Η) -dione is obtained. ES: 181 0
参考例 5  Reference Example 5
ジメチル 2-アミノテレフタラートより参考例 3と同様にして得たジメチル 2- [(アミノカ ルポニル)ァミノ]テレフタラートを、 1M水酸ィ匕ナトリウム水溶液中、 70°Cで 1時間処理し て、 2,4-ジォキソ -1,2, 3,4-テトラヒドロキナゾリン- 7-カルボン酸を得た。 F: 207。  Dimethyl 2-[(aminocarbonyl) amino] terephthalate obtained from dimethyl 2-aminoterephthalate in the same manner as in Reference Example 3 was treated in a 1 M aqueous sodium hydroxide solution at 70 ° C. for 1 hour to give 2,2. 4-Dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid was obtained. F: 207.
[0037] 参考例 6 2,4-ジォキソ -1,2, 3,4-テトラヒドロキナゾリン- 7-カルボン酸をエタノール中、塩化チ ォニルで処理して、ェチル 2,4-ジォキソ -1,2,3,4-テトラヒドロキナゾリン- 7-カルボキ シラートを得た。 FN : 233。 [0037] Reference Example 6 2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid is treated with thionyl chloride in ethanol to give ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline. -7-Carboxylate was obtained. FN: 233.
参考例 7 Reference Example 7
2-ァミノ- 4,5-ジクロロべンゾ-トリルの DMF溶液に DBUをカ卩え、二酸化炭素雰囲気 下、室温下、 22時間撹拌した。反応液を 1M塩酸水溶液に加え、生じた沈殿物をろ過 、減圧下乾燥し、 6,7-ジクロロキナゾリン- 2,4(1H,3H)-ジオンを得た。 NMR2 : 11.52 (1H, brs), 11.33 (1H, brs), 7.97 (1H, s)。  DBU was added to a DMF solution of 2-amino-4,5-dichlorobenzotolyl, and the mixture was stirred under a carbon dioxide atmosphere at room temperature for 22 hours. The reaction solution was added to a 1M aqueous hydrochloric acid solution, and the resulting precipitate was filtered and dried under reduced pressure to obtain 6,7-dichloroquinazoline-2,4 (1H, 3H) -dione. NMR2: 11.52 (1H, brs), 11.33 (1H, brs), 7.97 (1H, s).
参考例 8 Reference Example 8
6,7-ジクロロキナゾリン- 2,4(1H,3H)-ジオン、五塩化リン及びォキシ塩化リンの混合 物を 20時間加熱還流し、常法により後処理して、 2,4,6,7-テトラクロ口キナゾリンを得た 。 F : 2690 A mixture of 6,7-dichloroquinazoline-2,4 (1H, 3H) -dione, phosphorus pentachloride and phosphorus oxychloride was heated under reflux for 20 hours and post-treated by a conventional method to give 2,4,6,7 -A quinazoline with tetraclo mouth was obtained. F: 269 0
参考例 9 Reference Example 9
4-フルォロアントラ-ル酸と尿素を 200°C反応し、 7_フルォロキナゾリン  4-Fluoroanthronic acid and urea react at 200 ° C, 7_fluoroquinazoline
- 2,4-(lH,3H)_ジオンを得、更に参考例 8と同様にして、 2,4-ジクロロ- 7-フルォロキナ ゾリンを得た。 EI : 216。 -2,4- (lH, 3H) _dione was obtained, and 2,4-dichloro-7-fluoroquinazoline was obtained in the same manner as in Reference Example 8. EI: 216.
参考例 10 Reference example 10
メチル 5,5-ジメチル- 2-ォキソシクロへキサンカルボキシラートをエタノール中、ナト リウムメトキシド存在下、チォ尿素と反応して、 6,6-ジメチル -2-チォキソ -2,3,5,6,7,8- へキサヒドロキナゾリン- 4(1 H)-オンを得た。 ES： 211。  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. ES: 211.
参考例 11 Reference Example 11
6,6-ジメチル- 2-チォキソ -2, 3,5,6,7,8-へキサヒドロキナゾリン 4(1H)-オンを DMF中 、ヨウ化メチルと反応して、 6,6-ジメチル- 2- (メチルスルフヱ-ル- 5,6,7,8-テトラヒドロ キナゾリン- 4(3H)-オンを得た。 ES : 2250 6,6-Dimethyl-2-thioxo-2,3,5,6,7,8-hexahydroquinazolin 4 (1H) -one is reacted with methyl iodide in DMF to give 6,6-dimethyl- . 2- (Mechirusurufuwe - Le - 5,6,7,8-tetrahydro quinazoline - 4 (3H) - was obtained on ES: 225 0
参考例 12 Reference Example 12
6,6-ジメチル- 2- (メチルスルフヱ-ル) -5,6,7,8-テトラヒドロキナゾリン 4(3Η)-オンを ォキシ塩化リンと 2時間加熱還流して、 4-クロ口- 6,6-ジメチル -2- (メチルスルフエ-ル )-5,6,7,8-テトラヒドロキナゾリンを得た。 ES： 243。 参考例 13 6,6-Dimethyl-2- (methylsulfur) -5,6,7,8-tetrahydroquinazolin 4 (3Η) -one is heated under reflux with oxyphosphoric chloride for 2 hours to give 4-chloro-6,6 -Dimethyl-2- (methylsulfur) -5,6,7,8-tetrahydroquinazoline was obtained. ES: 243. Reference Example 13
6-フルォロ- 2-チォキソ- 2,3-ジヒドロキナゾリン 4(1H)-オンを用いて参考例 11及び 12と同様にして、 4-クロ口- 6-フルォロ- 2- (メチルスルフエニル)キナゾリンを得た。 F: 229。  In the same manner as in Reference Examples 11 and 12 using 6-fluoro-2-thioxo-2,3-dihydroquinazoline 4 (1H) -one, 4-chloro-6-fluoro-2- (methylsulfenyl) Quinazoline was obtained. F: 229.
参考例 14 Reference Example 14
シクロへプチルァミンと 2,4-ジクロロ- 6,7-ジメトキシキナゾリンを DMF中、室温下反 応して、 2-クロ口- N-シクロへプチル- 6,7-ジメトキシキナゾリン- 4-アミンを得た。 F: 336。  Cycloheptylamine and 2,4-dichloro-6,7-dimethoxyquinazoline were reacted in DMF at room temperature to obtain 2-chloro-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine. Was. F: 336.
参考例 15 Reference Example 15
2,4,7-トリクロ口キナゾリンと 4-クロロア-リンを 2-プロパノール中、 DIPEA存在下、 3.5 時間加熱還流して、 2,7-ジクロロ- N- (4-クロ口フエ-ル)キナゾリン- 4-アミンを得た。 ESN: 322。  2,4,7-Tricloquinoline and 4-chloroaline are heated in 2-propanol and refluxed for 3.5 hours in the presence of DIPEA to give 2,7-dichloro-N- (4-chloromouth phenyl) quinazoline. -The 4-amine was obtained. ESN: 322.
参考例 16 Reference Example 16
2,4-ジクロロ- 6,7-ジメトキシキナゾリンと 4-クロ口- 2-フルォロア二リンのエタノール溶 液に 1M塩酸水溶液を加え、 3時間加熱還流した。生じた沈殿物をろ過し、減圧下乾 燥して、 2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-6, 7-ジメトキシキナゾリン- 4-アミ ン塩酸塩を得た。 ES : 368  To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline and 4-chloro-2-fluoroaniline in ethanol was added a 1M aqueous hydrochloric acid solution, and the mixture was heated under reflux for 3 hours. The resulting precipitate is filtered and dried under reduced pressure to give 2-chloro-N- (4-chloro-2-fluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride. Was. ES: 368
参考例 17 Reference Example 17
2,4-ジクロロ- 6,7-ジメトキシキナゾリン及び 3,4,5-トリフルォロア二リンのエタノール 溶液に、 4M塩ィ匕水素/酢酸ェチル溶液をカ卩え、ー晚加熱還流して、 2-クロ口  To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline and 3,4,5-trifluoraniline in an ethanol solution, add a 4M salt / hydrogen / ethyl acetate solution, and heat under reflux to obtain 2- Black mouth
-N- (3,4,5-トリフルオロフヱ-ル)- 6,7-ジメトキシキナゾリン- 4-ァミン塩酸塩を得た。 ES : 3700 -N- (3,4,5-trifluoropropyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride was obtained. ES: 370 0
参考例 18 Reference Example 18
2, 4-ジクロロ- 6-フルォロキナゾリン及び 2-ァミノ- 5-ブロモベンゾ-トリルを THF中、 tert-ブトキシカリウム存在下反応して、 5-ブロモ -2-(2-クロ口- 6-フルォロ-キナゾリン -4-ィルァミノ)-ベンゾ-トリルを得た。 ES : 377, 379。  2,4-Dichloro-6-fluoroquinazoline and 2-amino-5-bromobenzo-tolyl are reacted in THF in the presence of potassium tert-butoxy to give 5-bromo-2- (2-chloro-6- Fluoro-quinazoline-4-ylamino) -benzo-tolyl was obtained. ES: 377, 379.
参考例 19 Reference Example 19
N- (4-クロ口フエ-ル)- 6,6-ジメチル- 2- (メチルスルフエ-ル) -5,6,7,8-テトラヒドロキ ナゾリン- 4-アミンをジクロロメタン中、氷冷下、 m-クロ口安息香酸で処理して、 N-(4-ク ロロフエ二ル)- 6,6-ジメチル- 2- (メチルスルフィニル) -5,6,7,8-テトラヒドロキナゾリン -4-アミンを得た。 F: 350。 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. F: 350.
参考例 20 Reference Example 20
ベンジル 4-ォキソピペリジン- 1-カルボキシラート及びピぺリジン- 3-ィルメタノール の混合物にチタニウムテトライソプロボキシドを加え、 80°Cで攪拌した。次いで、氷冷 下、エタノール及び水素化ホウ素ナトリウムをカ卩え、室温下反応して、ベンジル 3- (ヒ ドロキシメチル) -1,4'-ビピペリジン- 1'-カルボキシラートを得た。 ES： 333。  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.
参考例 21 Reference Example 21
ピぺリジン- 3-ィルァセトニトリル及びべンジル 4-ォキソピペリジン- 1-カルボキシラ ートを酢酸中、水素化トリァセトキシホウ素ナトリウム存在下反応して、ベンジル 3-( シァノメチル )- 1,4'-ビピペリジン- 1'-カルボキシラートを得た。 F: 342。  Reaction of piperidine-3-ylacetonitrile and benzyl 4-oxopiperidine-1-carboxylate in acetic acid in the presence of sodium triacetoxyborohydride results in benzyl 3- (cyanomethyl) -1. , 4'-Bipiperidine-1'-carboxylate was obtained. F: 342.
参考例 22 Reference Example 22
tert-ブチル 4-ォキソピペリジン- 1-カルボキシラート、 3-ピぺリジンメタノール、 10% ノ ラジウム炭素及びメタノール混合物を、水素雰囲気下攪拌して、 tert-ブチル 3- (ヒ ドロキシメチル) -1 ,4'-ビピペリジン- 1 '-カルボキシラートを得た。 ES： 299。  A mixture of tert-butyl 4-oxopiperidine-1-carboxylate, 3-piperidinemethanol, 10% noradium carbon and methanol is stirred under a hydrogen atmosphere to obtain tert-butyl 3- (hydroxymethyl) -1, 4′-Bipiperidine-1′-carboxylate was obtained. ES: 299.
参考例 23 Reference Example 23
アルゴン雰囲気下、水酸化ホウ素リチウムの THF懸濁液に、 tert-ブチル （3S)-3- エトキシカルボ-ル- 1,4'-ビピペリジン- 1'-カルボキシラートの THF溶液を氷冷下滴 下し、次いで、加熱還流下攪拌して、 tert-ブチル （3S)- 3- (ヒドロキシメチル) -1,4'-ビ ピぺリジン- 1'-カルボキシラートを得た。 ES： 299。  Under an argon atmosphere, 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.
参考例 24 Reference Example 24
tert-ブチル 3-エトキシカルボニル- 1,4'-ビピペリジン- 1'-カルボキシラートの THF 溶液に、室温で臭ィ匕メチルマグネシウムの THF溶液を滴下することにより、 tert-ブチ ル 3- (1-ヒドロキシ- 1-メチルェチル )- 1,4'-ビピペリジン- 1'-カルボキシラートを得た 。 F : 3270 To a THF solution of tert-butyl 3-ethoxycarbonyl-1,4′-bipiperidine-1′-carboxylate was added dropwise a THF solution of methyl magnesium bromide at room temperature to give tert-butyl 3- (1- Hydroxy-1-methylethyl) -1,4′-bipiperidine-1′-carboxylate was obtained. F: 327 0
参考例 25 Reference Example 25
三フッ化ジェチルァミノ硫黄のジクロロメタン溶液に、ベンジル 4-ヒドロキシ -1,4'- ビピペリジン- 1'-カルボキシラートのジクロロメタン溶液を氷冷下、 1時間かけて滴下し 、室温で 5時間撹拌して、ベンジル 4-フルォロ- 1,4'-ビピペリジン- 1'-カルボキシラ ートを得た。 ES : 3210 Benzyl 4-hydroxy -1,4'- A dichloromethane solution of bipiperidine-1'-carboxylate was added dropwise over 1 hour under ice-cooling, and the mixture was stirred at room temperature for 5 hours to give benzyl 4-fluoro-1,4'-bipiperidine-1'-carboxylate. Obtained. ES: 321 0
[0041] 参考例 26 Reference Example 26
tert-ブチル 3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1'-カルボキシラートを THF中 、水素化ナトリウムで処理し、次いでョードメタンと反応して、 tert-ブチル 3- (メトキシ メチル )- 1,4'-ビピペリジン- 1'-カルボキシラートを得た。 ES : 313。  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. ES: 313.
参考例 27  Reference Example 27
tert-ブチル 4-ォキソピペリジン- 1-カルボキシラートのジメチルァセトアミド溶液に ピぺリジン- 3-ィルメタノール、硫酸マグネシウム、アセトンシアンヒドリンをカ卩え、 40°C で 2.5日間反応して、 tert-ブチル 4'-シァノ -3- (ヒドロキシメチル) -1,4'-ビピペリジン -1'-カルボキシラートを得た。 ES : 324。  To a solution of tert-butyl 4-oxopiperidine-1-carboxylate in dimethylacetamide, add piperidine-3-ylmethanol, magnesium sulfate, and acetone cyanohydrin, and react at 40 ° C for 2.5 days. tert-Butyl 4′-cyano-3- (hydroxymethyl) -1,4′-bipiperidine-1′-carboxylate was obtained. ES: 324.
参考例 28  Reference Example 28
tert-ブチル 4'-シァノ -3- (ヒドロキシメチル) -1 ,4'-ビピペリジン- 1 '-カルボキシラー トを THF中、臭化メチルマグネシウムと室温下 4時間反応して、 tert-ブチル 3- (ヒドロ キシメチル) -4しメチル -1,4'-ビピペリジン- 1'-カルボキシラートを得た。 ES : 313。 参考例 29  tert-Butyl 4'-cyano-3- (hydroxymethyl) -1,4'-bipiperidine-1'-carboxylate is reacted with methylmagnesium bromide in THF at room temperature for 4 hours to give tert-butyl 3- (Hydroxymethyl) -4 methyl-1,4′-bipiperidine-1′-carboxylate was obtained. ES: 313. Reference Example 29
ベンジル 3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1'-カルボキシラート、 10%パラジ ゥム-炭素及びエタノール混合物を、水素雰囲気下、室温で攪拌して、 1,4'-ビピペリ ジン- 3-ィルメタノールを得た。 ES : 199。  Benzyl 3- (hydroxymethyl) -1,4'-bipiperidine-1'-carboxylate, 10% palladium-carbon and ethanol mixture are stirred at room temperature under hydrogen atmosphere to give 1,4'-bipiperidine -3-imethanol was obtained. ES: 199.
参考例 30  Reference example 30
tert-ブチル 3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1'-カルボキシラートをメタノー ル中、 4M塩酸-酢酸ェチル溶液で処理して、 1,4'-ビピペリジン- 3-メタノール 2塩酸塩 を得た。 ES : 199。  tert-Butyl 3- (hydroxymethyl) -1,4'-bipiperidine-1'-carboxylate is treated with 4M hydrochloric acid-ethyl acetate solution in methanol to give 1,4'-bipiperidine-3-methanol 2HCl Salt was obtained. ES: 199.
[0042] 参考例 31 [0042] Reference Example 31
tert-ブチル 3- (メトキシメチル)- 1,4'-ビピペリジン- 1'-カルボキシラートを氷冷下、 トリフルォロ酢酸で処理して、 3- (メトキシメチル) -1 ,4'-ビピペリジントリフルォロ酢酸塩 を得た。 ES : 2130 参考例 32 tert-Butyl 3- (methoxymethyl) -1,4'-bipiperidine-1'-carboxylate is treated with trifluoroacetic acid under ice cooling to give 3- (methoxymethyl) -1,4'-bipiperidine trifluoro The acetic acid salt was obtained. ES: 213 0 Reference Example 32
tert-ブチル 3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1'-カルボキシラートの THF溶 液にフタルイミド、トリフエ-ルホスフィン及びァゾジカルボン酸ジェチルを順次加え、 室温下反応して得られた化合物を、酢酸ェチル中、 4M塩ィ匕水素-酢酸ェチル溶液 で処理して、 2-(1,4'-ビピペリジン- 3-ィルメチル) -1H-イソインドール- 1,3(2H)_ジオン 2塩酸塩を得た。 F :4280 A compound obtained by sequentially adding phthalimide, triphenylphosphine and getyl azodicarboxylate to a THF solution of tert-butyl 3- (hydroxymethyl) -1,4'-bipiperidine-1'-carboxylate and reacting at room temperature. Is treated with a 4M solution of hydrogen chloride in ethyl acetate-ethyl acetate solution to give 2- (1,4'-bipiperidin-3-ylmethyl) -1H-isoindole-1,3 (2H) _dione dihydrochloride Salt was obtained. F: 428 0
参考例 33 Reference Example 33
2-クロ口- 6,7-ジメトキシキナゾリン- 4(1Η)-オン及び 3- (メトキシメチル) -1,4'-ビピペリ ジンを η-ブタノール中、 DBU存在下、 110°Cで 2.5日間反応して、 6,7-ジメトキシ -2-[3- (メトキシメチル) -1 ,4'-ビピペリジン- 1しィル]キナゾリン- 4(1H)-オンを得た。 ES :417。  2-Clot-6,7-dimethoxyquinazoline-4 (1Η) -one and 3- (methoxymethyl) -1,4'-bipiperidine in η-butanol in the presence of DBU at 110 ° C for 2.5 days Thus, 6,7-dimethoxy-2- [3- (methoxymethyl) -1,4'-bipiperidin-1silyl] quinazolin-4 (1H) -one was obtained. ES: 417.
参考例 34 Reference example 34
6,7-ジメトキシ -2-[3- (メトキシメチル) -1,4'-ビピペリジン- 1しィル]キナゾリン- 4(1H)- オンのォキシ塩化リン溶液に Ν,Ν-ジメチルァ-リンを添カ卩し、 1時間加熱還流して、 1' -(4-クロ口- 6,7-ジメトキシキナゾリ- 2-ニル)- 3- (メトキシメチル) -1,4'-ビピペリジンを得 た。 ES :435。  Ν, Ν-Dimethylaline was added to a solution of 6,7-dimethoxy-2- [3- (methoxymethyl) -1,4'-bipiperidin-1silyl] quinazoline-4 (1H) -one in phosphorus oxychloride. The mixture was heated and refluxed for 1 hour to obtain 1 '-(4-chloro-6,7-dimethoxyquinazoli-2-yl) -3- (methoxymethyl) -1,4'-bipiperidine. . ES: 435.
参考例 35 Reference Example 35
1- [l-(tert-ブトキシカルボ-ル)ピぺリジン- 4-ィル] - L-プロリンメチルエステルを用 V、て実施例 30と同様の操作を行 、、粗製の 1- (ピペリジン- 4-ィル) -L-プロリンメチル エステル 2塩酸塩を得た。この化合物をジォキサン中、実施例 3と同様にして、 1-(1-{4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }ピペリジン- 4-ィ ル)- L-プロリンメチルエステルを得た。 ES： 5270 Using 1- [l- (tert-butoxycarbol) piperidin-4-yl] -L-proline methyl ester, the same operation as in Example 30 was carried out to obtain crude 1- (piperidine -4-yl) -L-proline methyl ester dihydrochloride was obtained. This compound was treated with 1- (1- {4-[(4-chlorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} piperidine-4 in dioxane in the same manner as in Example 3. -Yl)-L-proline methyl ester was obtained. ES: 527 0
参考例 36 Reference Example 36
2-クロ口- Ν- (4-クロ口フエ-ル)- 6,7-ジメトキシキナゾリン- 4-ァミン塩酸塩より、後記 実施例 2と同様にして、 2-[(1'-{4-[(4_クロ口フエニル)ァミノ]- 6,7-ジメトキシキナゾリン -2-ィル }-1,4-ビピペリジン- 3-ィル)メチル ]-1Η-イソインドール- 1,3(2Η)_ジオンを得 た。 F : 6410 From 2-chloro --- (4-chloromethyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride, 2-[(1 ′-{4- [(4_Chlorophenyl) amino]-6,7-dimethoxyquinazoline-2-yl} -1,4-bipiperidin-3-yl) methyl] -1Η-isoindole-1,3 (2Η) _ I got Zeon. F: 641 0
参考例 37 1-ベンジル -3-メトキシメチルピロリジンを用いて参考例 22と同様の操作を行 、、粗 製の tert-ブチル 4-(3-メトキシピロリジン- 1-ィル)ピぺリジン- 1-カルボキシラートを得 た。この化合物を用いて参考例 30と同様の操作を行い、 4-(3-メトキシピロリジン- 1- ィル)ピぺリジン 2塩酸塩を得た。 F: 185。 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.
参考例 38— 125 Reference example 38—125
参考例 3の方法と同様にして参考例 38の化合物を、参考例 7の方法と同様にして 参考例 39の化合物を、参考例 8の方法と同様にして参考例 40— 44の化合物を、参 考例 9の方法と同様にして参考例 45の化合物を、参考例 11の方法と同様にして参 考例 46の化合物を、参考例 14の方法と同様にして参考例 47— 49の化合物を、参 考例 15の方法と同様にして参考例 50— 54の化合物、参考例 55— 65の化合物（伹 し、溶媒は DMF)、参考例 66— 69の化合物（但し、溶媒はァセトニトリル- THF(4 : 1)) 及び参考例 70— 72の化合物（但し、溶媒はジォキサン)を、参考例 16の方法と同様 にして参考例 73— 77の化合物及び参考例 78— 81の化合物（但し、溶媒は 2-プロ パノール）を、参考例 17の方法と同様にして参考例 82— 85の化合物及び参考例 86 一 90の化合物（但し、溶媒は 2-プロパノール)を、参考例 18の方法と同様にして参 考例 91の化合物を、参考例 19の方法と同様にして参考例 92の化合物を、参考例 2 0の方法と同様にして参考例 93の化合物を、参考例 22の方法と同様にして参考例 9 4一 104の化合物を、参考例 23の方法と同様にして参考例 105の化合物を、参考例 25の方法と同様にして参考例 106の化合物を、参考例 26の方法と同様にして参考 例 107— 109の化合物を、参考例 29の方法と同様にして参考例 110の化合物を、 参考例 30の方法と同様にして参考例 111一 124の化合物を、参考例 31の方法と同 様にして参考例 125の化合物を、それぞれ対応する原料を使用して製造した。参考 例 38— 125の化合物の構造及び物理ィ匕学的データを表 1一 6にそれぞれ示す。 参考例 126  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, and the compound of Reference Examples 47-49 was obtained in the same manner as in Reference Example 14. In the same manner as in the method of Reference Example 15, the compound of Reference Examples 50-54, the compound of Reference Examples 55-65 (where the solvent is DMF), and the compound of Reference Examples 66-69 (provided that the solvent is acetonitrile- THF (4: 1)) and the compound of Reference Examples 70-72 (the solvent is dioxane), and the compound of Reference Examples 73-77 and the compound of Reference Examples 78-81 (provided that the solvent is dioxane). The solvent was 2-propanol, and the compounds of Reference Examples 82 to 85 and the compounds of Reference Examples 86 to 90 (however, The medium of Reference Example 91 was used in the same manner as in Reference Example 18, and the compound of Reference Example 92 was used in the same manner as in Reference Example 20. The compound of Reference Example 93, the compound of Reference Example 944-1104 in the same manner as in the method of Reference Example 22, the compound of Reference Example 105 in the same manner as in the method of Reference Example 23, and the method of Reference Example 25 The compound of Reference Example 106, the compound of Reference Examples 107-109 in the same manner as in the method of Reference Example 26, the compound of Reference Example 110 in the same manner as in the method of Reference Example 29, and the same as the method of Reference Example 30 Then, the compounds of Reference Examples 111 to 124 and the compound of Reference Example 125 in the same manner as in the method of Reference Example 31 were produced using the corresponding starting materials. The structures and physical properties of the compounds of Reference Examples 38 to 125 are shown in Table 16 respectively. Reference Example 126
参考例 18の方法と同様にしてメチル 2-クロ口- 4-[(4-クロ口- 2-フルオロフェ -ル） ァミノ]キナゾリン- 7-カルボキシラートを対応する原料を使用して製造した。 F: 366。 参考例 127  Methyl 2-chloro-4-[(4-chloro-2-fluorophenyl) amino] quinazoline-7-carboxylate was produced in the same manner as in Reference Example 18 using the corresponding raw materials. F: 366. Reference Example 127
4,6-ジクロロ- 1-フエ-ル- 1H-ピラゾ口 [3,4- d]ピリミジンと 4-クロロア-リンを DIPEA存 在下、 1,4-ジォキサン中で 20時間 80°Cでカ卩熱して 6-クロ口- N-(4-クロ口フエ-ル) -1- フエ-ル- 1H-ピラゾ口 [3,4- d]ピリミジン- 4-アミンを得た。 ESN: 354。 4,6-dichloro-1-phenyl-1H-pyrazo-mouth [3,4-d] pyrimidine and 4-chloro-arine in DIPEA In the presence, heat caulk at 80 ° C for 20 hours in 1,4-dioxane, and heat 6-chloro-N- (4-chlorophenol) -1-phenyl-1H-pyrazo [3,4 -d] Pyrimidin-4-amine was obtained. ESN: 354.
参考例 128 Reference Example 128
4,6-ジクロロ- 1-フエニル- 1H-ピラゾ口 [3,4- d]ピリミジンと 4-クロ口- 2-フルォロア二リ ン用いて参考例 18の方法と同様にして、 6-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-1-フエ-ル- 1H-ピラゾ口 [3,4- d]ピリミジン- 4-アミンを得た。 ES: 374。  Using 4,6-dichloro-1-phenyl-1H-pyrazoline [3,4-d] pyrimidine and 4-chloro-2-2-fluoroalanine, the 6-chloro -N- (4-chloro-2-fluorophenyl) -1-phenyl-1H-pyrazo [3,4-d] pyrimidin-4-amine was obtained. ES: 374.
参考例 129 Reference Example 129
参考例 127の方法と同様にして 6-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-1-メチ ル -1H-ピラゾ口 [3,4-d]ピリミジン- 4-アミンを対応する原料を使用して製造した。 ES: 312。  In the same manner as in Reference Example 127, 6-chloro-N- (4-chloro-2-fluorophenyl) -1-methyl-1H-pyrazo [3,4-d] pyrimidine-4-amine Was produced using the corresponding raw materials. ES: 312.
参考例 130 Reference Example 130
4,5-ジフルォロアントラ-ル酸のエタノール溶液を硫酸存在下加熱還流して、ェチ ル 2-ァミノ- 4,5-ジフルォ口べンゾエートを得た。 NMR1: 6.42 (1H, dd, J=7.0, 12.0 Hz), 5.66 (2H, brs), 1.37 (3H, t, J=7.2 Hz)。  An ethanol solution of 4,5-difluoroanthrolic acid was heated under reflux in the presence of sulfuric acid to obtain ethyl 2-amino-4,5-difluorobenzoate. NMR1: 6.42 (1H, dd, J = 7.0, 12.0 Hz), 5.66 (2H, brs), 1.37 (3H, t, J = 7.2 Hz).
参考例 131 Reference Example 131
ェチル 2-ァミノ- 4,5-ジフルォ口べンゾエートとナトリウムメチルチオラートを DMSO 中、室温下 5時間反応させ、ェチル 2-ァミノ- 5-フルォ口- 4- (メチルスルファニル)ベ ンゾエートを得た。 F: 230。  The ethyl 2-amino-4,5-difluorobenzoate and sodium methylthiolate were reacted in DMSO at room temperature for 5 hours to obtain ethyl 2-amino-5-fluoro-4- (methylsulfanyl) benzoate. F: 230.
参考例 132 Reference Example 132
メチル 2-ァミノ- 4,5-ジフルォ口べンゾエートとェチル メルカプトァセタートの DMSO溶液に水素化ナトリウムをカ卩え、室温下 5日間反応させて、メチル 2-ァミノ -4-[(2-エトキシカルボニル- 2-ォキソェチル)チォ] -5フルォロベンゾエートを得た。 NMR1 : 3.67 (2H, s), 3.86 (3H, s), 6.67 (1H, d, J=6.0 Hz)  Sodium hydride was added to a DMSO solution of methyl 2-amino-4,5-difluorobenzoate and ethyl mercaptoacetate, and the mixture was reacted at room temperature for 5 days to give methyl 2-amino-4-[(2- Ethoxycarbonyl-2-oxoethyl) thio] -5-fluorobenzoate was obtained. NMR1: 3.67 (2H, s), 3.86 (3H, s), 6.67 (1H, d, J = 6.0 Hz)
参考例 133 Reference Example 133
メチル 2-ァミノ- 4,5-ジフルォ口べンゾエート、ェチル ピぺリジン- 4-カルボキシラ ート、炭酸カリウムのァセトニトリル溶液を 5日間加熱還流させて、ェチル 1- [5-ァミノ -2-フルォロ- 4- (メトキシカルボニル)フエニル]ピぺリジン- 4-カルボキシラートを得た。 ES： 325。 参考例 134 A solution of methyl 2-amino-4,5-difluorobenzoate, ethyl piperidine-4-carboxylate, and potassium carbonate in acetonitrile was heated to reflux for 5 days, and ethyl 1- [5-amino-2-fluoro was added. 4- (methoxycarbonyl) phenyl] piperidine-4-carboxylate was obtained. ES: 325. Reference Example 134
メチル 2-ァミノ- 4,5-ジフルォ口べンゾエートとシクロプロピルメタノールの THF溶液 を、 tert-ブトキシカリウム存在下に氷冷下 2時間攪拌して、シクロプロピルメチル 2- ァミノ- 4- (シクロプロピルメチルォキシ )-5-フルォロベンゾエートを得た。 NMR1： 3.47 (2H, d, J=7.2 Hz), 3.69 (2H, d, J=7.2 Hz), 7.22 (1H, d, J=12.4 Hz)。  A THF solution of methyl 2-amino-4,5-difluobenzoate and cyclopropylmethanol was stirred for 2 hours under ice-cooling in the presence of potassium tert-butoxide to give cyclopropylmethyl 2-amino-4- (cyclopropyl Methyloxy) -5-fluorobenzoate was obtained. NMR1: 3.47 (2H, d, J = 7.2 Hz), 3.69 (2H, d, J = 7.2 Hz), 7.22 (1H, d, J = 12.4 Hz).
参考例 135 Reference Example 135
2-ァミノ- 4,5-ジフルォ口べンズアミドを THF中、トリェチルァミン存在下、氷冷下トリ フルォロ酢酸無水物と 1.5時間反応させ、 N-(2-シァノ -4, 5-ジフルオロフヱ-ル )-2,2,2-トリフルォロアセトアミドを得た。 FN: 249。  2-Amino-4,5-difluorobenzamide was reacted with trifluoroacetic anhydride in THF in the presence of triethylamine under ice cooling for 1.5 hours to give N- (2-cyano-4,5-difluorophenyl)- 2,2,2-Trifluoroacetamide was obtained. FN: 249.
参考例 136 Reference Example 136
N- (2-シァノ -4,5-ジフルオロフェ-ル )-2,2,2-トリフルォロアセトアミドとエタノールを 用いて参考例 134と同様の操作を行 、、 N-(2-シァノ -5-エトキシ -4-フルオロフェ- ル)- 2,2,2-トリフルォロアセトアミドを得た。 F: 277。  The same operation as in Reference Example 134 was performed using N- (2-cyano-4,5-difluorophenyl) -2,2,2-trifluoroacetamide and ethanol, and N- (2-cyano- 5-ethoxy-4-fluorophenyl) -2,2,2-trifluoroacetamide was obtained. F: 277.
参考例 137 Reference Example 137
N- (2-シァノ -5-エトキシ- 4-フルオロフェ-ル )-2, 2,2-トリフルォロアセトアミドを含水 メタノール中、炭酸カリウムと 65°Cで 17時間反応させ、 2-ァミノ- 4-エトキシ -5-ベンゾ 二トリルを得た。 F: 181。  N- (2-Cyano-5-ethoxy-4-fluorophenyl) -2,2,2-trifluoroacetamide was reacted with potassium carbonate in aqueous methanol at 65 ° C for 17 hours to give 2-amino-4 -Ethoxy-5-benzonitrile was obtained. F: 181.
参考例 138 Reference Example 138
2-ァミノ- 3-メトキシ安息香酸のジクロロメタン溶液に、 N-ブロモコハク酸イミドをカロえ 、室温で 2時間攪拌して、 2-ァミノ- 5-ブロモ -3-メトキシ安息香酸を得た。 ES： 246, 248。  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.
参考例 139 Reference Example 139
2-ァミノ- 5-ブロモ -3-メトキシ安息香酸と尿素の混合物を 200°Cで 2時間加熱し、 6- ブロモ -8-メトキシキナゾリン- 2,4(1H,3H)-ジオンを得た。 ES： 270, 272  A mixture of 2-amino-5-bromo-3-methoxybenzoic acid and urea was heated at 200 ° C for 2 hours to obtain 6-bromo-8-methoxyquinazoline-2,4 (1H, 3H) -dione. ES: 270, 272
参考例 140 Reference Example 140
メチル 2-メチル -ァミノ- 5-フルォロベンゾエートのメタノール溶液に N-ブロモこはく 酸イミドと 48%臭化水素酸水溶液を加え、室温下 3時間反応させ、メチル 2-ァミノ -3-ブロモ -5-フルォロベンゾエートを得た。 EI: 247。 [0047] 参考例 141 To a solution of methyl 2-methyl-amino-5-fluorobenzoate in methanol is added N-bromosuccinimide and a 48% aqueous solution of hydrobromic acid, and the mixture is reacted at room temperature for 3 hours to give methyl 2-amino-3-bromo- 5-Fluorobenzoate was obtained. EI: 247. Reference Example 141
2-ァミノ- 4-メトキシベンゾ-トリルをジクロロェタン中、 N-クロ口こはく酸イミドと室温 下 17時間反応させ、 2-ァミノ- 5-クロ口- 4-メトキシベンゾ-トリルを得た。 ES: 183。 参考例 142  2-Amino-4-methoxybenzo-tolyl was reacted with N-chlorosuccinimide in dichloroethane at room temperature for 17 hours to obtain 2-amino-5-chloro-4-methoxybenzo-tolyl. ES: 183. Reference example 142
ジメチル 2-フルォロ- 5-ニトロテレフタルラートのメタノール- THF混合溶液に tert- ブトキシカリウムを 0°Cでカ卩えた後、 50°Cで 3時間反応させ、ジメチル 2-メトキシ -5-二 トロテレフタラートを得た。 ES： 270  Potassium tert-butoxide was added to a solution of dimethyl 2-fluoro-5-nitroterephthalate in methanol-THF at 0 ° C, and then reacted at 50 ° C for 3 hours. I got a tarat. ES: 270
参考例 143  Reference Example 143
ジメチル 2-メトキシ- 5-ニトロテレフタラートを EtOH- THF混合溶媒中、 10%パラジ ゥム-炭素存在下、水素雰囲気下、室温で攪拌してジメチル 2-ァミノ- 5-メトキシテレ フタラートを得た。 ES： 240  Dimethyl 2-methoxy-5-nitroterephthalate was stirred in a mixed solvent of EtOH-THF in the presence of 10% palladium-carbon under a hydrogen atmosphere at room temperature to obtain dimethyl 2-amino-5-methoxyterephthalate. ES: 240
参考例 144  Reference Example 144
メチル 6-メトキシ- 2,4-ジォキソ -1,2, 3,4-テトラヒドロキナゾリン- 7-カルボキシラート をトルエン中トリプロピルアミン存在下ォキシ塩化リンと 100°Cで 3日間反応させ、メチ ル 2,4-ジクロロ- 6-メトキシキナゾリン- 7-カルボキシラートを得た。  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.
参考例 145  Reference Example 145
4,5-ジフルォロ- 2-ニトロベンゼンカルボン酸を用いて参考例 142と同様の操作を 行い、 4-フルォ口- 5-メトキシ- 2-ニトロ安息香酸を得た。 FN:215。  The same operation as in Reference Example 142 was performed using 4,5-difluoro-2-nitrobenzenecarboxylic acid to obtain 4-fluoro-5-methoxy-2-nitrobenzoic acid. FN: 215.
[0048] 参考例 146 Reference Example 146
4-フルォ口- 5-メトキシ- 2-ニトロベンゼンカルボン酸の DMF溶液に、炭酸アンモ-ゥ ム、 HOBt、 WSC塩酸塩を加え、室温下 14時間反応させ、 4-フルォ口- 5-メトキシ -2- ニトロベンゼンアミドを得た。 FN:214。  To a DMF solution of 4-fluoro-5-methoxy-2-nitrobenzenecarboxylic acid was added ammonium carbonate, HOBt, and WSC hydrochloride, and the mixture was reacted at room temperature for 14 hours to give 4-fluoro-5-methoxy-2. -Nitrobenzene amide was obtained. FN: 214.
参考例 147  Reference Example 147
2-ァミノ- 4-フルォ口- 5-メトキシベンズアミドを N,N，-ジメチルイミダゾリジノン (DMI) 中、炭酸ジフエ-ルと 150°Cで 3.5時間反応させ、 7-フルォ口- 6-メトキシキナゾリン - 2,4(1H,3H)-ジオンを得た。 FN: 209。  2-Amino-4-fluoro-5-methoxybenzamide is reacted with diphenyl carbonate in N, N, -dimethylimidazolidinone (DMI) at 150 ° C for 3.5 hours to give 7-fluoro-6-methoxy Quinazoline-2,4 (1H, 3H) -dione was obtained. FN: 209.
参考例 148  Reference Example 148
2,5-ジブロモ- 4-クロロア-リンを DMI中、 160°Cでシアン化銅 (I)と 8時間反応させ、 2-ァミノ- 5-クロロテレフタ口-トリルを得た。 FN : 176。 2,5-dibromo-4-chloroa-line was reacted with copper (I) cyanide at 160 ° C for 8 hours in DMI, 2-Amino-5-chloroterephthalate mouth-tolyl was obtained. FN: 176.
参考例 149 Reference Example 149
ェチル [(6_フルォロ- 2,4-ジォキソ -1,2,3,4-テトラヒドロキナゾリン- 7_ィル)チォ]ァ セタート、ォキシ塩化リン、 N, Ν,-ジェチルァ-リンの混合物を 1時間加熱還流し、ェ チル [(2,4-ジクロロ- 6-フルォロキナゾリン- 7-ィル)チォ]ァセタートを得た。 NMR1 : 3.87 (2Η, s), 4.25 (2Η, q, J=7.2 Hz), 7.77-7.80 (1H, m)  Ethyl [(6_fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7_yl) thio] acetate, phosphorus oxychloride, N, Ν, The mixture was heated under reflux for an hour to obtain ethyl [(2,4-dichloro-6-fluoroquinazoline-7-yl) thio] acetate. NMR1: 3.87 (2Η, s), 4.25 (2Η, q, J = 7.2 Hz), 7.77-7.80 (1H, m)
参考例 150 Reference Example 150
[1,3]ジォキソロ [4,5-g]キナゾリン- 6,8(5H,7H)-ジオンを、フエ-ルホスホン酸ジクロリ ドと 185°Cで 15時間反応させ、 6,8-ジクロロ [1,3]ジォキソロ [4,5-g]キナゾリンを得た。 EI : 242。  [1,3] Dioxolo [4,5-g] quinazoline-6,8 (5H, 7H) -dione is reacted with phenylphosphonic acid dichloride at 185 ° C for 15 hours to give 6,8-dichloro [1 [4,5-g] quinazoline was obtained. EI: 242.
参考例 151 Reference Example 151
6-クロ口- 2,4-ジォキソ -1,2,3,4-テトラヒドロキナゾリン- 7-カルボ-トリルを用いて参 考例 149と同様の操作を行い、 2,4,6-トリクロ口キナゾリン- 7-カルボ-トリルを得た。こ の化合物と 4-クロ口- 2-フルォロア-リンを用いて参考例 127と同様の操作を行い、 2,6-ジクロロ- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]キナゾリン- 7-カルボ-トリルを 得た。 ESN: 365。  The same operation as in Reference Example 149 was performed using 6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carbo-tolyl to give 2,4,6-trichloroquinazoline. -7-Carbo-tolyl is obtained. The same operation as in Reference Example 127 was carried out using this compound and 4-chloro-2-fluoroaline to give 2,6-dichloro-4-[(4-chloro-2-fluorophenyl) amino] Quinazoline-7-carbo-tolyl was obtained. ESN: 365.
参考例 152 Reference Example 152
2,4-ジォキソ -1,2,3,4-テトラヒドロキナゾリン- 6-カルボキサミドを用いて参考例 8と同 様の操作を行い、 2,4-ジクロロキナゾリン- 6-カルボ-トリルを得た。 FN: 223。  The same operation as in Reference Example 8 was carried out using 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxamide to obtain 2,4-dichloroquinazoline-6-carbo-tolyl. FN: 223.
参考例 153 Reference Example 153
2-ァミノ- 4- (メチルスルホ -ル)安息香酸をメタノール中、硫酸存在下 3日間加熱還 流してメチル 2-ァミノ- 4- (メチルスルホ -ル)ベンゾエートを得た。この化合物を用い て参考例 3と同様にして、 7- (メチルスルホ -ル)キナゾリン- 2,4(1H,3H)_ジオンを得た 。 ESN: 239  2-Amino-4- (methylsulfol) benzoic acid was heated and refluxed in methanol in the presence of sulfuric acid for 3 days to obtain methyl 2-amino-4- (methylsulfol) benzoate. In the same manner as in Reference Example 3 using this compound, 7- (methylsulfol) quinazoline-2,4 (1H, 3H) _dione was obtained. ESN: 239
参考例 154 Reference Example 154
7- (メチルスルホ -ル)キナゾリン- 2,4(1H,3H)-ジオン用いて参考例 8と同様にして 2,4-ジクロロ- 7- (メチルスルホ -ル)キナゾリンを得、更に参考例 18の方法と同様にし て、 2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-7- (メチルスルホ -ル)キナゾリン- 4-ァ ミンを得た。 ES: 387 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. In the same manner as in the method, 2-chloro-N- (4-chloro-2-fluorophenyl) -7- (methylsulfol) quinazoline-4-a Got Min. ES: 387
参考例 155 Reference Example 155
2-クロ口- N- (4-クロ口- 2-フルオロフェニル )-8-メトキシキナゾリン- 4-アミンをトリフル ォロ酢酸中、濃硫酸存在下 N-プロモコハク酸イミドと室温下 2時間反応させ、 5-プロ モ- 2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-8-メトキシキナゾリン- 4-アミンを得た。 ES： 416, 418。  The 2-chloro-N- (4-chloro-2-fluorophenyl) -8-methoxyquinazolin-4-amine was reacted with N-bromosuccinimide in trifluoroacetic acid in the presence of concentrated sulfuric acid for 2 hours at room temperature. This gave 5-promo-2-chloro-N- (4-chloro-2-fluorophenyl) -8-methoxyquinazolin-4-amine. ES: 416, 418.
参考例 156 Reference Example 156
2-クロ口- N- (4-クロ口- 2-フルオロフェニル )-8-メトキシキナゾリン- 4-アミンをジクロ口 メタン中、氷冷下三臭化ホウ素と反応させ、 2-クロ口- 4-[(4-クロ口- 2-フルオロフェ- ル)ァミノ]キナゾリン- 8-オールを得た。 ES： 324  2-Chloro-N- (4-Chloro-2-fluorophenyl) -8-methoxyquinazoline-4-amine is reacted with boron tribromide in dichroic methane under ice-cooling. -[(4-Chloro-2-fluorophenyl) amino] quinazolin-8-ol was obtained. ES: 324
参考例 157 Reference Example 157
2-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]キナゾリン- 8-オールを DMF中、 炭酸カリウム存在下、プロモアセトニトリルと 80°Cで 2日間反応させ、（{2-クロ口- 4-[(4- クロ口- 2-フルオロフェ -ル)ァミノ]キナゾリン- 8-ィル }ォキシ)ァセトニトリルを得た。 F： 363  2-chloro-4-[(4-chloro-2-fluorophenyl) amino] quinazolin-8-ol was reacted with bromoacetonitrile at 80 ° C for 2 days in the presence of potassium carbonate in DMF, and ({ 2-chloro-4-[[4-chloro-2-fluorophenyl) amino] quinazoline-8-yl} oxy) acetonitrile was obtained. F: 363
参考例 158 Reference Example 158
5-ブロモ -2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-8-メトキシキナゾリン- 4-ァミン を DMF中シアン化銅 (I)と 85°Cで 3時間反応させ、 2-クロ口- 4-[(4-クロ口- 2-フルオロフ ェ -ル)ァミノ] -8-メトキシキナゾリン- 5-カルボ-トリルを得た。 ESN: 361  5-bromo-2-chloro-N- (4-chloro-2-fluorophenyl) -8-methoxyquinazoline-4-amine was reacted with copper (I) cyanide in DMF at 85 ° C for 3 hours. , 2-chloro-4-[[4-chloro-2-fluorophenyl) amino] -8-methoxyquinazoline-5-carbo-tolyl was obtained. ESN: 361
参考例 159 Reference Example 159
メチル 2,4-ジクロロ- 6-メトキシキナゾリン- 7-カルボキシラートのメタノール- THF混 合溶液に 1M水酸化ナトリウム水溶液を加え、室温下 22時間反応させ、 2-クロ口 -4-[(4-クロ口- 2-フルオロフェ -ル)ァミノ] -6-メトキシキナゾリン- 7-カルボン酸を得た 。この化合物の THF溶液に塩ィ匕ォキザリル、 DMFを加え室温で 5時間攪拌した。反応 液を濃縮した後、飽和アンモニア水溶液へ加え、 2-クロ口- 4-[(4-クロ口- 2-フルオロフ ェ -ル)ァミノ] -6-メトキシキナゾリン- 7-カルボキサミドを得た。 ES： 381  To a mixed solution of methyl 2,4-dichloro-6-methoxyquinazoline-7-carboxylate in methanol-THF was added 1M aqueous sodium hydroxide solution, and the mixture was reacted at room temperature for 22 hours. 2-Port 2-fluorophenyl) amino] -6-methoxyquinazoline-7-carboxylic acid was obtained. To a THF solution of this compound was added Shiojiroxalil and DMF, and the mixture was stirred at room temperature for 5 hours. After the reaction solution was concentrated, the solution was added to a saturated aqueous ammonia solution to obtain 2-chloro-4-[(4-chloro-2-fluorophenyl) amino] -6-methoxyquinazoline-7-carboxamide. ES: 381
参考例 160 Reference Example 160
2-クロ口- 4-[(4-クロ口- 2-フルオロフェ -ル)ァミノ] -6-メトキシキナゾリン- 7-カルボキ サミド、 DIPEAの THF溶液にトリフルォロ酢酸無水物を- 20°Cでカ卩えた後、 0°Cで 17時 間反応させ、 2-クロ口- 4-[(4-クロ口- 2-フルオロフェ -ル)ァミノ] -6-メトキシキナゾリン -7-カルボ-トリルを得た。 ES： 363 2-black mouth-4-[(4-black mouth-2-fluorophenyl) amino] -6-methoxyquinazoline-7-carboxy Trifluoroacetic anhydride is added to a THF solution of samide and DIPEA at −20 ° C., and the mixture is reacted at 0 ° C. for 17 hours to obtain 2-chloro-4-([4-chloro-2-fluorophen- Ru) amino] -6-methoxyquinazoline-7-carbo-tolyl. ES: 363
参考例 161 Reference Example 161
2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-6-フルォロ- 7- (メチルスルファ -ル)キ ナゾリン- 4_アミンをジクロロメタン中、氷冷下、 m-クロ口過安息香酸で処理して、 2-ク ロロ- N- (4-クロ口- 2-フルオロフェ-ル )-6-フルォロ- 7- (メチルスルホ -ル)キナゾリン -4-ァミン並びに 2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-6-フルォロ- 7- (メチルス ルフィエル)キナゾリン- 4-アミンを得た。  2-chloro-N- (4-chloro-2-fluorophenyl) -6-fluoro-7- (methylsulfur) quinazoline-4_amine in dichloromethane under ice-cooling Treatment with benzoic acid yields 2-chloro-N- (4-chloro-2-fluorophenyl) -6-fluoro-7- (methylsulfol) quinazoline-4-amine and 2-chloro-N -(4-Chloro-2-fluorophenyl) -6-fluoro-7- (methylsulfiel) quinazolin-4-amine was obtained.
2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-6-フルォロ- 7- (メチルスルホ -ル)キナ ゾリン- 4-ァミン： NMR2: 2.95 (3H, s), 7.98 (1H, d, J=6 Hz), 10.46 (1H, s)。  2-chloro-N- (4-chloro-2-fluorophenyl) -6-fluoro-7- (methylsulfol) quinazoline-4-amine: NMR 2: 2.95 (3H, s), 7.98 (1H , d, J = 6 Hz), 10.46 (1H, s).
2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-6-フルォロ- 7- (メチルスルフィ -ル)キ ナゾリン- 4-ァミン： F: 404  2-chloro-N- (4-chloro-2-fluorophenyl) -6-fluoro-7- (methylsulfuryl) quinazoline-4-amine: F: 404
参考例 162 Reference Example 162
2, 4, 6-トリクロ口ピリミジン- 5-カルボキシアルデヒドと 2-ヒドラジノエタノールをトリエ チルァミン存在下メタノール中 4°Cで 18時間反応させ、 2-(4,6-ジクロロ- 1H-ピラゾ口 [3,4- d]ピリミジン- 1-ィル)エタノールを得た。 AP: 233。  2,4,6-Trichloropyrimidine-5-carboxaldehyde and 2-hydrazinoethanol are reacted in methanol at 4 ° C for 18 hours in the presence of triethylamine, and 2- (4,6-dichloro-1H-pyrazo-mouth [ 3,4-d] Pyrimidine-1-yl) ethanol was obtained. AP: 233.
参考例 163 Reference Example 163
4,6-ジクロロ- 1-イソプロピル- 1H-ピラゾ口 [3,4-d]ピリミジンを用いて参考例 15の方 法と同様に (但し、溶媒としてトルエン、添加剤としてテトラプチルアンモ-ゥムブロミド 用いて加熱還流下で 2.5日間反応させた）して、 6-クロ口- N- (4-クロ口- 2-フルオロフェ -ル) -1-イソプロピル- 1H-ピラゾ口 [3,4-d]ピリミジン- 4-アミンを得た。 F： 340。  4,6-Dichloro-1-isopropyl-1H-pyrazo-mouth [3,4-d] pyrimidine was used in the same manner as in Reference Example 15 except that toluene was used as a solvent and tetrabutylammonium-bromobromide was used as an additive. And reacted under heating and reflux for 2.5 days) to give 6-chloro-N- (4-chloro-2-fluorophenyl) -1-isopropyl-1H-pyrazo [3,4-d] pyrimidine -The 4-amine was obtained. F: 340.
参考例 164 Reference Example 164
2- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリミジン -1-ィル }エタノールを用いて参考例 25と同様にして、 6-クロ口- N- (4-クロ口- 2-フルォ 口フエ-ル) -1-(2-フルォロェチル) -1H-ピラゾ口 [3,4-d]ピリミジン- 4-アミンを得た。 ES Reference example using 2- {6-clo mouth-4-[(4-clo mouth-2-fluorophenyl) amino] -1H-pyrazo mouth [3,4-d] pyrimidine-1-yl} ethanol In the same manner as in 25, 6-chloro-N- (4-chloro-2-fluoromethyl) -1- (2-fluoroethyl) -1H-pyrazo [3,4-d] pyrimidine-4 -You have an amine. ES
： 344 : 344
参考例 165 2- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリミジン -1-ィル }エタノールをジクロロメタン中、トリェチルァミン存在下、室温下メタンスルホ ユルク口リドと反応させ、 2- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピ ラゾロ [3,4-d]ピリミジン- 1-ィル }ェチル メタンスルホナートを得た。 ESN： 418。 Reference Example 165 2- {6-chloro mouth-4-[(4-chloro-2-fluorophenyl) amino] -1H-pyrazo [3,4-d] pyrimidine-1-yl} Ethanol in dichloromethane, triethylamine In the presence, at room temperature, is reacted with methanesulfo-yurukulide to give 2- {6-cloguchi-4-[(4-cloguchi-2-fluorophenyl) amino] -1H-pyrazolo [3,4-d] Pyrimidine-1-yl} ethyl methanesulfonate was obtained. ESN: 418.
参考例 166 Reference Example 166
2- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリミジン -1-ィル }工チル メタンスルホンナートを DMF中、シアン化ナトリウムと 55°Cで 13時間 反応させ、 3- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d] ピリミジン- 1-ィル }プロパン-トリルを得た。 ESN： 349  2- {6-chloro mouth-4-[(4-chloro mouth-2-fluorophenyl) amino] -1H-pyrazo mouth [3,4-d] pyrimidine-1-yl} The mixture was reacted with sodium cyanide in DMF at 55 ° C for 13 hours to give 3- {6-chloro-4-([4-chloro-2-fluorophenyl) amino] -1H-pyrazo [3,4 -d] pyrimidine-1-yl} propane-tolyl was obtained. ESN: 349
参考例 167 Reference Example 167
ェチル {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリ ミジン- 1-ィル }ァセタートを EtOH- THF混合溶媒中、 1M NaOH水溶液と室温下 22時 間反応させ、 6-クロ口- 4-[(4-クロ口- 2-フルオロフェ -ル)ァミノ] -1H-ピラゾ口 [3,4-d]ピ リミジン- 1-ィル }酢酸を得た。 ES: 356。  Ethyl {6-chloro mouth-4-[(4-chloro mouth-2-fluorophenyl) amino] -1H-pyrazo mouth [3,4-d] pyrimidin-1-yl} acetate mixed with EtOH-THF Reaction with a 1M aqueous solution of NaOH in a solvent at room temperature for 22 hours yields 6-chloro-4-[(4-chloro-2-fluorophenyl) amino] -1H-pyrazo [3,4-d] pi Limidine-1-yl} acetic acid was obtained. ES: 356.
参考例 168 Reference Example 168
{6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリミジン- 1- ィル }酢酸の THF溶液に WSC塩酸塩及び炭酸アンモニゥムをカ卩え、室温下 14時間反 応させ、 2- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリ ミジン- 1-ィル }ァセトアミドを得た。 ESN： 353。  {6-chloro-4-4-[(4-chloro-2-fluorophenyl) amino] -1H-pyrazo [3,4-d] pyrimidine-1-yl} WSC hydrochloride in THF solution of acetic acid And ammonium carbonate were reacted at room temperature for 14 hours to give 2- {6-chloro-4-([4-chloro-2-fluorophenyl) amino] -1H-pyrazo [3,4 -d] pyrimidine-1-yl} acetoamide was obtained. ESN: 353.
参考例 169 Reference Example 169
2- {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリミジン -1-ィル }ァセトアミドをピリジン中、室温下トリフルォロ酢酸無水物と 7時間反応させ、 {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1H-ピラゾ口 [3,4- d]ピリミジン- 1- ィル }ァセトニトリルを得た。 ES： 337。  2- {6-clo mouth-4-[(4-clo-2-2-fluorophenyl) amino] -1H-pyrazo [3,4-d] pyrimidine-1-yl} acetoamide in pyridine at room temperature The reaction was carried out for 7 hours with trifluoroacetic anhydride under the following conditions, and {6-clo-4-4-[(4-clo-2-2-fluorophenyl) amino] -1H-pyrazo [3,4-d] pyrimidine-1- I have obtained acetonitrile. ES: 337.
参考例 170 Reference Example 170
臭化シアンのジクロロメタン溶液に、氷冷下ェチルヒドラジンと炭酸ナトリウムの水溶 液を滴下した後に 3時間反応させ、 1-シァノ - 1-ェチルヒドラジンを得た。 NMR1： 1.27 (3H, t, J=7.2 Hz), 3.22 (2H, q, J=7.2 Hz), 4.02 (2H, brs)。 参考例 171 An aqueous solution of ethyl hydrazine and sodium carbonate was added dropwise to a dichloromethane solution of cyanogen bromide under ice cooling, and the mixture was reacted for 3 hours to obtain 1-cyano-1-ethyl hydrazine. NMR1: 1.27 (3H, t, J = 7.2 Hz), 3.22 (2H, q, J = 7.2 Hz), 4.02 (2H, brs). Reference Example 171
ェチル 4-メチル -3-ォキソペンタノエートと 1-シァノ -1-ェチルヒドラジンの混合物 を 60°Cで 5日間反応させた後、反応液に室温下クロ口ホルム、無水硫酸マグネシウム を加えた。不溶物を濾過した後濾液の溶媒を留去して得られた残渣に EtOH、水酸 ィ匕カリウムを加え、室温下 4日間反応させ、ェチル 5-ァミノ- 1-ェチル -3-イソプロピ ル -1H-ピラゾール- 4-カルボキシラートを得た。 ES： 226  After reacting a mixture of ethyl 4-methyl-3-oxopentanoate and 1-cyano-1-ethylhydrazine at 60 ° C for 5 days, add chloroform and anhydrous magnesium sulfate to the reaction mixture at room temperature. Was. After filtration of the insoluble matter, the solvent of the filtrate was distilled off, and EtOH and potassium hydroxide were added to the residue obtained.The mixture was reacted at room temperature for 4 days, and ethyl 5-amino-1-ethyl-3-isopropyl- 1H-Pyrazole-4-carboxylate was obtained. ES: 226
参考例 172 Reference Example 172
tert-ブチル 3-エトキシカルボニル- 1,4'-ビピペリジン- 1'-カルボキシラートの THF 溶液にリチウムジイソプロピルアミド (LDA)を- 78°Cでカ卩ぇ 30分間攪拌した後ヨウ化メチ ルを加え、氷冷下 8時間反応させ、 tert-ブチル 3-エトキシカルボ-ル -3-メチル -1,4'-ビピペリジン- 1'-カルボキシラートを得た。 ES： 355  Lithium diisopropylamide (LDA) was stirred in a THF solution of tert-butyl 3-ethoxycarbonyl-1,4'-bipiperidine-1'-carboxylate at -78 ° C for 30 minutes, and then methyl iodide was added. The mixture was reacted for 8 hours under ice cooling to obtain tert-butyl 3-ethoxycarbol-3-methyl-1,4'-bipiperidine-1'-carboxylate. ES: 355
参考例 173 Reference Example 173
tert-ブチル 3-エトキシカルボニル- 3-メチル -1 ,4'-ビピペリジン- 1 '-カルボキシラ ートを THF中、氷冷下水素化リチウムアルミニウムと反応させ、 tert-ブチル 3- (ヒドロ キシメチル) -3-メチル -1,4'-ビピペリジン- 1'-カルボキシラートを得た。 ES: 313 参考例 174  tert-Butyl 3-ethoxycarbonyl-3-methyl-1,4'-bipiperidine-1'-carboxylate is reacted with lithium aluminum hydride in THF under ice-cooling to give tert-butyl 3- (hydroxymethyl) 3-Methyl-1,4'-bipiperidine-1'-carboxylate was obtained. ES: 313 Reference example 174
ベンジル 4-ォキソピペリジン- 1-カルボキシラートと tert-ブチル （2-アミノエチル） 力ルバマートのジクロロエタン溶液に、氷冷下、トリァセトキシ水素化ホウ素ナトリウム を加え、室温で 18時間反応させ、ベンジル 4-({2-[(tert-ブトキシカルボニル)ァミノ] ェチル }ァミノ)ピぺリジン- 1-カルボキシラートを得た。 F: 378。  Sodium triacetoxyborohydride was added to a solution of benzyl 4-oxopiperidine-1-carboxylate and tert-butyl (2-aminoethyl) dirubane in dichloroethane under ice-cooling, and the mixture was reacted at room temperature for 18 hours. ({2-[(tert-Butoxycarbonyl) amino] ethyl} amino) piperidine-1-carboxylate was obtained. F: 378.
参考例 175 Reference Example 175
ベンジル 4-({2-[(tert-ブトキシカルボ-ル)ァミノ]ェチル }ァミノ)ピぺリジン- 1-カル ボキシラートをジクロロェタン中、トリェチルァミン存在下、氷冷下クロロアセチルクロリ ドと反応させ、ベンジル [{2-[(tert-ブトキシカルボ-ル)ァミノ]ェチル }(クロロアセチル )ァミノ]ピぺリジン- 1-カルボキシラートを得た。この化合物を DMF中、水素化ナトリウ ムと、 80°Cで 15時間反応させ、 tert-ブチル 4-{1- [(ベンジルォキシ)カルボ-ル]ピぺ リジン- 4_ィル }_3_ォキソピペラジン- 1-カルボキシラートを得た。この化合物用いて参 考例 30と同様の操作を行い、ベンジル 4-(2-ォキソピペラジン- 1-ィル)ピぺリジン -1-カルボキシラートを得た。この化合物とホルムアルデヒド水溶液、ジクロロェタンの 混合物を、室温下トリァセトキシ水素化ホウ素ナトリウムと反応させ、ベンジル 4-(4-メ チル- 2-ォキソピペラジン- 1-ィル)ピぺリジン- 1-カルボキシラートを得た。 F: 332。 参考例 176 Benzyl 4-({2-[(tert-butoxycarbol) amino] ethyl} amino) piperidine-1-carboxylate is reacted with chloroacetyl chloride in dichloroethane in the presence of triethylamine under ice-cooling. [{2-[(tert-Butoxycarbol) amino] ethyl} (chloroacetyl) amino] piperidine-1-carboxylate was obtained. This compound was reacted with sodium hydride in DMF at 80 ° C for 15 hours to obtain tert-butyl 4- {1-[(benzyloxy) carbol] pyridine-4-yl} _3_oxo. Piperazine-1-carboxylate was obtained. Using this compound, the same operation as in Reference Example 30 was carried out to give benzyl 4- (2-oxopiperazine-1-yl) piperidine. 1-carboxylate was obtained. A mixture of this compound, an aqueous formaldehyde solution and dichloroethane is reacted with sodium triacetoxyborohydride at room temperature to give benzyl 4- (4-methyl-2-oxopiperazine-1-yl) piperidine-1-carboxylate. Got. F: 332. Reference Example 176
tert-ブチル 4-アミノピペリジン- 1-カルボキシラートをエタノール中、ビニルスルホ ンと 0°Cから室温で 18時間反応させ、 tert-ブチル 4-(1,1-ジォキシドチオモルホリン -4-ィル)ピぺリジン- 1-カルボキシラートを得た。 F： 319。  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.
参考例 177 Reference Example 177
tert-ブチル 4-(1 , 1-ジォキシドチオモルホリン- 4-ィル)ピぺリジン- 1-カルボキシラ ートを THF中、 - 78°Cで LDAと 10分間反応させ、更にギ酸ェチルと- 78°Cから 5°Cで 5 時間反応させて、 tert-ブチル 4-(2-ホルミル- 1,1-ジォキシドチオモルホリン- 4-ィル )ピペリジン- 1-カルボキシラートを得た。 FN： 345。  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.
参考例 178 Reference Example 178
tert-ブチル 4-(2-ホルミル- 1,1-ジォキシドチオモルホリン- 4-ィル)ピぺリジン- 1- カルボキシラートをメタノール中、水素化ホウ素ナトリウムと 0°Cから 10°Cで 4時間反応 させ、 tert-ブチル 4-[2- (ヒドロキシメチル) -1,1-ジォキシドチオモルホリン- 4-ィル]ピ ペリジン- 1-カルボキシラートを得た。 F: 349。  tert-Butyl 4- (2-formyl-1,1-dioxidethiomorpholine-4-yl) piperidine-1-carboxylate in methanol with sodium borohydride at 0 ° C to 10 ° C The reaction was carried out for 4 hours to obtain tert-butyl 4- [2- (hydroxymethyl) -1,1-dioxidethiomorpholin-4-yl] piperidine-1-carboxylate. F: 349.
参考例 179 Reference Example 179
6,7-ジメチル- 2- (メチルスルファ -ル)プテリジン- 4-オールをジクロロェタン中、トリ ェチルァミン存在下、メタンスルホユルク口リドと室温下ー晚反応させ、 6,7-ジメチル -2- (メチルチオ)プテリジン- 4-ィル メタンスルホナートを得た。この化合物と 2-クロ口 -4-フルォロア-リンを、エタノール中メタンスルホン酸存在下、 6時間反応加熱還流 させ、 N- (4-クロ口- 2-フルオロフェ-ル )-6, 7-ジメチル- 2- (メチルチオ)プテリジン- 4- アミンを得た。 F: 350。  6,7-Dimethyl-2- (methylsulfuryl) pteridin-4-ol is reacted with methanesulfuryl chloride in dichloroethane in the presence of triethylamine at room temperature to give 6,7-dimethyl-2- (methylthiophene). ) Pteridin-4-yl methanesulfonate was obtained. This compound was reacted with 2-chloro-4-fluorofluorin in ethanol in the presence of methanesulfonic acid for 6 hours under heating and reflux to give N- (4-chloro-2-fluorophenyl) -6,7-dimethyl. -2- (Methylthio) pteridin-4-amine was obtained. F: 350.
参考例 180 Reference Example 180
4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1,4'-ビピペリジン -1'-ィル]キナゾリン- 7-カルボン酸 (実施例 102)を用いて参考例 146と同様に (但し 、炭酸アンモ-ゥムの代わりにメトキシメチルァミン塩酸塩を用いた）して 4- [(4-クロ口 -2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1 ,4'-ビピペリジン- 1しィル] -N- メトキシ- N-メチルキナゾリン- 7-カルボキサミドを得た。 ES: 557 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidine-1'-yl] quinazoline-7-carboxylic acid (Example 102) and the same procedure as in Reference Example 146 (however, methoxymethylamine hydrochloride was used in place of ammonium carbonate) to give 4-[(4-chlorophenol 2-Fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidine-1-yl] -N-methoxy-N-methylquinazoline-7-carboxamide was obtained. ES: 557
[0055] 参考例 181 [0055] Reference Example 181
6-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-1-ェチル -3- (メトキシメチル)- 1H-ピラ ゾロ [3,4-d]ピリミジン 4ーァミンにジクロロメタン中、氷冷下、三臭化ホウ素を反応させ て、 {6-クロ口- 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 1-ェチル -1H-ピラゾ口 [3,4- d] ピリミジン- 3-ィル }メタノールを得た。 ES: 356  6-chloro-N- (4-chloro-2-fluorophenyl) -1-ethyl-3- (methoxymethyl) -1H-pyrazolo [3,4-d] pyrimidine 4-amine in dichloromethane in ice Under cooling, boron tribromide is reacted to give {6-chloro-4-4-[(4-chloro-2-fluorophenyl) amino] -1-ethyl-1H-pyrazo [3,4-d Pyrimidine-3-yl} methanol was obtained. ES: 356
参考例 182— 272  Reference example 182—272
参考例 133の方法と同様にして参考例 182の化合物を、参考例 138の方法と同様 にして参考例 183の化合物を、参考例 171の方法と同様にして参考例 184— 186の 化合物を、参考例 3の方法と同様にして参考例 187— 193の化合物を、参考例 7の 方法と同様にして参考例 194一 197の化合物を、参考例 139の方法と同様にして参 考例 198— 201の化合物を、参考例 147の方法と同様にして参考例 202の化合物 を、参考例 8の方法と同様にして参考例 203— 207の化合物を、参考例 149の方法 と同様にして参考例 208— 212の化合物を、参考例 144の方法と同様にして参考例 213— 215の化合物、参考例 216の化合物（但し塩基は DIPEA)を、参考例 162の 方法と同様にして参考例 217— 221の化合物を、参考例 15の方法と同様にして参 考例 222の化合物、参考例 223の化合物（但し溶媒は 1,2-ジクロロエタン）、参考例 2 24— 225の化合物（但し溶媒は THF-ァセトニトリル)を、参考例 127の方法と同様に して参考例 226— 228、 256— 261のィ匕合物を、参考例 18の方法と同様にして参考 例 229— 255の化合物を、参考例 155の方法と同様にして参考例 262の化合物を、 参考例 158の方法と同様にして参考例 263の化合物を、参考例 163の方法と同様に して参考例 264の化合物を、参考例 22の方法と同様にして参考例 265— 266の化 合物を、参考例 30の方法と同様にして参考例 267— 271の化合物を、参考例 29の 方法と同様にして参考例 272の化合物を、それぞれ対応する原料を使用して製造し た。参考例 182— 272の化合物の構造及び物理ィ匕学的データを表 7— 14にそれぞ れ示す。  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. In the same manner as in the method of Reference Example 18, the compound of Reference Example 229-255, the compound of Reference Example 262 in the same manner as in the method of Reference Example 155, and the compound of Reference Example 263 in the same manner as in the method of Reference Example 158 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.
[0056] 実施例 1 2-クロ口- N- (4-クロ口フエ-ル)- 6-フルォロキナゾリン- 4-ァミン 1.20 gのジォキサン 50 ml溶液に（3S)-1,4，-ビピペリジン- 3-ィルメタノール 2塩酸塩 1.10 g及び DBU 1.82 mlを順次加え、 90°Cで 3日間攪拌した。反応液を室温まで降温し、溶媒を留去 して得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロ口ホルムで抽出した。 有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。 得られた残渣をシリカゲルカラムクロマトグラフィー (クロ口ホルム-メタノール- 28%アン モ-ァ水)で精製し、（(3S)- 1'- {4- [(4-クロ口フエ-ル)ァミノ]- 6-フルォロキナゾリン- 2- ィル }-1, 4'-ビピペリジン- 3-ィル)メタノールを淡黄色結晶として得た。この化合物をメ タノール 30 ml及び THF 15 mlに溶解し、 4M塩化水素-酢酸ェチル溶液 4.0 mlを 加えて塩酸塩とした後、溶媒を留去した。得られた粗結晶をエタノール力 再結晶し て、（(3S)-1し {4- [(4-クロ口フエ-ル)ァミノ]- 6-フルォロキナゾリン- 2-ィル }- 1,4'-ビピぺ リジン- 3-ィル)メタノール 2塩酸塩 1.22 gを微黄色結晶として得た。 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. The resulting residue was purified by silica gel column chromatography (form-form-methanol-28% aqueous ammonia) to give ((3S) -1 ′-{4-[(4-form mouth phenol) amino ]-6-Fluoroquinazolin-2-yl} -1,4'-bipiperidin-3-yl) methanol was obtained as pale yellow crystals. This compound was dissolved in 30 ml of methanol and 15 ml of THF, and 4.0 ml of a 4M hydrogen chloride-ethyl acetate solution was added to form a hydrochloride. Then, the solvent was distilled off. The obtained crude crystals were recrystallized from ethanol to give ((3S) -1 and {4-[(4-chlorophenol) amino] -6-fluoroquinazoline-2-yl} -1 1.22 g of 4,4'-bipiperidin-3-yl) methanol dihydrochloride was obtained as pale yellow crystals.
実施例 2 Example 2
(2-クロ口- 6,7-ジメトキシ-キナゾリン- 4-ィル) -[2- (4-フルオロフェ -ル)ェチル]ァミン 525 mgを用いて実施例 1の方法と同様に（但し、溶媒として n-ブタノールを用いて 110 °Cで 3日間反応させた）して、（1'-{4-[2-(4-フルォロ-フエ-ル)-ェチルァミノ] -6,7-ジ メトキシ-キナゾリン- 2-ィル }-1,4'-ビピペリジン- 3-ィル) -メタノール 2塩酸塩 170 mg を白色結晶として得た。  (2-chloro opening-6,7-dimethoxy-quinazoline-4-yl)-[2- (4-fluorophenyl) ethyl] amine (525 mg) was used in the same manner as in Example 1 except that the solvent was (1 '-{4- [2- (4-fluoro-phenyl) -ethylamino] -6,7-dimethoxy-) 170 mg of quinazoline-2-yl} -1,4'-bipiperidin-3-yl) -methanol dihydrochloride was obtained as white crystals.
実施例 3 Example 3
2-クロ口- N- (4-クロ口フエ-ル)- 6,7-ジメトキシキナゾリン- 4-ァミン塩酸塩 940 mgを 用いて、実施例 1の方法と同様に（但し、溶媒として n-ブタノール 50 ml、塩基として DBUの代わりに DIPEA 900 mgを用いて 110°Cで反応させた）して、（(3S)-l'-{4-[(4-ク ロロフエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピペリジン- 3-ィル)メタ ノール 2塩酸塩 510 mgを無色結晶として得た。  Using 940 mg of 2-chloro-N- (4-chlorophenol) -6,7-dimethoxyquinazoline-4-amine hydrochloride in the same manner as in Example 1, except that n- The reaction was carried out at 110 ° C using 50 ml of butanol and 900 mg of DIPEA instead of DBU as a base), and then ((3S) -l '-{4-[(4-chlorophenyl) amino]- 510 mg of 6,7-dimethoxyquinazoline-2-yl} -1,4-bipiperidin-3-yl) methanol dihydrochloride was obtained as colorless crystals.
実施例 4 Example 4
2-クロ口- N-シクロへプチル- 6,7-ジメトキシキナゾリン- 4-ァミン 1.01 gを用いて、実 施例 1の方法と同様に（但し、溶媒として n-ブタノール、ァミンとして 4-ピロリジン- 1-ィ ルビペリジンを 930 mg (2等量)用い、 DBUは用いずに 3時間加熱還流下反応させた )して、 N-シクロへプチル- 6,7-ジメトキシ -2- (4-ピロリジン- 1-ィルピペリジン- 1-ィル） キナゾリン- 4-ァミン 740 mgを淡黄色結晶として得た。 Using 1.01 g of 2-chloro-N-cycloheptyl-6,7-dimethoxyquinazoline-4-amine, in the same manner as in Example 1, except that n-butanol is used as the solvent and 4-pyrrolidine is used as the amine. Reaction was carried out under heating and refluxing for 3 hours using 930 mg (2 equivalents) of 1-ylbiperidine ) To give 740 mg of N-cycloheptyl-6,7-dimethoxy-2- (4-pyrrolidine-1-ylpiperidine-1-yl) quinazoline-4-amine as pale yellow crystals.
実施例 5 Example 5
(2-クロ口- 6,7-ジメトキシキナゾリン- 4-ィル) -(2,3,4-トリフルォロベンジル)ァミン 500 mgを用いて実施例 1の方法と同様に (但し、溶媒として DMF、塩基として DBUの代 わりに炭酸カリウム 540 mgを用いて 80。Cで 5日間反応させた）して、 {1'-[6,7-ジメトキ シ- 4-(2,3,4-トリフルォロベンジルァミノ)キナゾリン- 2-ィル] -1,4'-ビピペリジン- 3-ィ ル}メタノール 2塩酸塩 79 mgを白色結晶として得た。  (2-chloro-6,7-dimethoxyquinazoline-4-yl)-(2,3,4-trifluorobenzyl) amine in the same manner as in Example 1 using 500 mg (provided that the solvent DMF was reacted with 540 mg of potassium carbonate instead of DBU as the base for 80 days, and reacted at C for 5 days) to give {1 '-[6,7-dimethoxy-4- (2,3,4-trifluene). (Orobenzylamino) quinazoline-2-yl] -1,4'-bipiperidin-3-yl} methanol dihydrochloride 79 mg was obtained as white crystals.
実施例 6 Example 6
N- (4-クロ口フエ-ル)- 6,6-ジメチル- 2- (メチルスルフィ -ル) -5,6,7,8-テトラヒドロキ ナゾリン- 4-ァミン 300 mgを用いて、実施例 1の方法と同様に（但し、溶媒として 1,2- ジエトキシェタン 10 mlを用いて 140°Cで 1.5日間反応させた）して、（1'-{4-[(4-クロ口 フエ-ル)ァミノ] -6,6-ジメチル -5,6,7,8-テトラヒドロキナゾリン- 2-ィル }-1,4'-ビピペリ ジン- 3-ィル)メタノール 2塩酸塩 38 mgを微茶褐色結晶として得た。  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.
実施例 7 Example 7
2,4-ジクロロ- 6,7-ジメトキシキナゾリン 777mgと 3,4-ジフルォロア-リン 387 mgを用 いて前述の参考例 16と同様の操作を行って 2_クロ口- N_(3,4-ジフルオロフェ-ル )-6,7-ジメトキシキナゾリン- 4-ァミン塩酸塩の粗結晶 903 mgを得た。この化合物を用 いて実施例 3と同様にして、（1'-{4-[(3,4-ジフルオロフェ -ル)ァミノ] -6,7-ジメトキシキ ナゾリン- 2-ィル }-1,4'-ビピペリジン- 3-ィル)メタノール 2塩酸塩 513 mgを白色結晶と して得た。  Using 777 mg of 2,4-dichloro-6,7-dimethoxyquinazoline and 387 mg of 3,4-difluoroa-line, the same operation as in the above-mentioned Reference Example 16 was carried out to obtain 2_cloguchi-N_ (3,4-difluoro Thus, 903 mg of crude crystals of fer) -6,7-dimethoxyquinazoline-4-amine hydrochloride were obtained. Using this compound and in the same manner as in Example 3, (1 ′-{4-[(3,4-difluorophenyl) amino] -6,7-dimethoxyquinazolin-2-yl} -1,4 '-Bipiperidine-3-yl) methanol dihydrochloride (513 mg) was obtained as white crystals.
実施例 8 Example 8
2,4,6-トリクロ口キナゾリン 315 mgと 4-クロロア-リン 172 mgを用いて前述の参考例 15と同様の操作を行って、 2-クロ口- N- (4-クロ口フエ-ル)- 6-クロ口キナゾリン- 4-アミ ンの粗結晶 474 mgを得た。この化合物を用いて実施例 3と同様にして、（1'-{6-クロ口 -4-[(4-クロ口フエ-ル)ァミノ]キナゾリン- 2-ィル }-1,4しビピペリジン- 3-ィル)メタノール The same operation as in Reference Example 15 described above was performed using 315 mg of 2,4,6-trichloroquinazoline and 172 mg of 4-chloroaline to obtain 2-chloro-N- (4-chloromouth 474 mg of crude crystals of) -6-chloroquinazoline-4-amine were obtained. In the same manner as in Example 3 using this compound, (1 ′-{6-chloro-4-([4-chlorophenol) amino] quinazoline-2-yl} -1,4, bipiperidine -3-yl) methanol
2塩酸塩 244 mgを無色結晶として得た。 244 mg of dihydrochloride was obtained as colorless crystals.
実施例 9 2,4-ジクロロ- 6,7-ジメトキシキナゾリン 518mgと 2,4,6-トリフルォロア二リン 294 mgを 用いて前述の参考例 17と同様の操作を行い、 2-クロ口- N- (2,4,6-トリフルオロフェ- ル)- 6,7-ジメトキシキナゾリン- 4-ァミン塩酸塩の粗結晶 400 mgを得た。この化合物を 用いて実施例 3と同様にして、（1'- {4- [(2,4,6-トリフルオロフェ -ル)ァミノ]- 6,7-ジメト キシキナゾリン- 2-ィル }-1, 4'-ビピペリジン- 3-ィル)メタノール 2塩酸塩 225 mgを無色 結晶として得た。 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. In the same manner as in Example 3 using this compound, (1 ′-{4-[(2,4,6-trifluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} 225 mg of -1,4'-bipiperidin-3-yl) methanol dihydrochloride was obtained as colorless crystals.
実施例 10 Example 10
2,4-ジクロロ- 6,7-ジメトキシキナゾリンキナゾリン 500mg、 2,6-ジフルォロ- 4-ブロモ ァ-リン 401mg、を用いて前述の参考例 17と同様の操作を行い、粗製の 2-クロ口 -N- (4-ブロモ -2, 6-ジフルオロフェ-ル )-6,7-ジメトキシキナゾリン- 4-ァミン塩酸塩 1.24 gを得た。この内 1.10 gを用いて実施例 3と同様にして、 {1'-[4-(4-ブロモ -2,6- ジフルオロフェニルァミノ) -6,7-ジメトキシキナゾリン- 2-ィル] -1,4'-ビピペリジン- 3-ィ ル}メタノール 2塩酸塩 169mgを無色結晶として得た。  The same operation as in Reference Example 17 was performed using 500 mg of 2,4-dichloro-6,7-dimethoxyquinazoline quinazoline and 401 mg of 2,6-difluoro-4-bromofurin to obtain a crude 2-chloro 1.24 g of -N- (4-bromo-2,6-difluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride was obtained. {1 ′-[4- (4-Bromo-2,6-difluorophenylamino) -6,7-dimethoxyquinazoline-2-yl]- 169 mg of 1,4'-bipiperidin-3-yl} methanol dihydrochloride was obtained as colorless crystals.
実施例 11 Example 11
2,4-ジクロロ- 6-メチルキナゾリン 213 mgに 4-クロロア二リン 128 mgを加え、ェタノ ール 10 mlに溶解した。ェチルジイソプロピルアミン 0.21 mlを加え、 2時間還流した 。室温に冷却後、飽和炭酸水素ナトリウム水溶液を加え、クロ口ホルムで抽出し、有機 層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を留去し、 2-クロ 口- N- (4-クロ口フエ-ル) -6-メチルキナゾリン- 4-ァミンの粗生成物 358 mgを得た。こ の化合物を用いて実施例 3と同様にして、（1'-{4-[(4-クロ口フエニル)ァミノ] -6-メチル キナゾリン- 2-ィル }-1,4'-ビピペリジン- 3-ィル)メタノール 2塩酸塩 291 mgを無色結 晶として得た。  128 mg of 4-chloroaniline was added to 213 mg of 2,4-dichloro-6-methylquinazoline and dissolved in 10 ml of ethanol. 0.21 ml of ethyldiisopropylamine was added, and the mixture was refluxed for 2 hours. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 358 mg of a crude 2-chloro-N- (4-chlorophenol) -6-methylquinazoline-4-amine. In the same manner as in Example 3 using this compound, (1 '-{4-[(4-chlorophenyl) amino] -6-methylquinazoline-2-yl} -1,4'-bipiperidine- 291 mg of 3-yl) methanol dihydrochloride were obtained as colorless crystals.
実施例 12 Example 12
3- (シァノメチル)- 1,4'-ビピペリジン- 1'-カルボン酸べンジル 500 mgにパラジウム 炭素 50 mg、メタノール 15 mlを順次加え、水素雰囲気下室温にて 4時間撹拌した。反 応液をセライトで濾過し、溶媒を留去して、 3- (シァノメチル) -1,4'-ビピペリジン粗成生 物 273 mgを得た。この生成物を 1-ブタノール 15 mlに溶解し、 2-クロ口- N-(4-クロ口 フエ-ル)- 6,7-ジメトキシキナゾリン- 4-ァミン 564 mg、 DBU 889 mgをカ卩え、 110°Cで 2 日間撹拌した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロ口ホル ム /メタノール/ 28%アンモニア水）で精製後、クロ口ホルム/ジイソプロピルエーテル/へ キサンで固化させ、沈殿物を濾取して、（1'-{4-[(4-クロ口フエニル)ァミノ]- 6,7-ジメトキ シキナゾリン- 2-ィル }-1,4しビピペリジン- 3-ィル)ァセトニトリル 411 mgを得た。このう ちの 208 mgを酢酸ェチル 4 ml及びメタノール 4 mlに溶解し、氷冷下 4M塩化水素 -酢酸ェチル溶液 0.2 mlをカ卩え、溶媒を留去した後、残渣をメタノールより再結晶して 、（1し {4-[(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピベリジ ン -3-ィル)ァセトニトリル 2塩酸塩 125 mgを無色粉末として得た。 To 500 mg of benzyl 3- (cyanomethyl) -1,4′-bipiperidine-1′-carboxylate, 50 mg of palladium carbon and 15 ml of methanol were sequentially added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through celite, and the solvent was distilled off to obtain 273 mg of a crude product of 3- (cyanomethyl) -1,4'-bipiperidine. This product was dissolved in 15 ml of 1-butanol, and 564 mg of 2-chloro-N- (4-chlorophenol) -6,7-dimethoxyquinazoline-4-amine and 889 mg of DBU were added. At 110 ° C 2 Stirred for days. The solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform / methanol / 28% aqueous ammonia), solidified with chloroform / diisopropyl ether / hexane, and the precipitate was collected by filtration. 411 mg of (1 ′-{4-[(4-chlorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4-bipiperidin-3-yl) acetonitrile was obtained. 208 mg of this was dissolved in 4 ml of ethyl acetate and 4 ml of methanol, 0.2 ml of a 4M hydrogen chloride-ethyl acetate solution was removed under ice cooling, the solvent was distilled off, and the residue was recrystallized from methanol. , (1- {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4-shibipiberidin-3-yl) acetonitrile dihydrochloride 125 mg was obtained as a colorless powder.
実施例 13 Example 13
2,4,6,7-テトラクロ口キナゾリン 234 mgと 4-クロロア-リン 111 mgを用いて前述の参 考例 15と同様の操作を行って、 2-クロ口- N- (4-クロ口フエ-ル)- 6,7-ジクロロキナゾリ ン -4-ァミン 310 mgを得た。この化合物を用いて実施例 2と同様にして、（1'-{6,7-ジク ロロ- 4- [(4-クロ口フエ-ル)ァミノ]キナゾリ- 2-ニル}- 1,4'-ビピベリジ- 3-二ル)メタノー ル 2塩酸塩 303 mgを無色結晶として得た。  Using 234 mg of 2,4,6,7-tetracloquinoquinazoline and 111 mg of 4-chloroaline, the same operation as in Reference Example 15 was performed to obtain 2-clo-N- (4-clo 310 mg of (phenyl) -6,7-dichloroquinazolin-4-amine were obtained. In the same manner as in Example 2 using this compound, (1 ′-{6,7-dichloro-4-[(4-chlorophenol) amino] quinazoli-2-yl} -1,4 ′ -Bipiberidi-3-nil) methanol dihydrochloride 303 mg was obtained as colorless crystals.
実施例 14 Example 14
1-(1- {4- [(4-クロ口フエ-ル)ァミノ]- 6,7-ジメトキシキナゾリン- 2-ィル }ピペリジン- 4- ィル) -L-プロリンメチルエステル 370 mgのメタノール 10 ml溶液に 5M水酸化ナトリ ゥム水溶液 1.0 mlを加え、 50°Cで 12時間攪拌した。反応溶液を 1M塩酸で中和後、 溶媒を留去し、エタノールで抽出した。不溶物を濾去後、溶媒を留去し、得られた結 晶性残渣をエタノール-ジェチルエーテル混合溶媒で洗浄することにより、  1- (1- {4-[(4-chlorophenol) amino]-6,7-dimethoxyquinazoline-2-yl} piperidin-4-yl) -L-proline methyl ester 370 mg of methanol 1.0 ml of a 5 M aqueous sodium hydroxide solution was added to the 10 ml solution, and the mixture was stirred at 50 ° C for 12 hours. After neutralizing the reaction solution with 1M hydrochloric acid, the solvent was distilled off, and extracted with ethanol. After filtering off the insoluble matter, the solvent was distilled off, and the obtained crystalline residue was washed with a mixed solvent of ethanol and getyl ether to obtain a residue.
1-(1-{4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }ピペリジン- 4-ィ ル)- L-プロリン 2塩酸塩 300 mgを淡黄色結晶として得た。 300 mg of 1- (1- {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} piperidin-4-yl) -L-proline dihydrochloride Obtained as pale yellow crystals.
実施例 15 Example 15
(1し {4-[(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピベリジ ン -3-ィル)メタノール 400 mgのピリジン 10 ml溶液に無水酢酸 180 mg及び DMAP 12 mgをカ卩え、室温で 2時間撹拌した。溶媒を留去し、残渣をシリカゲルカラムクロマトグ ラフィー (クロ口ホルム-メタノール- 28%アンモニア水)で精製し、 (1し {4-[(4-クロ口フエ- ル)ァミノ] -6,7-ジメトキシキナゾリ- 2--ル}-1,4'-ビピベリジ- 3--ル)メチルアセテート 390 mgを無色結晶として得た。この化合物 172 mgを酢酸ェチル 3 mlに溶解し、 4M 塩酸-酢酸ェチル溶液 0.2 mlを加え、室温で 1時間撹拌した。溶媒を留去し、残渣を エーテルで洗浄して、酢酸（1 '-{4- [(4-クロ口フエ-ル)ァミノ]- 6,7-ジメトキシキナゾリ - 2-ニル}-1,4'-ビピベリジ- 3-ニル)メチル 2塩酸塩 194 mgを淡黄色結晶として得た。 実施例 16 (1- {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazolin-2-yl} -1,4-shibipiberidin-3-yl) methanol 400 mg pyridine 10 180 ml of acetic anhydride and 12 mg of DMAP were added to the ml solution and stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform-methanol-28% aqueous ammonia) to give (1-({4-[(4-chloromethyl) amino) -6,7 -Dimethoxyquinazoly-2-yl} -1,4'-bipiberidi-3-yl) methyl acetate 390 mg were obtained as colorless crystals. 172 mg of this compound was dissolved in 3 ml of ethyl acetate, 0.2 ml of a 4M hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. The solvent is distilled off, and the residue is washed with ether, and acetic acid (1 ′-{4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoly-2-yn} -1, 194 mg of 4'-bipiberidi-3-nyl) methyl dihydrochloride was obtained as pale yellow crystals. Example 16
1'- (4-クロ口- 6,7-ジメトキシキナゾリン- 2-ィル) -3- (メトキシメチル)- 1,4'-ビピベリジ ン 217 mg及び [2- (4-クロ口フエ-ル)ェチル]ァミン 93 mgの DMF溶液に DBU 114 mg を加え、室温で 2時間、 80°Cで 2時間、 100°Cで 18時間撹拌した。溶媒を留去し、残渣 をシリカゲルカラムクロマトグラフィー (クロ口ホルム-メタノール- 28%アンモニア水)で精 製し、 N- [2- (4-クロ口フエ-ル)ェチル ]-6, 7-ジメトキシ- 2- [3- (メトキシメチル)- 1,4'-ビ ピぺリジン- 1'-ィル]キナゾリン- 4_ァミン 125 mgを黄色の液体として得た。この化合物 を酢酸ェチル 5 mlに溶解し、 4M塩酸-酢酸ェチル溶液 0.15 mlを加え、室温で 1時間 撹拌した。溶媒を留去し、残渣を 2-プロパノールで再結晶して、 N-[2- (4-クロ口フエ- ル)ェチル ]-6,7-ジメトキシ -2-[3- (メトキシメチル) -1,4しビピペリジン- 1しィル]キナゾリ ン -4-ァミン 2塩酸塩 67 mgを無色結晶として得た。  1 '-(4-chloro-6,7-dimethoxyquinazoline-2-yl) -3- (methoxymethyl) -1,4'-bipiberidine 217 mg ) Ethyl] amine 93 mg of DMF was added to a DMF solution, and the mixture was stirred at room temperature for 2 hours, at 80 ° C for 2 hours, and at 100 ° C for 18 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform-methanol-28% aqueous ammonia) to give N- [2- (4-chlorophyll) ethyl] -6,7- 125 mg of dimethoxy-2- [3- (methoxymethyl) -1,4′-bipiperidine-1′-yl] quinazoline-4-amine was obtained as a yellow liquid. This compound was dissolved in 5 ml of ethyl acetate, 0.15 ml of a 4M hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was recrystallized from 2-propanol to give N- [2- (4-chlorophenol) ethyl] -6,7-dimethoxy-2- [3- (methoxymethyl)- 67 mg of 1,4-bipiperidine-1-yl] quinazoline-4-amine dihydrochloride was obtained as colorless crystals.
実施例 17 Example 17
ヒドラジン 1水和物 48 mgのエタノール 20 ml溶液に 2-[(1'-{4-[(4-クロ口フエ-ル） ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4'-ビピペリジン- 3-ィル)メチル ]-1Η-イソ インドール- 1,3(2H)-ジオン 320 mgをカ卩え、 4時間還流した。溶媒を留去し、残渣をメ タノールに溶解し、 4M塩ィ匕水素の酢酸ェチル溶液 0.5 mlをカ卩えた後、溶媒を留去し た。残渣にメタノール 5 mlをカ卩ぇ還流した後、室温で一晩撹拌し、固体を濾過後、溶 媒を留去し、残渣をエタノール力も再結晶して、 2-[3- (アミノメチル) -1,4'-ビピベリジ ン- 1'-ィル] -N- (4-クロ口フエ-ル)- 6,7-ジメトキシキナゾリン- 4-ァミン 2塩酸塩 182 mgを無色結晶として得た。  2-[(1 '-{4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} -1 in a solution of 48 mg of hydrazine monohydrate in 20 ml of ethanol , 4'-Bipiperidin-3-yl) methyl] -1Η-isoindole-1,3 (2H) -dione (320 mg) was added and refluxed for 4 hours. The solvent was distilled off, the residue was dissolved in methanol, and 0.5 ml of a 4 M solution of hydrogen chloride in ethyl acetate was removed, followed by distilling off the solvent. The residue was refluxed with methanol (5 ml), stirred at room temperature overnight, filtered through a solid, the solvent was distilled off, and the residue was recrystallized from ethanol to give 2- [3- (aminomethyl) [1,4'-Bipiberidin-1'-yl] -N- (4-chlorophenol) -6,7-dimethoxyquinazoline-4-amine dihydrochloride (182 mg) was obtained as colorless crystals.
実施例 18 Example 18
2-[(1し {4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピぺ リジン- 3-ィル)メチル ]-1Η-イソインドール- 1,3(2H)_ジオン 320 mgを用いて実施例 1 7と同様にして、 2- [3- (アミノメチル)- 1 ,4しビピペリジン- 1しィル] -N- (4-クロ口フエ-ル )-6,7-ジメトキシキナゾリン- 4-アミンを得た。この化合物をジクロロメタン 5 mlに溶解 し、無水酢酸 102 mg、ピリジン 79 mgをカ卩えた後、更にピリジン 1 mlをカ卩え、室温下 2 時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、室温下 2時間撹拌後、クロロホ ルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を留去し、シリカゲ ルカラムクロマトグラフィー（クロ口ホルム/メタノール/ 28%アンモニア水）にて精製し、 N-[(lし {4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピペリ ジン- 3-ィル)メチル]ァセトアミド 244 mgを淡黄色固体として得た。この化合物 240 mgを酢酸ェチル 5 ml及びメタノール 1 mlに溶解し、 4M塩化水素-酢酸ェチル溶液 0.5 mlをカ卩え、溶媒を留去し、残渣をエタノールより再結晶して、 N-[(l'-{4-[(4-クロ口 フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4'-ビピペリジン- 3-ィル)メチル] ァセトアミド 2塩酸塩 132 mgを無色結晶として得た。 2-[(1 し {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4 し bipiridin-3-yl) methyl ] -1Η-Isoindole-1,3 (2H) _dione, using 320 mg, in the same manner as in Example 17 to give 2- [3- (aminomethyl) -1,4 and bipiperidine-1yl] -N- (4-cloth mouth ) -6,7-Dimethoxyquinazolin-4-amine was 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. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (form-form / methanol / 28% aqueous ammonia) to give N-[(l and {4-[(4 244 mg of [-clo) phenyl] amino] -6,7-dimethoxyquinazoline-2-yl} -1,4 ^ bipiperidin-3-yl) methyl] acetoamide was obtained as a pale yellow solid. 240 mg of this compound was dissolved in 5 ml of ethyl acetate and 1 ml of methanol, 0.5 ml of a 4M hydrogen chloride-ethyl acetate solution was removed, the solvent was distilled off, and the residue was recrystallized from ethanol to give N-[( l '-{4-[(4-chlorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4'-bipiperidin-3-yl) methyl] acetamide dihydrochloride 132 mg were obtained as colorless crystals.
実施例 19 Example 19
2-[(1し {4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピぺ リジン- 3-ィル)メチル ]-1Η-イソインドール- 1,3(2H)_ジオン 320 mgを用いて実施例 1 7と同様にして、 2- [3- (アミノメチル)- 1 ,4しビピペリジン- 1しィル] -N- (4-クロ口フエ-ル )-6,7_ジメトキシキナゾリン- 4_アミンを得た。この化合物をジクロロメタン 10 mlに溶解 し、氷冷下メタンスルホユルクロリド 114 mg及びトリェチルァミン 1 mlを加え、氷冷下 2時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、室温下 2時間撹拌後、クロ口 ホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を留去し、シリカ ゲルカラムクロマトグラフィー（クロ口ホルム/メタノール/ 28%アンモニア水）で精製し、 残渣にジイソプロピルエーテルを加えて固化させ、沈殿物を濾取、乾燥して、 N-[(lし {4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピペリ ジン- 3-ィル)メチル]メタンスルホンアミド 257 mgを淡黄色固体として得た。この化合 物 253 mgを酢酸ェチル 5 ml及びメタノール 1 mlに溶解し、 4M塩化水素-酢酸ェ チル溶液 0.5 mlを加えた後、溶媒を留去し、残渣をメタノールより再結晶して、 N-[(lし {4- [(4-クロ口フエ-ル)ァミノ] -6,7-ジメトキシキナゾリン- 2-ィル }-1,4しビピペリ ジン- 3-ィル)メチル]メタンスルホンアミド 2塩酸塩 161 mgを無色結晶として得た。 実施例 20 (1し {4- [(4-クロ口フエ-ル)ァミノ]- 6--トロキナゾリン- 2-ィル }- 1,4'-ビピペラジン- 3- ィル)メタノール 3.16 gのメタノール 200 ml溶液にアルゴン雰囲気下、 10%パラジウム -炭素 300 mgを加え、一気圧水素雰囲気下で 3時間攪拌した。反応終了後、反応液 をセライト濾過し、溶媒を減圧下留去した。得られた残渣にジェチルエーテル 200 ml をカロえ沈殿物を濾取し、（1'- {4- [(4-クロ口フエ-ル)ァミノ]- 6-アミノキナゾリン- 2-ィル }-1,4'-ビピペラジン- 3-ィル)メタノール 1.33 gを黄色固体として得た。この化合物 200 mgをクロ口ホルム 10 mlに溶解し、 4M塩酸/酢酸ェチル溶液 1 mlを加えた後、 減圧下溶媒を留去し、エタノール-ジェチルエーテルより再結晶して、（1'-{4-[(4-クロ 口フエ-ル)ァミノ] -6-アミノキナゾリン- 2-ィル }-1, 4しビピペラジン- 3-ィル)メタノール 2 塩酸塩 210 mgを褐色結晶として得た。 2-[(1 し {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4 し bipiridin-3-yl) methyl ] -1Η-Isoindole-1,3 (2H) _dione, using 320 mg, in the same manner as in Example 17 to give 2- [3- (aminomethyl) -1,4 and bipiperidine-1yl] This gave -N- (4-chlorophenol) -6,7_dimethoxyquinazoline-4-amine. This compound was dissolved in 10 ml of dichloromethane, 114 mg of methanesulfoyl chloride and 1 ml of triethylamine were added under ice cooling, and the mixture was stirred for 2 hours under ice cooling. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 2 hours, and extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (form: methanol / 28% aqueous ammonia), and solidified by adding diisopropyl ether to the residue. After filtration and drying, N-[(l- {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4 and bipiperidin-3 -(Yl) methyl] methanesulfonamide (257 mg) was obtained as a pale yellow solid. 253 mg of this compound was dissolved in 5 ml of ethyl acetate and 1 ml of methanol, and 0.5 ml of a 4M hydrogen chloride-ethyl acetate solution was added.The solvent was distilled off, and the residue was recrystallized from methanol to give N- [(l- {4-[(4-chlorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4-shibipiperidin-3-yl) methyl] methanesulfonamide 161 mg of the dihydrochloride was obtained as colorless crystals. 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. (1 '-{4-[(4-chlorophenol) amino] -6-aminoquinazoline-2-yl} 1.33 g of -1,4′-bipiperazine-3-yl) methanol was obtained as a yellow solid. After dissolving 200 mg of this compound in 10 ml of chloroform and adding 1 ml of 4M hydrochloric acid / ethyl acetate solution, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ethyl ether. {4-[(4-Chlorophenyl) amino] -6-aminoquinazoline-2-yl} -1,4shibipiperazine-3-yl) methanol dihydrochloride 210 mg was obtained as brown crystals. .
実施例 21 Example 21
(1し {4- [(4-クロ口フエ-ル)ァミノ]- 6-アミノキナゾリン- 2-ィル }- 1,4'-ビピペリジン- 3- ィル)メタノール 300 mgのジクロロメタン 50 ml溶液にピリジン 5 ml、無水酢酸 0.66 mlを順次加え室温で 48時間攪拌した。反応液を減圧下濃縮し、酢酸ェチルを加え 飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後 、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (クロ口ホルム-メタノール )で精製後、クロ口ホルム 10 mlに溶解し、 4 M塩ィ匕水素-酢酸ェチル溶液 1 mlを加え 、減圧下濃縮し、エタノール-ジェチルエーテルより再結晶して、 N-{4-[(4-クロ口フエ -ル)ァミノ] -2-[3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1しィル]キナゾリン- 6-ィル }ァ セトアミド 2塩酸塩 2水和物 280 mgを橙色結晶として得た。  (1) {4-[(4-chlorophthyl) amino] -6-aminoquinazoline-2-yl} -1,4'-bipiperidin-3-yl) Methanol 300 mg in dichloromethane 50 ml 5 ml of pyridine and 0.66 ml of acetic anhydride were sequentially added to the mixture, and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (form-form methanol), dissolved in form-form 10 ml, added with 1 ml of a 4 M sodium chloride-ethyl acetate solution, and concentrated under reduced pressure. Recrystallized from ether to give N- {4-[(4-chlorophenol) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidine-1yl] quinazoline-6 280 mg of -yl} acetoamide dihydrochloride dihydrate were obtained as orange crystals.
実施例 22 Example 22
2-メチルスルファ -ル- N- (4-クロ口- 2-フルオロフェ-ル )-6,7,8,9-テトラヒドロ- 5H- シクロへプタ [d]ピリミジン- 4-ァミン 1塩酸塩 1.21 gのジクロロメタン 20 ml混合溶液に 、氷冷下、 m-クロ口過安息香酸 956 mgを加え、 5°Cで 1時間攪拌した。さらに m-クロ 口過安息香酸 291 mgを加え、室温で 1時間攪拌した。反応液にチォ硫酸ナトリウム 水溶液を加え、クロ口ホルムで抽出した。有機層を水、次いで飽和食塩水で洗浄し、 無水硫酸ナトリウムで乾燥し、溶媒を留去して、 N- (4-クロ口- 2-フルオロフェニル )-2-( メチルスルフィ -ル) -6,7,8,9-テトラヒドロ- 5H-シクロへプタ [d]ピリミジン- 4-ァミンと N- (4-クロ口- 2-フルオロフェ-ル )-2- (メチルスルホ-ル)- 6,7,8,9-テトラヒドロ- 5H-シ クロへプタ [d]ピリミジン- 4-ァミンの混合物を得た。この混合物を用いて実施例 6と同 様にして、（1'- {4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 6,7,8,9-テトラヒドロ- 5H-シク 口へプタ [d]ピリミジン- 2-ィル }-1,4しビピペリジン- 3-ィル)メタノール 2塩酸塩 331 mg を無定形黄色固体として得た。 1.21 g of 2-methylsulfur-N- (4-chloro-2-fluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [d] pyrimidine-4-amine monohydrochloride To a mixed solution of 20 ml of dichloromethane was added 956 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring at 5 ° C for 1 hour. Further, 291 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer is washed with water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain N- (4-chloro-2-fluorophenyl) -2- (methylsulfuryl) -6. , 7,8,9-Tetrahydro-5H-cyclohepta [d] pyrimidine-4-amine A mixture of N- (4-chloro-2-fluorophenyl) -2- (methylsulfol) -6,7,8,9-tetrahydro-5H-cyclohepta [d] pyrimidine-4-amine Obtained. Using this mixture and in the same manner as in Example 6, (1 '-{4-[(4-chloro-2-fluorophenyl) amino] -6,7,8,9-tetrahydro-5H-cyclyl) Mouth hepta [d] pyrimidin-2-yl} -1,4, bipiperidin-3-yl) methanol dihydrochloride (331 mg) was obtained as an amorphous yellow solid.
実施例 23— 101 Example 23—101
実施例 1一 22の方法と同様にして後記表 16— 24に示す実施例 23— 101の化合 物を、それぞれ対応する原料を使用して製造した。  Compounds of Examples 23 to 101 shown in Tables 16 to 24 below were produced using the corresponding raw materials in the same manner as in Example 122.
実施例 102 Example 102
4- [(4-クロ口- 2-フルオロフェ -ル）ァミノ]- 2- [3- (ヒドロキシメチル) -1 ,4'-ビピベリジ ン- 1'-ィル]キナゾリン- 7-カルボン酸メチル 152 mgのメタノール 1.5 ml溶液に 1M 水酸化ナトリウム水溶液 0.43 mlを加え、室温で 2時間攪拌した。さら〖こ THF 1.5 ml, クロ口ホルム 2 ml,メタノール 1.5ml及び 1M水酸化ナトリウム水溶液 1.4 mlを数回 に分けて加え、室温で一晩攪拌した。溶媒を留去して得られた残渣を 1M塩酸にて 中和し、析出した結晶を濾取した後、水で洗浄し、減圧乾燥して、 4-[(4-クロ口- 2-フ ルォロフエニル）ァミノ] -2-[3- (ヒドロキシメチル) -1 ,4'-ビピペリジン- 1しィル]キナゾリ ン- 7-カルボン酸 136 mgを結晶として得た。この化合物をエタノール 2 mlに溶解し 、 4M塩ィ匕水素-酢酸ェチル溶液 0.165 mlをカ卩えて塩酸塩とした後、溶媒を留去し た。得られた粗結晶をァセトニトリル-ジェチルエーテル力も再結晶して、 4-[(4-クロ口 -2-フルオロフェ -ル）ァミノ] -2-[3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1しィル]キ ナゾリン- 7-カルボン酸 2塩酸塩 100 mgを淡黄色結晶として得た。  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 residue obtained by distilling off the solvent was neutralized with 1M hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure, and dried under 4-[(4-chloro-2-f. 136 mg of (fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidine-1silyl] quinazoline-7-carboxylic acid were obtained as crystals. This compound was dissolved in 2 ml of ethanol, and 0.165 ml of a 4M solution of hydrogen chloride-ethyl acetate was added to form a hydrochloride, and the solvent was distilled off. The obtained crude crystals were recrystallized with acetonitrile-ethyl ether power to give 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'- 100 mg of bipiperidine-1 [yl] quinazoline-7-carboxylic acid dihydrochloride was obtained as pale yellow crystals.
実施例 103 Example 103
4- [(4-クロ口- 2-フルオロフェ -ル）ァミノ]- 2- [3- (ヒドロキシメチル) -1 ,4'-ビピベリジ ン- 1しィル]キナゾリン- 7-カルボン酸 1.8 gの DMF 40 mlと THF 10 mlの混合溶液 に WSC塩酸塩 1.5 g、 HOBt 1.1 g及び炭酸アンモ-ゥム 1.0 gを加え、室温でー晚 攪拌した。溶媒を留去し、シリカゲルカラムクロマトグラフィー（クロ口ホルム/メタノール /28%アンモニア水）にて精製し、 4- [(4-クロ口- 2-フルオロフェ -ル）ァミノ]- 2- [3- (ヒド 口キシメチル) -1,4'-ビピペリジン- 1しィル]キナゾリン- 7-カルボキサミド 1.15 gを結晶 として得た。この化合物 120 mgをエタノール 1.5 mlに溶解し、 4M塩化水素-酢酸 ェチル溶液 0.15 mlをカ卩えて室温で攪拌した。析出した結晶を濾取して、 4-[(4-クロ 口- 2-フルオロフェ -ル）ァミノ] -2-[3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1しィル]キ ナゾリン- 7-カルボキサミド 2塩酸塩 60 mgを淡黄色結晶として得た。 1.8 g of 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiberidin-1silyl] quinazoline-7-carboxylic acid To a mixed solution of 40 ml of DMF and 10 ml of THF were added 1.5 g of WSC hydrochloride, 1.1 g of HOBt and 1.0 g of ammonium carbonate, and the mixture was stirred at room temperature with stirring. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol / 28% aqueous ammonia) to give 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- 1.15 g of (Hydroxoxymethyl) -1,4'-bipiperidine-1silyl] quinazoline-7-carboxamide As obtained. 120 mg of this compound was dissolved in 1.5 ml of ethanol, 0.15 ml of a 4M hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature. The precipitated crystals are collected by filtration to give 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidin-1yl] ki. Nazoline-7-carboxamide dihydrochloride (60 mg) was obtained as pale yellow crystals.
実施例 104 Example 104
4- [(4-クロ口- 2-フルオロフェ -ル）ァミノ]- 2- [3- (ヒドロキシメチル) -1 ,4'-ビピベリジ ン- 1'-ィル]キナゾリン- 7-カルボキサミド 454 mgのクロ口ホルム 2 mlとピリジン 0.7 mlの混合溶液をメタノール 氷浴にて冷却し、トリフルォロ酢酸無水物 0.19 mlを滴 下した。 -15度で 10分攪拌した後に、さらにトリフルォロ酢酸無水物 0.3 mlを 2回に 分けて滴下し、 10°Cで 2時間攪拌した。反応溶液に 1M水酸化ナトリウム水溶液を 加えて塩基性にした後に、クロ口ホルムで抽出した。有機層を飽和食塩水で洗浄し， 無水硫酸マグネシウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラム クロマトグラフィー（クロ口ホルム/メタノール/ 28%アンモニア水）にて精製し、 4-[(4-クロ 口- 2-フルオロフェ -ル）ァミノ] -2-[3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1しィル]キ ナゾリン- 7-カルボ-トリル 451 mgを結晶として得た。この化合物 82 mgをエタノー ル 2 mlに溶解し、 4M塩ィ匕水素-酢酸ェチル溶液 0.1 mlを加えて、室温で攪拌した 。析出した結晶を濾取して、 4-[(4-クロ口- 2-フルオロフェ -ル）ァミノ] -2-[3- (ヒドロキ シメチル) -1,4'-ビピペリジン- 1しィル]キナゾリン- 7-カルボ-トリル 2塩酸塩 78 mgを 淡桃色結晶として得た。  4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiberidin-1'-yl] quinazoline-7-carboxamide 454 mg A mixed solution of 2 ml of black-mouthed form and 0.7 ml of pyridine was cooled in a methanol ice bath, and 0.19 ml of trifluoroacetic anhydride was dropped. After stirring at −15 ° C. for 10 minutes, 0.3 ml of trifluoroacetic anhydride was further added dropwise in two portions, and the mixture was stirred at 10 ° C. for 2 hours. 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. 82 mg of this compound was dissolved in 2 ml of ethanol, 0.1 ml of a 4 M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature. The precipitated crystals are collected by filtration to give 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidine-1-yl] quinazoline -78 mg of 7-carbo-tolyl dihydrochloride was obtained as pale pink crystals.
実施例 105 Example 105
6-クロ口- N- (4-クロ口フエ-ル)- 1-フエ-ル- 1H-ピラゾ口 [3,4- d]ピリミジン- 4-ァミン 136 mgの 1,4-ジォキサン 20 ml溶液に 1,4'-ビベリジ-ル -3-ィルメタノール 2塩酸 塩 103 mg、 DBU 191 mgを加え、 3日間 100°Cにて加熱した。シリカゲルを加え溶媒 を留去した後、シリカゲルカラムクロマトグラフィー (クロ口ホルム-メタノール)で精製し、 (1'- {4- [(4-クロ口フエ-ル)ァミノ]- 1-フエ-ル- 1H-ピラゾ口 [3,4- d]ピリミジン- 6-ィル }-1,4'-ビピペリジン- 3-ィル)メタノール 102 mgを薄紫色無定形結晶として得た。この 化合物をメタノールに溶解し、 4M塩酸/酢酸ェチル溶液 0.20 mlを加えて塩酸塩とし た後、メタノールで洗浄して、 1'-{4-[(4-クロ口フエ-ル)ァミノ] -1-フエ-ル- 1H-ピラゾ 口 [3,4-d]ピリミジン- 6-ィル }-1,4'-ビピペリジン- 3-ィル)メタノール塩酸塩 68 mgを無 色結晶として得た。 6-clo-N- (4-clo-mouth) -1-phenyl-1H-pyrazo-mouth [3,4-d] pyrimidine-4-amine 20 ml of 1,4-dioxane solution in 136 mg To this was added 103 mg of 1,4′-biveridyl-3-ylmethanol dihydrochloride and 191 mg of DBU, and the mixture was heated at 100 ° C. for 3 days. After silica gel was added and the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform-methanol) to give (1 '-{4-[(4-clophorephenyl) amino] -1-phenyl). 102 mg of 1H-pyrazo [3,4-d] pyrimidine-6-yl} -1,4′-bipiperidin-3-yl) methanol was obtained as light purple amorphous crystals. This compound was dissolved in methanol, and 0.20 ml of a 4 M hydrochloric acid / ethyl acetate solution was added to form a hydrochloride. After washing with methanol, 1 ′-{4-[(4-chlorophenol) amino]- 1-Ferul-1H-pyrazo [3,4-d] pyrimidine-6-yl} -1,4'-bipiperidin-3-yl) methanol hydrochloride (68 mg) was obtained as colorless crystals.
実施例 106— 107 Example 106—107
実施例 105の方法と同様にして後記表 24に示す実施例 106— 107の化合物を、 それぞれ対応する原料を使用して製造した。  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.
実施例 108— 172 Example 108—172
実施例 1一 22の方法と同様にして後記表 25— 34に示す実施例 108— 172の化合 物を、それぞれ対応する原料を使用して製造した。  Compounds of Examples 108 to 172 shown in Tables 25 to 34 below were produced using the corresponding raw materials in the same manner as in Example 122.
実施例 173 Example 173
2-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )-6, 7-ジメトキシキナゾリン- 4-ァミン塩酸 塩 400 mgおよび (4， -メチル -1,4，-ビピペリジン- 3-ィル)メタノール 2塩酸塩 338 mg を用いて、実施例 1の方法と同様に (但し、溶媒として 2-エトキシエタノール 10 ml、塩 基として DBUの代わりに DIPEA 0.75 mlを用いて 130°Cで反応させた）して、（  2-chloro-N- (4-chloro-2-fluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride 400 mg and (4, -methyl-1,4, -bipiperidine-3- Yl) Using 338 mg of methanol dihydrochloride in the same manner as in Example 1 (however, at 130 ° C using 10 ml of 2-ethoxyethanol as the solvent and 0.75 ml of DIPEA instead of DBU as the base) Reacted), then (
-{4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 6,7-ジメトキシキナゾリン- 2-ィル }- 4' -メチ ル -1,4，-ビピペリジン- 3-ィル)メタノール 2塩酸塩 217 mgを淡黄色結晶として得た。 実施例 174 -{4- [(4-chloro-2-fluorophenyl) amino]-6,7-dimethoxyquinazoline-2-yl} -4'-methyl-1,4, -bipiperidin-3-yl ) 217 mg of methanol dihydrochloride were obtained as pale yellow crystals. Example 174
水素化リチウムアルミニウム 14 mgのテトラヒドロフラン 2 ml溶液に氷冷下メチル 4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1,4'-ビピペリジン -1'-ィル]キナゾリン- 7-カルボキシラート 169 mgのテトラヒドロフラン 2 ml溶液を滴 下した。 5°Cで 1時間攪拌した後、さらに水素化リチウムアルミニウム 15 mgを加え、 5 °Cから室温に昇温しながら 1時間攪拌した。反応溶液に硫酸ナトリウム · 10水和物を 加えて沈殿物を濾去し、メタノール及びクロ口ホルムにて洗浄した。溶媒を留去し、シ リカゲルカラムクロマトグラフィー（クロ口ホルム/メタノール/ 28%アンモニア水）にて精 製し、 {4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1,4'-ビピぺ リジン- 1'-ィル]キナゾリン- 7-ィル }メタノール 67 mgを得た。この化合物 87 mgのエタ ノール 1 ml溶液に、 4M塩化水素-酢酸ェチル溶液 0.11 mlを加えて塩酸塩とした 後、溶媒を留去した。得られた粗結晶を酢酸ェチル-エタノールにて結晶化して、 {4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1,4'-ビピペリジン -1'-ィル]キナゾリン- 7-ィル }メタノール 2塩酸塩 86 mgを淡茶色結晶として得た。 Methyl 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidine was added to a solution of lithium aluminum hydride (14 mg) in tetrahydrofuran (2 ml) under ice cooling. A solution of 169 mg of [-1′-yl] quinazoline-7-carboxylate in 2 ml of tetrahydrofuran was dropped. After stirring at 5 ° C for 1 hour, 15 mg of lithium aluminum hydride was further added, and the mixture was stirred for 1 hour while heating from 5 ° C to room temperature. Sodium sulfate 10-hydrate was added to the reaction solution, and the precipitate was filtered off and washed with methanol and chloroform. The solvent was distilled off, and the residue was purified by silica gel column chromatography (form: methanol / 28% aqueous ammonia) to give {4-[(4-chloro-2-fluorophenyl) amino] -2- 67 mg of [3- (hydroxymethyl) -1,4′-bipyridin-1′-yl] quinazoline-7-yl} methanol were obtained. To a solution of 87 mg of this compound in 1 ml of ethanol was added 0.11 ml of a 4M hydrogen chloride-ethyl acetate solution to form a hydrochloride, and the solvent was distilled off. The obtained crude crystal was crystallized from ethyl acetate-ethanol to give {4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'- Bipiperidine [-1′-yl] quinazoline-7-yl} methanol dihydrochloride (86 mg) was obtained as pale brown crystals.
[0067] 実施例 175 Example 175
4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1,4'-ビピペリジン -1'-ィル] -N-メトキシ- N-メチルキナゾリン- 7-カルボキサミド 456 mgのテトラヒドロフ ラン 12 ml溶液に氷浴下メチルリチウム 1.5 mlを加え、室温で攪拌した。さら〖こメチル リチウム 1 mlを 2回加え、室温で攪拌した。反応溶液に飽和塩化アンモ-ゥム水溶 液を加え、酢酸ェチル-テトラヒドロフランで抽出した。有機層を飽和食塩水で洗浄し 、無水硫酸ナトリウムで乾燥後、溶媒を留去し、シリカゲルカラムクロマトグラフィー (ク ロロホルム/メタノール/ 28%アンモニア水）にて精製し、 1-{4- [(4-クロ口- 2-フルオロフ ェ -ル)ァミノ] -2-[3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1しィル]キナゾリン- 7-ィル } エタノン 76 mgを得た。この化合物 76 mgのエタノール 4 ml溶液に、 4M塩化水素- 酢酸ェチル溶液 0.11 mlを加えて室温で攪拌した。析出した結晶を濾取して、 4-[(4-chloro-2-fluorophenyl) amino]-2- [3- (hydroxymethyl) -1,4'-bipiperidine-1'-yl] -N-methoxy-N-methylquinazoline -To a solution of 456 mg of 7-carboxamide in 12 ml of tetrahydrofuran was added 1.5 ml of methyllithium in an ice bath, followed by stirring at room temperature. 1 ml of Sarakoko methyl lithium was added twice and stirred at room temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol / 28% aqueous ammonia) to obtain 1- {4-[( 4-Chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1,4'-bipiperidin-1yl] quinazoline-7-yl} ethanone 76 mg was obtained. . To a solution of 76 mg of this compound in 4 ml of ethanol was added 0.11 ml of a 4 M hydrogen chloride-ethyl acetate solution, followed by stirring at room temperature. The precipitated crystals are collected by filtration,
1- {4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 2- [3- (ヒドロキシメチル) -1,4'-ビピベリジ ン- 1'-ィル]キナゾリン- 7-ィル }エタノン 2塩酸塩 55 mgを淡黄色結晶として得た。 実施例 176 1- {4- [(4-chloro-2-fluorophenyl) amino]-2- [3- (hydroxymethyl) -1,4'-bipiberidin-1'-yl] quinazoline-7- 55 mg of le} ethanone dihydrochloride was obtained as pale yellow crystals. Example 176
{2-クロ口- 4-[(4-クロ口- 2-フルオロフェ -ル)ァミノ] -8-メトキシキナゾリン- 5-カルボ 二トリル 106 mg、 1,4'-ビピペリジン- 3-ィルメタノール 2塩酸塩 79 mg、 DBU 133 mg の 1,4-ジォキサン 20 mlの溶液を 100°Cで 4日間攪拌した。反応液を降温し溶媒を留 去し、残渣にクロ口ホルムと水をカ卩え、水層をクロ口ホルムで抽出し、溶媒を留去した 。残渣をシリカゲルカラムクロマトグラフィー（クロ口ホルム/メタノール)で精製後、薄黄 色無定形結晶として得られた化合物 114 mgをイソプロパノール 5 ml≡THF 15 mlの 混合溶液に溶解し、 4M塩ィ匕水素-酢酸ェチル溶液 0.16 mlを加えて室温で攪拌し た。溶媒を留去し得られた結晶を酢酸ェチル-イソプロノ V—ルで洗浄して 4-[(4-クロ 口- 2-フルオロフェ -ル)ァミノ] -2-[3- (ヒドロキシメチル) -1,4'-ビピペリジン- 1しィル] -8-メトキシキナゾリン- 5-カルボキサミド 2塩酸塩 80 mgを白色結晶として得た。  {2-chloro-4-[(4-chloro-2-fluorophenyl) amino] -8-methoxyquinazoline-5-carbon nitrile 106 mg, 1,4'-bipiperidin-3-ylmethanol dihydrochloride A solution of 79 mg and DBU 133 mg in 1,4-dioxane 20 ml was stirred at 100 ° C. for 4 days. The reaction solution was cooled down, the solvent was distilled off, the residue was mixed with chloroform and water, the aqueous layer was extracted with chloroform, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol), and 114 mg of the compound obtained as pale yellow amorphous crystals was dissolved in a mixed solution of 5 ml of isopropanol and 15 ml of THF. -Ethyl acetate solution (0.16 ml) was added and stirred at room temperature. The solvent is distilled off, and the obtained crystals are washed with ethyl acetate-isopronoyl phenol to give 4-[(4-chloro-2-fluorophenyl) amino] -2- [3- (hydroxymethyl) -1 , 4′-Bipiperidine-1silyl] -8-methoxyquinazoline-5-carboxamide dihydrochloride (80 mg) was obtained as white crystals.
[0068] 実施例 177 Example 177
6,8—ジクロロ [1,3]ジォキソロ [4,5— g]キナゾリン 600 mgのエタノーノレ 15 ml溶液に、 6,8-Dichloro [1,3] dioxolo [4,5-g] quinazoline 600 mg in ethanol 15 ml solution
2-クロ口- 4-フルォロア-リン 359 mg、メタンスルホン酸 0.05 mlを順次加え、 85°Cで 終夜攪拌した。反応液を室温まで降温し、炭酸水素ナトリウム水溶液を加え、クロロホ ルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られ た残渣をシリカゲルカラムクロマトグラフィー (酢酸ェチル -へキサン)で精製し、 6-クロ 口- N- (4-クロ口- 2-フルオロフェ-ル )[1,3]ジォキソロ [4,5- g]キナゾリン- 8-ァミン 85 mgを得た。また、 6,8-ジクロロ [1,3]ジォキソロ [4,5- g]キナゾリン 568 mgに tert-ブタノ ール 30 ml、ジォキサン 30 ml、 2-クロ口- 4-フルォロア-リン 334 mg、 4M塩化水素- ジォキサン溶液 0.1 mlを加え、 100°Cで 6時間攪拌した。反応液を室温まで降温し、 炭酸水素ナトリウム水溶液を加え、クロ口ホルムで抽出した。有機層を無水硫酸マグ ネシゥムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ 一 (酢酸ェチル -へキサン)で精製し、 6-クロ口- N- (4-クロ口- 2-フルオロフェ-ル )[1 ,3] ジォキソロ [4,5-g]キナゾリン- 8-ァミン 30 mgを得た。これら 2回の反応で得られた、 6- クロ口- N- (4-クロ口- 2-フルオロフェ-ル )[1,3]ジォキソロ [4,5- g]キナゾリン- 8-ァミン 115 mgと 1.4，-ビピペリジン- 3-ィルメタノール 2塩酸塩 80 mgの混合物に、 1,2-ジェ トキシェタン 5 ml、 DBU 0.14 mlを順次カ卩え、 120°Cで終夜攪拌した。反応液を室温 まで降温し、水を加え、クロ口ホルムで抽出した。有機層を飽和食塩水で洗浄、無水 硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマ トグラフィー (クロ口ホルム-メタノール- 28%アンモニア水)で精製し、 (1， -{8-[(4-クロ口 -2-フルオロフェ -ル)ァミノ] [1,3]ジォキソロ [4,5-g]キナゾリン- 6-ィル }-1,4，-ビピペリ ジン- 3-ィル)メタノール 38 mgをベージュ色アモルファスとして得た。この化合物をメ タノール 5 mlに溶解し、 4M塩化水素-ジォキサン溶液 0.3 mlをカ卩えて塩酸塩とし た後、溶媒を留去した。得られた粗生成物をジイソプロピルエーテルで洗浄して、（ -{8- [(4-クロ口- 2-フルオロフェ -ル)ァミノ] [1,3]ジォキソロ [4,5- g]キナゾリン- 6-ィル }-1, 4' -ビピペリジン- 3-ィル)メタノール 2塩酸塩 30 mgをベージュ色の結晶として得 た。 359 mg of 2-chloro-4-fluorine-phosphorus and 0.05 ml of methanesulfonic acid were added sequentially, and the mixture was added at 85 ° C. Stirred overnight. The reaction solution was cooled to room temperature, an aqueous sodium hydrogen carbonate solution 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 (ethyl acetate-hexane) to give 6-chloro-N- (4-chloro-2-fluorophenyl) [1,3] dioxolo [4,5- g] Quinazoline-8-amine 85 mg was obtained. 568 mg of 6,8-dichloro [1,3] dioxolo [4,5-g] quinazoline was added to 30 ml of tert-butanol, 30 ml of dioxane, 334 mg of 2-chloro-4-fluorofluorin-phosphorus, and 4M of 4M. 0.1 ml of a hydrogen chloride-dioxane solution was added, and the mixture was stirred at 100 ° C for 6 hours. The reaction solution was cooled to room temperature, an aqueous solution of sodium hydrogen carbonate 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 obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 6-chloro-N- (4-chloro-2-fluorophenyl) [1,3] dioxolo [4,5- g] 30 mg of quinazoline-8-amine were obtained. 115 mg of 6-chloro-N- (4-chloro-2-fluorophenyl) [1,3] dioxolo [4,5-g] quinazoline-8-amine obtained from these two reactions was used. To a mixture of 1.4, -bipiperidine-3-ylmethanol dihydrochloride (80 mg), 1,2-jetoxetane (5 ml) and DBU (0.14 ml) were successively added and stirred at 120 ° C overnight. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with black hole form. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (form: methanol-28% aqueous ammonia) to give (1,-{8-[(4-chloro-2-fluorophenyl) amino] [1 [3,3] Dioxolo [4,5-g] quinazoline-6-yl} -1,4, -bipiperidin-3-yl) methanol 38 mg was obtained as a beige amorphous. The compound was dissolved in 5 ml of methanol, and 0.3 ml of a 4M hydrogen chloride-dioxane solution was added to form a hydrochloride, and the solvent was distilled off. The obtained crude product was washed with diisopropyl ether to give (-{8-[(4-chloro-2-fluorophenyl) amino] [1,3] dioxolo [4,5-g] quinazoline-6. -Yl} -1,4'-Bipiperidin-3-yl) methanol dihydrochloride (30 mg) was obtained as beige crystals.
実施例 178 Example 178
N- (4-クロ口- 2-フルオロフェ-ル )-6,7-ジメチル- 2- (メチルチオ)プテリジン- 4-ァミン 850 mgのクロロホノレム 80 ml溶液に、氷冷下 m-クロ口過安息香酸 (〉65%) 645 mgを 加え、 0°C力も室温で 3時間攪拌した。反応液に水を加え、クロ口ホルムで抽出した。 有機層をチォ硫酸ナトリウム水溶液、炭酸水素ナトリウム水溶液で順次洗浄し、無水 硫酸マグネシウムで乾燥し、溶媒を留去することにより、 N-(4-クロ口- 2-フルオロフェ -ル) -6,7-ジメチル- 2- (メチルスルフィ -ル)プテリジン- 4-ァミン 884 mgを得た。この 化合物 364 mgと 1.4，-ビピペリジン- 3-ィルメタノール 2塩酸塩 260 mgの混合物に、 1,2-ジエトキシェタン 20 ml、 DBU 0.52 mlを順次カ卩え、 115°Cで終夜攪拌した。反応 液を室温まで降温し、水を加え、クロ口ホルムで抽出した。有機層を無水硫酸マグネ シゥムで乾燥し、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (クロ口ホルム-メタノール- 28%アンモニア水)で精製し、 (1， -{4-[(4-クロ口- 2-フルォロ フエ-ル)ァミノ] -6,7-ジメチルプテリジン- 2-ィル }-1,4' -ビピペリジン- 3-ィル)メタノー ル 130 mgを得た。この化合物をメタノール 5 mlに溶解し、 4M塩化水素-ジォキサ ン溶液 0.3 mlを加えて塩酸塩とした後、溶媒を留去した。得られた粗生成物をァセト 二トリルで洗浄して、（1， -{4-[(4-クロ口- 2-フルオロフェ -ル)ァミノ] -6,7-ジメチルプテ リジン- 2-ィル }-1,4' -ビピペリジン- 3-ィル)メタノール 2塩酸塩 95 mgを褐色結晶とし て得た。 To a solution of 850 mg of N- (4-chloro-2-fluorophenyl) -6,7-dimethyl-2- (methylthio) pteridine-4-amine in 80 ml of chlorophonolem under ice-cooling m-chloroperbenzoic acid (> 65%) 645 mg was added and the mixture was stirred at room temperature for 3 hours at 0 ° C. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed successively with an aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated to remove N- (4-chloro-2-fluorophenyl) -6,7. There was obtained 884 mg of -dimethyl-2- (methylsulfuryl) pteridine-4-amine. To a mixture of 364 mg of this compound and 260 mg of 1.4, -bipiperidin-3-ylmethanol dihydrochloride, 20 ml of 1,2-dietoxetane and 0.52 ml of DBU were successively added and stirred at 115 ° C overnight. The 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. This compound was dissolved in 5 ml of methanol, and 0.3 ml of a 4M hydrogen chloride-dioxane solution was added to form a hydrochloride, and the solvent was distilled off. The obtained crude product was washed with acetate nitrile and (1,-{4-[(4-chloro-2-fluorophenyl) amino] -6,7-dimethylpteridin-2-yl} 95 mg of -1,4′-bipiperidin-3-yl) methanol dihydrochloride was obtained as brown crystals.
実施例 179 Example 179
({4- [(4-クロ口フエ-ル)ァミノ]- 6-フルォロ- 2- [3- (ヒドロキシメチル) -1,4'-ビピベリジ ン- 1しィル]キナゾリン- 7-ィル }チォ）酢酸ェチル 80 mgの 6M塩酸水溶液 10 ml溶 液を 16時間加熱還流した。反応液を室温まで降温し、析出した粗結晶をエタノール で洗浄して、（{4- [(4-クロ口フエ-ル)ァミノ]- 6-フルォロ- 2- [3- (ヒドロキシメチル) -1 ,4'- ビピペリジン- 1'-ィル]キナゾリン- 7-ィル }チォ）酢酸 2塩酸塩 78mgを白色結晶とし て得た。  ({4- [(4-chloromethyl) amino] -6-fluoro-2- 2- [3- (hydroxymethyl) -1,4'-bipiberidin-1yl] quinazoline-7-yl } Cho) A solution of 80 mg of ethyl acetate in 10 ml of a 6M aqueous hydrochloric acid solution was heated to reflux for 16 hours. The reaction solution was cooled to room temperature, and the precipitated crude crystals were washed with ethanol, and ({4-[(4-chlorophenol) amino] -6-fluoro-2- [3- (hydroxymethyl)- 1,4′-Bipiperidin-1′-yl] quinazoline-7-yl} thio) acetic acid dihydrochloride (78 mg) was obtained as white crystals.
実施例 180 Example 180
ェチル 1， -{4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 7-シァノキナゾリン- 2-ィル }-1,4，-ビピペリジン- 3-カルボキシラート 941 mgのエタノール 10 ml溶液に 1M水 酸化ナトリウム水溶液 3.50 mlを加え、室温下 8時間攪拌した。反応液に 1M塩酸 3.50 mlをカ卩えた後、反応液を濃縮して得られた残渣をエタノール-水力 再結晶を 行！ヽ、 1， -{4- [(4-クロ口- 2-フルオロフェ -ル)ァミノ]- 7-シァノキナゾリン- 2-ィル }- 1,4- ビピペリジン- 3-カルボン酸 449 mgを黄色結晶として得た。 実施例 181 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. After 3.50 ml of 1M hydrochloric acid was added to the reaction mixture, the residue obtained by concentrating the reaction mixture was recrystallized from ethanol and hydropower!ヽ, 1,-{4-[(4-chloro-2-fluorophenyl) amino] -7-cyanoquinazolin-2-yl} -1,4-bipiperidine-3-carboxylic acid 449 mg in yellow Obtained as crystals. Example 181
実施例 179の方法と同様にして後記表 29に示す実施例 181の化合物を、対応す る原料を使用して製造した。  In the same manner as in the method of Example 179, the compound of Example 181 shown in Table 29 below was produced using the corresponding starting materials.
実施例 182— 188 Example 182—188
実施例 103の方法と同様にして後記表 27— 33に示す実施例 182— 188の化合物 を、それぞれ対応する原料を使用して製造した。  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.
実施例 1一 188の化合物の構造及び物理化学的データを表 15— 34に示す。また 、表 35— 37に本発明の別の化合物の構造を示す。これらは、上記の製造法や実施 例に記載の方法及び当業者にとって自明である方法、又はこれらの変法を用いるこ とにより、容易に合成することができる。  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.
[表 1] [table 1]
Figure imgf000052_0001
Figure imgf000052_0001
[表 2] [Table 2]
Figure imgf000053_0001
Figure imgf000053_0001
[0071] [表 3] [Table 3]
Figure imgf000054_0001
Figure imgf000054_0001
Figure imgf000054_0002
.0ZC00/S00Zdf/X3d 89 S98Z80/S00Z OAV
Figure imgf000054_0002
.0ZC00 / S00Zdf / X3d 89 S98Z80 / S00Z OAV
[s挲] [εζοο] [s 挲] [εζοο]
Figure imgf000055_0001
.OZCOO/SOOZdf/X3d S98Z80/S00Z OAV
Figure imgf000055_0001
.OZCOO / SOOZdf / X3d S98Z80 / S00Z OAV
Figure imgf000056_0001
.0ZC00/S00Zdf/X3d 99 S98Z80/S00Z OAV s007
Figure imgf000056_0001
.0ZC00 / S00Zdf / X3d 99 S98Z80 / S00Z OAV s007
Figure imgf000057_0001
Figure imgf000057_0001
Figure imgf000058_0001
8]
Figure imgf000059_0001
9]
Figure imgf000058_0001
8]
Figure imgf000059_0001
9]
Figure imgf000060_0001
Figure imgf000060_0001
Figure imgf000060_0002
.0ZC00/S00Zdf/X3d 69 S98Z80/S00Z OAV
Figure imgf000060_0002
.0ZC00 / S00Zdf / X3d 69 S98Z80 / S00Z OAV
Figure imgf000061_0001
Figure imgf000061_0001
Figure imgf000061_0002
.0ZC00/S00Zdf/X3d 09 S98Z80/S00Z OAV
Figure imgf000061_0002
.0ZC00 / S00Zdf / X3d 09 S98Z80 / S00Z OAV
Figure imgf000062_0001
.0ZC00/S00Zdf/X3d 1-9 S98Z80/S00Z OAV
Figure imgf000063_0001
Figure imgf000062_0001
.0ZC00 / S00Zdf / X3d 1-9 S98Z80 / S00Z OAV
Figure imgf000063_0001
Figure imgf000063_0002
.0ZC00/S00Zdf/X3d 39 S98Z80/S00Z OAV
Figure imgf000064_0001
Figure imgf000064_0003
Figure imgf000063_0002
.0ZC00 / S00Zdf / X3d 39 S98Z80 / S00Z OAV
Figure imgf000064_0001
Figure imgf000064_0003
[0082] [表 14]
Figure imgf000064_0002
Figure imgf000064_0004
[0082] [Table 14]
Figure imgf000064_0002
Figure imgf000064_0004
[0083] [表 15] [0083] [Table 15]
Figure imgf000065_0001
16]
Figure imgf000066_0001
Figure imgf000065_0001
16]
Figure imgf000066_0001
Figure imgf000066_0002
.0ZC00/S00Zdf/X3d 99 S98Z80/S00Z OAV
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000066_0002
.0ZC00 / S00Zdf / X3d 99 S98Z80 / S00Z OAV
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000069_0001
o8800
Figure imgf000070_0001
o8800
Figure imgf000070_0001
Figure imgf000071_0001
22] F: 470； EA: Cal (C>5H2VC1FN50. 2HC1.
Figure imgf000071_0001
twenty two] F: 470; EA: Cal (C> 5 H 2V C1FN 5 0.2HC1.
0.5H:O) C， 54.41 ; H, 5.84; N, 12.69; F， 0.5H: O) C, 54.41; H, 5.84; N, 12.69; F,
78 1 Xrcl 3.44; CI, 19.27. Fnd: C, 54.12; H， 5.62; N， 78 1 Xr cl 3.44; CI, 19.27. Fnd: C, 54.12; H, 5.62; N,
12.45; F, 3.40; CI, 19.30.； Sal: 2HC1. 0.5H2O . 12.45; F, 3.40; CI , 19.30 .; Sal: 2HC1 0.5H 2 O
F: 459； NMR2: 8.29 (I H, d, J=4.4 Hz), F: 459; NMR 2: 8.29 (I H, d, J = 4.4 Hz),
79 1 Xrcl 7.71 (2H, d， J=8.8 Hz), 1.10- L.19 (IH, m)； 79 1 Xr cl 7.71 (2H, d, J = 8.8 Hz), 1.10- L.19 (IH, m);
Sal: 2HC1. H20 Sal:. 2HC1 H 2 0
F: 459； NMR2: 7.45 (2H, d, J=8.4 Hz), F: 459; NMR2: 7.45 (2H, d, J = 8.4 Hz),
80 1 XTCI 7.27 (III, d, J=6.0 Hz), 1.12- 1.18 (IH, m)； 80 1 XT CI 7.27 (III, d, J = 6.0 Hz), 1.12- 1.18 (IH, m);
Sal: 2HC1. 1.5H20 Sal: 2HC 1.1.5H 2 0
F: 483； NMR2: 7.77 (IH, d， J=8.8 Hz), F: 483; NMR2: 7.77 (IH, d, J = 8.8 Hz),
81 1 Xrcl 7.46- 7.50 (2H, m), 1.05-1.19 (IH, m)； 81 1 Xr cl 7.46- 7.50 (2H, m), 1.05-1.19 (IH, m);
Sal: 2HC1. 2H20 Sal: 2HC1.2H 2 0
MeO  MeO
F: 520； NMR2: 8.18 (IH, d， J=8.3 Hz), F: 520; NMR2: 8.18 (IH, d, J = 8.3 Hz),
82 1 JCI FsCci 7.56 (2H, d, J=8.8 Hz), 1.15 (ΊΗ, qd, J=12.7, 82 1 J CI FsC ci 7.56 (2H, d, J = 8.8 Hz), 1.15 (ΊΗ, qd, J = 12.7,
3.4 Hz)； Sal: 2HC1. H20 . 3.4 Hz); Sal: 2HC1 H 2 0
F: 532， 530 ; NMR2: 8.93 (l H，s)，フ.74 F: 532, 530; NMR 2: 8.93 (lH, s), f. 74
83 1 XJcl (2H， d， J=8.8 Hz), 7.55 (2H， d, J=8.8 Hz)； 83 1 XJ cl (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz);
Sal: 2HC1. H20 Sal:. 2HC1 H 2 0
ES: 497； NMR2: 9.58 (IH, s), 7.75 (2H, ES: 497; NMR2: 9.58 (IH, s), 7.75 (2H,
84 1 XJa XJN d, J=8.8 Hz), 7.55 (2H， d， J=8.8 Hz)； 84 1 XJ a XJ N d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz);
人 Sal: 211C1. 3H20People Sal:. 211C1 3H 2 0
: 546； NMR 1： 77.81 (1 H, hds), 3.95 : 546; NMR 1: 77.81 (1 H, hds), 3.95
85 1 XJa (3H, s)， 3.68-3.83 (211， m)； Sal: 21 IC1. 85 1 XJ a (3H, s), 3.68-3.83 (211, m); Sal: 21 IC1.
1.5H20 1.5H 2 0
b: 524； NMR2: 7.83 (2H, d， J=8.8 Hz), b: 524; NMR2: 7.83 (2H, d, J = 8.8 Hz),
86 1 7.45 (2H, d, J=8.8 Hz),4.35 (2H， q， J=7.3
Figure imgf000072_0001
IIz)； Sal: 2HC1. 2H20 86 1 7.45 (2H, d, J = 8.8 Hz), 4.35 (2H, q, J = 7.3
Figure imgf000072_0001
. IIz); Sal: 2HC1 2H 2 0
F: 540； NMRl : 7.86 (I H, bds), 7.66 (IH, F: 540; NMRl: 7.86 (I H, bds), 7.66 (IH,
87 1 NCXrBr d, J=7.6 Hz), 1.12- 1.15 (I H, m)； 87 1 NC Xr Br d, J = 7.6 Hz), 1.12- 1.15 (IH, m);
Sal: 2HC1. 3H20 Sal: 2HC1.3H 2 0
F: 470； NMR2: 8.64-8.72 (IH, m), 7.55 F: 470; NMR2: 8.64-8.72 (IH, m), 7.55
88 2 XJCI (2H， d， J=8.8 Hz), 1.08-1.21 (IH, m)； 88 2 XJ CI (2H, d, J = 8.8 Hz), 1.08-1.21 (IH, m);
Sal: 2HC1. H20 Sal:. 2HC1 H 2 0
F: 486； NMR2: 8.73 (IH, d, J=8.3 Hz), F: 486; NMR2: 8.73 (IH, d, J = 8.3 Hz),
89 3 8.36 ( I H, s), 7.75 (2H, d, J=8.8 Hz)； 89 3 8.36 (I H, s), 7.75 (2H, d, J = 8.8 Hz);
Sal: 2HC1. 2H20 23]
Figure imgf000073_0001
Sal: 2HC1.2H 2 0 23]
Figure imgf000073_0001
Figure imgf000073_0002
.0ZC00/S00Zdf/X3d 3Z S98Z80/S00Z OAV
Figure imgf000073_0002
.0ZC00 / S00Zdf / X3d 3Z S98Z80 / S00Z OAV
Figure imgf000074_0001
25]
Figure imgf000074_0001
twenty five]
Figure imgf000075_0001
Figure imgf000075_0001
o] .0ZC00/S00Zdf/X3d 9Z S98Z80/S00Z OAV
Figure imgf000077_0001
27] o] .0ZC00 / S00Zdf / X3d 9Z S98Z80 / S00Z OAV
Figure imgf000077_0001
27]
； ;
F， N, F, N,
Sal: Sal:
Figure imgf000078_0001
〔 u〔〕ss9600
Figure imgf000078_0001
(U () ss9600
Figure imgf000079_0001
Figure imgf000079_0001
〔 u〕62SOO
Figure imgf000080_0001
30] (U) 62SOO
Figure imgf000080_0001
30]
Figure imgf000081_0001
表 31]
Figure imgf000082_0001
表 32]
Figure imgf000081_0001
Table 31]
Figure imgf000082_0001
Table 32]
Figure imgf000083_0001
表 33]
Figure imgf000084_0001
表 34]
Figure imgf000083_0001
Table 33]
Figure imgf000084_0001
Table 34]
[ss挲] [εοιο] [ss 挲] [εοιο]
Figure imgf000085_0002
Figure imgf000085_0002
Figure imgf000085_0001
.0ZC00/S00Zdf/X3d ャ8 S98Z80/S00Z OAV [9ε挲] [雨 ο]
Figure imgf000086_0001
Figure imgf000085_0001
.0ZC00 / S00Zdf / X3d 8 S98Z80 / S00Z OAV [9ε 挲] [rain ο]
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000088_0001
産業上の利用可能性 本発明の縮合二環性ピリミジン誘導体は、 CCR4或いは TARC及び Z又は MDCの 機能調節作用を有することから、種々の炎症性疾患、アレルギー疾患、自己免疫疾 患等〔例えば、喘息、アレルギー性鼻炎、アレルギー性結膜炎、花粉症、皮膚炎 (アト ピー性皮膚炎、接触性皮膚炎)、乾癬、関節リウマチ、全身性エリテマトーデス、多発 性硬化症、インスリン依存型糖尿病（IDDM)、臓器移植時の拒絶反応、癌、炎症性 腸疾患 (潰瘍性大腸炎、クローン病)、間質性膀胱炎、敗血症、疼痛〕の予防，治療 薬として有用である。特に、喘息、アトピー性皮膚炎又は関節リウマチの予防 '治療 薬として期待できる。 Industrial applicability Since 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]. In particular, it can be expected as a therapeutic agent for preventing asthma, atopic dermatitis or rheumatoid arthritis.

Claims

請求の範囲 一般式 (I)で示される縮合二環性ピリミジン誘導体又はその塩。 Claims A fused bicyclic pyrimidine derivative represented by the general formula (I) or a salt thereof.
[化 1] [Chemical 1]
Figure imgf000090_0001
Figure imgf000090_0001
(式中の記号は以下の意味を示す。  (The symbols in the formula have the following meanings.
A：置換されて!、てもよ!/、ァリール、置換されて!、てもよ 、シクロアルキル又は置換さ れて 、てもよ 、単環式 6員へテロァリール、  A: substituted !, may! /, Aryl, substituted !, may, cycloalkyl or substituted, may be, monocyclic 6 membered heteroaryl,
[化 2] [Formula 2]
Figure imgf000090_0002
Figure imgf000090_0002
Ra： H、置換されて!、てもよ 、低級アルキル、置換されて!、てもよ 、シクロアルキル、 置換されて 、てもよ 、フエ-ル、置換されて!、てもよ 、単環若しくは二環式へテロ環 基、 R a : H, substituted !, may, lower alkyl, substituted !, may, cycloalkyl, substituted, may, phenyl, substituted !, A monocyclic or bicyclic heterocyclic group,
：じ 又は  : Ji or
Y: CR4又は N、但し、 X力 SCR3のとき Yは Nを、 X力 のとき Yは CR4を示す、 Y: CR 4 or N, where X force SCR 3 Y indicates N, X force Y indicates CR 4 ,
Z: CR5R6、 NR7、 0、 S、 S(O)又は S(O)、 Z: CR 5 R 6 , NR 7 , 0, S, S (O) or S (O),
2  2
R1 :同一又は互いに異なって、 - OH、 - CN、ハロゲン、置換されていてもよい低級ァ ルキル、 -O- (置換されていてもよい低級アルキル)、 -S- (置換されていてもよい低級ァ ルキル)、 -SO -(置換されていてもよい低級アルキル)、 -NO、 - N(R8)(R9)、 - CO- R。、 R 1 : the same or different, -OH, -CN, halogen, optionally substituted lower radical Alkyl, -O- (optionally substituted lower alkyl), -S- (optionally substituted lower alkyl), -SO-(optionally substituted lower alkyl), -NO, -N (R 8 ) (R 9 ), -CO-R. ,
2 2  twenty two
-CO - R。、 - N(R8)COR。、 - N(R8)CO R。、 - N(R8)SO R。、置換されていてもよいフエ-ル、-CO-R. , -N (R 8 ) COR. , -N (R 8 ) CO R. , -N (R 8 ) SO R. , An optionally substituted phenol,
2 2 2 2 2 2
- CO- R°、 -CO H、 - CO- N(R8)(R9)、 - R°°- CO- N(R8)(R9)、置換されていてもよい単環若 - CO- R °, -CO H, - CO- N (R 8) (R 9), - R °° - CO- N (R 8) (R 9), monocyclic young optionally substituted
2  2
しくは二環式へテロ環基又は- CO- (置換されて 、てもよ 、単環若しくは二環式へテロ 環基)、  Or a bicyclic heterocyclic group or -CO- (substituted or a monocyclic or bicyclic heterocyclic group),
R°：低級アルキル又はフエ-ル、  R °: lower alkyl or phenol,
R2 :同一又は互いに異なって、 - R°、ハロゲン、ハロゲノ低級アルキル、 - E-OH、 — E— 0— R°、— E— N(R8)(R9)、— E— CN、— E— N(R8)— CO— R°、— E— N(R8)— SO— R。、 R 2 : the same or different, -R °, halogen, halogeno lower alkyl, -E-OH, —E—0—R °, —E—N (R 8 ) (R 9 ), —E—CN, — E—N (R 8 ) —CO—R °, — E—N (R 8 ) —SO—R. ,
2  2
- E- 0- CO- R°、 - E- CO H、 - E- CO - R°、 - E- CON(R8)(R9)又はォキソ、 - E- 0- CO- R °, - E- CO H, - E- CO - R °, - E- CON (R 8) (R 9) or Okiso,
2 2  twenty two
E：結合又は低級アルキレン、  E: bond or lower alkylene,
R3及び R4:同一又は互いに異なって、 H、低級アルキル又は CN、 R 3 and R 4 : the same or different, H, lower alkyl or CN,
R8及び R9 :同一又は互いに異なって、 H又は低級アルキル、 R 8 and R 9 : the same or different, H or lower alkyl,
R5及び R6:同一又は互いに異なって、 H又は R2に記載の基、或いは R5及び R6がー体 となって才キソ、 R 5 and R 6 : the same or different, the groups described in H or R 2 or R 5 and R 6 are
R7: H、低級アルキル、ハロゲノ低級アルキル、 - R°°- 0H、 - CON(R8)(R9)、 - R°°- 0- R。 、 - R。。- N(R8)(R9)、 - R。。- CNゝ - R。。- N(R8)- CO- R。、 - R。。- N(R8)- SO - R。、 - R。。- 0- CO- R。 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 ゝ-R. . - N (R 8) - CO- R. , -R. . - N (R 8) - SO - R. , -R. . -0-CO-R.
2  2
、 - R°°- CO - R。又は- R°°- CON(R8)(R9)、 , -R °° -CO-R. Or - R °° - CON (R 8 ) (R 9),
2  2
RQQ:低級アルキレン、 R QQ : lower alkylene,
n: 0、 1、 2又は 3、  n: 0, 1, 2, or 3,
m: 0、 1、 2、 3又は 4、  m: 0, 1, 2, 3, or 4,
j: 0、 1、 2又は 3、  j: 0, 1, 2, or 3,
k: 0、 1又は 2。 )  k: 0, 1 or 2. )
[2] 請求の範囲 1記載の縮合二環性ピリミジン誘導体又はその製薬学的に許容される塩 と、製薬学的に許容される担体とからなる医薬組成物。  [2] A pharmaceutical composition comprising the fused bicyclic pyrimidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[3] 請求の範囲 1記載の縮合二環性ピリミジン誘導体又はその製薬学的に許容される塩 と、製薬学的に許容される担体とからなる CCR4或いは TARC及び Z又は MDCの機 能調節剤。 [3] A functional regulator of CCR4 or TARC and Z or MDC, comprising the fused bicyclic pyrimidine derivative or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier. .
[4] 炎症性疾患、アレルギー疾患、又は、自己免疫疾患の予防 ·治療薬である請求の範 囲 2記載の医薬組成物。 [4] The pharmaceutical composition according to claim 2, which is a preventive / therapeutic agent for an inflammatory disease, an allergic disease, or an autoimmune disease.
[5] 喘息の予防'治療薬である請求の範囲 2記載の医薬組成物。 [5] The pharmaceutical composition according to claim 2, which is an agent for preventing or treating asthma.
[6] アトピー性皮膚炎の予防'治療薬である請求の範囲 2記載の医薬組成物。 [6] The pharmaceutical composition according to claim 2, which is an agent for preventing or treating atopic dermatitis.
[7] 関節リウマチ等の予防'治療薬である請求の範囲 2記載の医薬組成物。 [7] The pharmaceutical composition according to claim 2, which is an agent for preventing or treating rheumatoid arthritis.
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