WO2006137421A1 - Agent for topical administration - Google Patents

Agent for topical administration Download PDF

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Publication number
WO2006137421A1
WO2006137421A1 PCT/JP2006/312378 JP2006312378W WO2006137421A1 WO 2006137421 A1 WO2006137421 A1 WO 2006137421A1 JP 2006312378 W JP2006312378 W JP 2006312378W WO 2006137421 A1 WO2006137421 A1 WO 2006137421A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
acceptable salt
lower alkyl
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PCT/JP2006/312378
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French (fr)
Japanese (ja)
Inventor
Toshihide Ikemura
Etsuo Ohshima
Kaori Horikoshi
Satoko Ohtsuka
Kiyotoshi Mori
Hiroko Kusaka
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Kyowa Hakko Kogyo Co., Ltd.
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Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Publication of WO2006137421A1 publication Critical patent/WO2006137421A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms

Definitions

  • the present invention relates to a topical administration agent containing a compound having p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient.
  • p38MAPK Mitogen-Activated Protein Kinase
  • P38MAPK inhibitors (hereinafter referred to as P38MAPK inhibitors) containing a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient are inflammatory diseases, autoimmune diseases, cancers, etc. It is known to be useful for treatment. For example, the following reports have been made.
  • P38MAPK inhibitors suppress adjuvant-induced arthritis in rats [Arthritis & Rheumatism, 43, 175-183 (2000); bioorganic 'and' Medicinal Chemistry Letters, Vol. 8, pp. 2689-2694 (1998)].
  • P38MAP K inhibitors suppress arthritis induced by streptococcal cell walls in rats [Bioorganic & Medicinal Chemistry Letters, Vol. 11, 693- 656 (2001)].
  • P38MAPK inhibitors suppress antigen-induced eosinophil infiltration in mice and guinea pigs [Journal of 'Pharmacology 1' and Xperimental Therapeut Pharmacology and Experimental Therapeutics), 293, 281-288 (2000)].
  • P38MAPK inhibitor suppresses lipopolysaccharide-induced inflammatory site force-in production in the lung and infiltration of neutrophils into the lung [American's Journal of Physiology —American Journal of Physiol ogy-Lung Cellular and Molecular Physiology, Vol. 279, L895-902 (2000)].
  • P38MAPK inhibitors suppress the increase in the number of neutrophils in the peripheral blood and the increase in the site force-in concentration such as interleukin 6 induced by lipopolysaccharide in humans [Journal 'Ob 'Journal of Immunology, 168, 4070-4077 (2002)].
  • P38MAPK inhibitor suppresses bleomycin-induced lung fibrosis [American Journal of Physiology ⁇ —— Lang Cellular ⁇ ⁇ and And Molecular ⁇ ⁇ American Journal of Physiology- Lung Cellular ana Molecular Physiology) ⁇ 279, L895-902 (2000)].
  • the inhibition type is an allosteric type, and it has been reported that it has enhanced action and persistence as follows (Nature 1 Bistructural Nature). 9: 268-272 (2002); Bioorganic & Medicinal Chemistry Letters, 14: 5389-5394 (2004); Nature ⁇ ⁇ ⁇ Structural 'Molecular ⁇ ⁇ ⁇ Biology (Nature Structural Molecular Biology), 11th, pp. 192-1197 (2004)].
  • Patent Document 1 US Patent Application Publication No. 2004/0209904
  • Patent Document 2 International Publication No. 04/092144 Pamphlet
  • An object of the present invention is to contain a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient, and to separate side effects from systemic exposure and pharmacological effects at a target disease site. It is to provide a topical agent.
  • the present invention relates to the following (1) to (66).
  • the local concentration of a compound having a P38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or its pharmacologically acceptable salt when administered locally is 350 times or more of its plasma concentration.
  • the topical administration agent comprising, as an active ingredient, the compound having a p38MAPK inhibitory action or a pharmacologically acceptable salt thereof.
  • the P38MAPK in which the local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is 1000 times or more of its plasma concentration
  • the topical administration agent comprising a compound having an inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkyl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower cycloalkyl force sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group Or CO NR 5a R 5b (wherein R 5a and R 5b are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl),
  • X is a bond, oxygen atom, sulfur atom, CR 6a R 6b (wherein R 6a and R 6b are the same or different and are a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl or substituted Is a force representing unsubstituted lower alkoxy, or R 6a and R 6b together represent an oxygen atom) or NR 7 (wherein R 7 is a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or non-substituted) Represents a substituted lower alkanoyl),
  • R 3 is a substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted.
  • R and R 8b are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl, Represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or R and R 8b together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocyclic group)
  • R 3 is Represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
  • R 4 is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Heterocyclic group, CONR 9a R 9b (wherein R 9a and R 9b are as defined above for R 8a and R 8b respectively) or COR 1Q (wherein R 1Q is a hydrogen atom, hydroxy, substituted or unsubstituted) Lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or The above-mentioned (1) to (4), which are 2-aminoquinazoline derivatives represented by the above
  • R 2a is a substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic group or CR U R 12 R 13 [wherein R 11 is a hydrogen atom or substituted or unsubstituted Represents unsubstituted lower alkyl,
  • R 12 and R 13 are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, OR 14 (wherein R 14 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl. , Substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group), S (O) R 14a (wherein R 11 ⁇ 2 Is synonymous with R 14 above, p represents an integer of 0-2), C
  • R 12 and R 13 together with the adjacent carbon atom form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted alicyclic heterocyclic group.
  • R 11 is a hydrogen atom
  • R 12 and R 13 are not hydrogen atoms at the same time.
  • R 2a is CR Ua R 12a R 13a (wherein R Ua represents a hydrogen atom or a substituted or unsubstituted lower alkyl;
  • R 12a and R 13a are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R 12a and R 13a together with an adjacent carbon atom are substituted or unsubstituted cycloalkyl or Forms a substituted or unsubstituted alicyclic heterocyclic group.
  • R Ua is a hydrogen atom
  • R 12a and R 13a are not hydrogen atoms at the same time.
  • R 4 is halogen or substituted or unsubstituted aryl.
  • the topical administration agent according to any one of the above.
  • r represents an integer from 0 to 4,
  • Y is an oxygen atom
  • C 0, NR 17 (wherein R 17 is a hydrogen atom, sulfiated carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxy Carb or substituted or unsubstituted lower alkyl sulfol) or CHR 18 (wherein R 18 is a hydrogen atom, hydroxy, amino-substituted carboxy, sulfur-substituted substituted or unsubstituted lower alkyl, substituted or unsubstituted Substituted lower alkoxy, mono or di (substituted or unsubstituted lower alkyl) amino-substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkyl sulfol, NR 19 COR 2
  • R 3a represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
  • R 16 is amino, hydroxy, sulfi-substituted carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, mono- or di (substituted or unsubstituted lower alkyl) ami-substituted or unsubstituted lower alkanol, Substituted or unsubstituted lower Lucoxycarbol, substituted or unsubstituted lower alkyl sulfole, NR COR (wherein R 21a and R 22a are as defined above for R 19 and R 2 °) or NR 21b S (0) R 22b ( formula
  • R 21b and R 22b are the same as R 19 and R 2 °, respectively.
  • each R 16 may be the same or different, and is a 2-aminoquinazoline derivative represented by> or a pharmacologically acceptable salt thereof.
  • the topical administration agent according to any one of (1) to (4).
  • R la and R 2b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted.
  • R 3b represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
  • R 4a represents a hydrogen atom or halogen
  • Xa represents an oxygen atom or a sulfur atom
  • a conductor or a pharmacologically acceptable salt thereof is provided.
  • a conductor or a pharmacologically acceptable salt thereof is provided.
  • R 2a is CR Ua R 12a R 13a (wherein R Ua , R 12a and R 13a are each as defined above) or the 2-aminoquinazoline derivative according to (32) or a pharmacological thereof Acceptable salt.
  • R 23 represents a hydrogen atom, halogen or lower alkyl
  • R 24 is selected from lower alkyl, cycloalkyl, lower alkoxy, aryl, substituent A force selected from 1 to aryl substituted with a substitutable number of substituents, aromatic heterocyclic group or substituent A force 1 Represents an aromatic heterocyclic group substituted with one to a substitutable number of substituents.
  • s is an integer from 2 to 4, each R 23 may be the same or different;
  • Substituent A neurogen, lower alkyl, hydroxy lower alkyl, cycloalkyl, aryl, 1 to substitutable number of halogens and Z or 1 to substitutable number of lower alkyl substituted with- NR 25a R 25b (wherein R 25a and R 25b are the same or different and represent a hydrogen atom, lower alkyl or cycloalkyl, or R 25a and R 25b together with the adjacent nitrogen atom are cycloaliphatic
  • R 24 is - (wherein, R 25a and R 25b have the same meanings as defined above) NR 25a R 25b is substituted with Hue - le or - NR 25a R 25b (wherein, R 25a And R 25b is as defined above, and the 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to (36), which is pyridyl substituted with
  • R 24 is a one or more substitutable number substituted with a halogen substituted with one to substitutable number of halogens and Z or one to substitutable number of lower alkyl, or one to substitutable
  • R 4b represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group) or a pharmacologically acceptable salt thereof.
  • R la is a hydrogen atom
  • R 2a is CR Ua R 12a R 13a (wherein R n R 12a and R 13a have the same meanings as defined above), An aminoquinazoline derivative or a pharmacologically acceptable salt thereof.
  • a compound having a p38MAPK (Mitogen-Activated Protein Kinase) inhibitory activity is any one of the 2-aminoquinazoline derivatives described in any one of (24) to (48) above or a pharmacologically acceptable salt thereof.
  • the local concentration of a compound having p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof when administered locally is 350 times or more of its plasma concentration.
  • a method for treating a disease by local administration comprising a step of administering an effective amount of the compound having a p38MAPK inhibitory action or a pharmacologically acceptable salt thereof.
  • a method for treating a disease by local administration comprising a step of administering an effective amount of a compound or a pharmaceutically acceptable salt thereof.
  • the local concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is the plasma concentration.
  • the local concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is 1000 with respect to its plasma concentration.
  • the concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically for the production of a topical agent is 2000 with respect to its plasma concentration.
  • a topical administration agent or the like containing a compound having a p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient is provided.
  • p38MAPK Mitogen-Activated Protein Kinase
  • local means the affected area, specifically, for example, the eyeball and surrounding tissues, respiratory organs (more specifically, nasal cavity, sinuses, oral cavity, pharynx, Tonsils, trachea, trachea, alveoli, etc.), digestive organs, skin, spinal cord and the like. Also included are diseased tissues such as benign and malignant tumor tissues, polyps, abscesses, cysts and the like. The nearby vasculature associated with them is also included.
  • the topical administration agent of the present invention can be used to treat, for example, respiratory diseases.
  • respiratory diseases include respiratory diseases accompanied by contraction of bronchial smooth muscle, respiratory diseases involving airway vasculature contraction, and the like.
  • Respiratory disease with reversible, respiratory disease with reversible or irreversible degeneration of the alveoli respiratory disease with reversible or irreversible tissue degeneration of the nasal cavity, reversible or irreversible tissue of the sinuses
  • Respiratory diseases with mechanical degeneration and more specifically, bronchial asthma, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • skin diseases can be treated with the topical administration agent of the present invention.
  • the skin diseases include skin diseases accompanied by inflammation, reversible or irreversible tissue degeneration of skin tissues, and the like.
  • the topical administration agent of the present invention can treat, for example, eye diseases.
  • eye diseases include, for example, eye diseases accompanied by inflammation, reversible or irreversible of the eyeball and surrounding tissues.
  • Ocular diseases with systemic degeneration ocular diseases with reversible or irreversible systemic degeneration of the peripheral vasculature, and more specifically, allergic conjunctivitis, uveitis, cataract, glaucoma, retina
  • examples include exfoliation, macular degeneration, and dry eye.
  • gastrointestinal diseases with the topical administration agent of the present invention.
  • the digestive diseases include digestive diseases with inflammation, digestive diseases with mucus secretion, Digestive tract diseases with reversible or irreversible systemic degeneration of the digestive tract, digestive tract diseases with reversible or irreversible systemic degeneration of the peripheral GI system, and more specifically inflammation Examples include ulcerative colitis, Crohn's disease, stomatitis, irritable colitis, colon cancer, rectal cancer, and colon cancer.
  • central nervous system diseases can be treated with the topical administration agent of the present invention.
  • the central nervous system diseases include, for example, central nervous system diseases accompanied by inflammation, reversible or irreversible nerves.
  • ALS amyotrophic lateral sclerosis
  • Examples of the method for administering the topical administration agent of the present invention include local injection, local inhalation, and topical application.
  • the compound having a P38MAPK inhibitory action, or its pharmacology whose local AUC (local concentration) is 350 times or more that of plasma AUC (plasma concentration)
  • the compound having the P38MAPK inhibitory action or its pharmacology at a concentration of 500 times or more, more preferably 1000 times or more, and even more preferably 2000 times or more is acceptable. Salts that are acceptable.
  • More specific examples of the substance used as the active ingredient of the topical administration agent of the present invention include substances having the following properties, which are used as the active ingredient of the topical administration agent of the present invention.
  • the material to be used is not limited to these.
  • P38MAPK inhibitory compounds or pharmacologically acceptable salts are collectively referred to as substances. Absorption of locally administered substances from the administration site was very slow, and after transferring to circulating blood, it was quickly inactivated by hepatic metabolism, while substances leaked in the digestive tract also absorbed intestinal force. Later, it is also metabolically inactivated in the liver as quickly.
  • the lower alkyl part of lower alkyl, lower alkoxy, lower alkoxy carbo, mono- or di-lower alkylamino and lower alkylsulfonyl includes, for example, linear or Or branched alkyl having 1 to 10 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl , Octyl, nonyl, decyl and the like.
  • the two lower alkyl moieties of the di-lower alkylamino may be the same or different.
  • the alkylene part of hydroxy lower alkyl has the same meaning as that obtained by removing one hydrogen atom from the lower alkyl force.
  • lower alkenyl examples include linear or branched alkenyl having 2 to 10 carbon atoms, more specifically vinyl, allyl, 1-propenyl, methacryl, crotyl, 1-butenyl, 3- Butyl, 2-Pentel, 4-Pentel, 2-Hexel, 5-Hexel, 2-Heptel, 2-Otatur, 2-Nonele, 2-Deseal Etc.
  • Examples of the lower alkynyl include straight-chain or branched alkynyl having 2 to 10 carbon atoms, more specifically, etul, 2-probule, 2-butyur, 2-pentyl, 2-hexyl, Examples include 2-heptur, 2-octyl, 2-nonyl, and 2-decyl.
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and more specifically cyclopropynole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like.
  • the cycloalkenyl includes, for example, a cycloalkenyl having 3 to 8 carbon atoms, more specifically, cyclopropeninole, cyclobuteninole, cyclopenteninole, cyclohexenole, cycloheptenyl, cyclootatur and the like.
  • lower alkanoyl examples include linear or branched alkanoyl having 1 to 8 carbon atoms, more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, heptanoyl, otatanyl and the like.
  • the cycloalkyl moiety in the cycloalkyl carbocycle has the same meaning as the above cycloalkyl.
  • aryl examples include aryl having 6 to 14 carbon atoms, and more specifically, ferrule, naphthyl, and anthryl.
  • aralkyl for example, carbon number? ⁇ 15 aralkyl, more specifically benzyl, Examples include phenethyl, benzhydryl, naphthylmethyl, and the like.
  • Examples of the aromatic heterocyclic group include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, Examples include condensed bicyclic or tricyclic condensed rings containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • pyraduryl pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazol Ril, tetrazolyl, chenyl, furyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, ben
  • Examples include zotriazolyl, benzothiazolyl, benzoxazolyl, purinyl and the like.
  • heterocyclic group examples include the aromatic heterocyclic group and the alicyclic heterocyclic group.
  • alicyclic heterocyclic group include at least one selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • condensed alicyclic heterocyclic groups containing one atom and more specifically pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidyl, homopiperadil, tetrahydropyridinyl, tetrahydro
  • Examples include quinolyl, tetrahydroisoquinol, tetrahydrofural, tetrahydrobiral, and dihydrobenzofural.
  • Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group). May contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed ring-containing heterocyclic group containing 3 to 8 membered rings and containing at least one nitrogen atom (The condensed polycyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, pyrrolidyl, piperidyl-containing piperazil, morpholino, Homopiperadil with thiomorpholine, tetrahydropyridyl, tetrahydroquinolyl, teto And lahydroisoquinolyl.
  • the cycloalkyl formed together with the adjacent carbon atoms has the same meaning as the above cycloalkyl.
  • the alicyclic heterocyclic group formed together with adjacent carbon atoms has the same meaning as the alicyclic heterocyclic group.
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • substituted cycloalkyl formed with amino, substituted lower alkanol, substituted cycloalkyl carbo yl, substituted lower alkoxycarbonyl, substituted lower alkyl sulphone and adjacent carbon atom (substituent a)
  • substituted cycloalkyl formed with amino, substituted lower alkanol, substituted cycloalkyl carbo yl, substituted lower alkoxycarbonyl, substituted lower alkyl sulphone and adjacent carbon atom
  • substituted cycloalkyl formed with amino, substituted lower alkanol, substituted cycloalkyl carbo yl, substituted lower alkoxycarbonyl, substituted lower alkyl sulphone and adjacent carbon atom (substituent a)
  • substitutions more specifically, halogen, hydroxyimine-containing lower alkoximino, sia-containing cycloalkyl, lower alkanoyloxy, substituted or unsubstituted aryl
  • substituted aryl are, for example, the same or different and having 1 to 3 substituents, more specifically, halogen, amino-containing hydroxy, cyanated carboxy, lower alkyl, lower alkoxy, lower alkanol, mono or Di-lower alkylamino-containing heterocyclic groups, etc.), substituted or unsubstituted heterocyclic groups (including Examples of the substituent in the substituted heterocyclic group include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, amino, hydroxy, carboxy-containing, lower alkyl, lower alkoxy, lower alkanol, lower alkylsulfo- CONR 26a R 26b wherein R 26a and R 26b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, the same or different Differently substituted 1 to 3, more
  • Substituted or unsubstituted lower alkynyl substituted lower alkynyl
  • substituted lower alkynyl substituted lower alkynyl
  • substituted lower alkynyl substituted lower alkynyl
  • substituted lower alkoxy substituted lower alkoxy
  • substituted lower alkoxy substituted lower alkoxy are, for example, the
  • R 26a and R 26b are substituted together with the adjacent nitrogen atom
  • an unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group formed together with the adjacent nitrogen atom is, for example, the same or different, the number of substitution is 1 to 3, more specifically, NR 26 26d (wherein R 26e and R 26d have the same meanings as R 26a and R 26b , respectively), 0 R 27b ( In the formula, R is as defined above for R 27 ), COR 27e (where R 27e is as defined above for R 27 ), CO R 27d (wherein R TM is as defined above for R 27 ) , S (O) R 27e (where pi represents an integer from 0 to 2)
  • R 27e has the same meaning as R 27 ), SO NR 26 26f (wherein R 26e and R 26f are each R 26a
  • Substituents in substituted cycloalkyl and substituted cycloalkenyl are substituted or unsubstituted lower alkyl in addition to the above-mentioned substituents (substituents in the substituted lower alkyl are, for example, the same or different, having 1 to 3 substitutions, Specific examples thereof include halogen, hydroxy, lower alkoxy and the like.
  • the lower alkanoyl moiety of alkanoyloxy, aryl, aromatic heterocyclic group, heterocyclic group and heterocyclic group formed together with the adjacent nitrogen atom are as defined above, respectively, lower alkyloximino and lower alkylsulfo-
  • the lower alkyl part of luamino has the same meaning as the lower alkyl.
  • substituent in the formed substituted alicyclic heterocyclic group include, for example, the same or different and the number of substitutions of 1 to 3, more specifically, halogen, nitro, hydroxy, carboxy-substituted, lower alkanoyloxy, Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl has the same meaning as the substituent a), substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy has the same meaning as the substituent a) A substituted or unsubstituted lower alkanol (the substituent in the substituted lower alkanol is as defined above for the substituent a), substituted or non-substituted Lower al
  • the lower alkyl part of halogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl and lower alkylsulfol, and the lower alkanol part of lower alkanoyloxy and lower alkanoyloxy are as defined above.
  • the pharmacologically acceptable salts of the compound having P38MAPK inhibitory activity include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmacologically acceptable acid addition salts of compounds having P38MAPK inhibitory action include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, acetate, maleate, and fumarate. And organic acid salts such as citrate, and pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, Aluminum salts, zinc salts, etc. can be mentioned, and pharmacologically acceptable ammonium salts include ammonium salts, tetramethyl ammonium salts, etc., which are pharmacologically acceptable.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, acetate, maleate, and fumarate.
  • organic acid salts such as citrate
  • pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such
  • organic amine addition salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include addition of glycine, ferrolanine, lysine, aspartic acid, glutamic acid and the like. Salt I can get lost.
  • the 2-aminoquinazoline derivative or pharmacologically acceptable salt thereof used in the present invention and the 2-aminoquinazoline derivative or pharmacologically acceptable salt thereof of the present invention include, for example, the following kinases: It can also be used as an inhibitor.
  • KINASE INSERT DOMAIN RECEPTOR KDR
  • KDR ABELSON MURINE LEUKEMIA VI RAL ONCOGENE HOMOLOG 1
  • ABLl ACTIVATED P21CDC42HS KINASE
  • a CK ACTIVATED P21CDC42HS KINASE
  • TYR03 PROTEIN TYROSINE KINASE
  • CSK CYTOPLASMIC TYROSIN E KINASE
  • EPHRIN RECEPTOR EphA2 EPHRIN RECEPTOR EphA2
  • EPHB4 EPHRIN RECEPTOR Ep hB4
  • PROTEIN- TYROSINE KINASE CYTOPLASMIC B (FGFRl)
  • INSULIN-LIKE GROWTH FAC TOR I RECEPTOR IGFIR
  • JANUS KINASE 3 JANUS KINASE 3
  • Compound (I) can be produced, for example, by a known method (US2004 / 0209904, WO04 / 092144).
  • Compound (I) can also be produced, for example, by the following steps. Manufacturing method 1
  • a compound (Id) in which X is a bond and R 3 is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group is produced, for example, according to the following steps. can do.
  • R 3 ° represents a substituted or unsubstituted lower alkyl
  • Compound (III) can be obtained by reacting Compound (II) with 1 to 20 equivalents of bromine in a solvent.
  • a solvent for example, acetic acid, carbon tetrachloride, chloroform, formaldehyde, dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran (THF), ethyl acetate, etc. can be used, and preferably acetic acid is used. be able to.
  • the reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 60 ° C. for about 5 minutes to 48 hours.
  • N-bromosuccinimide for example, N-bromosuccinimide, pyrrolidone tripromide, cuprous bromide, pyridinium mutobide amide and the like can be used.
  • the solvent include acetonitrile, methanol, ethanol, dichloromethane, 1,2-dichloroethane, chlorohonolem, dimethoxyethane, ⁇ , ⁇ -dimethylformamide (DMF), dioxane, THF, jetyl ether, diisopropyl ether.
  • ⁇ , ⁇ -dimethylimidazolidinone, ⁇ -methylpyrrolidone, sulfolane and the like can be used, and preferably DMF can be used.
  • Compound (II) is a commercially available product or a known method from a fluorobenzene derivative ⁇ referred to fluorination of a fluorobenzene derivative [for example, see Chemical Reviews, 90 pp. 879 (1990), etc.] ] Then, formylation [see, for example, Experimental Chemistry Course, page 21, page 30 (1991), etc.] etc. ⁇ or a method analogous thereto can be obtained.
  • Compound (V) can be obtained by known methods [for example, see Journal of Heterocyclic Chemistry, 34, 385 (1997)] or a method analogous thereto. It can be obtained by reacting (III) with 1 to 20 equivalents of compound (IV) in a solvent in the presence of 1 to 20 equivalents of a base.
  • ⁇ ⁇ , ⁇ -dimethylacetamide (DMA), DMF, N-methylpyrrolidone, dimethyl sulfoxide (DMSO) and the like can be used, and DMA can be preferably used.
  • DMA ⁇ , ⁇ -dimethylacetamide
  • DMF dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide and the like can be used, and potassium carbonate or cesium carbonate is preferably used.
  • the reaction is carried out at a temperature between room temperature and 180 ° C, preferably at 160 ° C, for 5 minutes and for 48 hours. Done about.
  • Compound (IV) is a commercially available product or a known method [see, for example, Journal of Organic Chemistry, page 57, page 2497 (1992)] or a method equivalent thereto. Can be obtained.
  • Compound (VIII) is obtained by reacting Compound (V) with 1 to 20 equivalents of Compound (VI) or (VII) in the presence of 0.1 to 10 equivalents of base and 0.001 to 1 equivalents of palladium catalyst in a solvent. be able to.
  • Examples of the solvent include acetonitrile, methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform, DMA, DMF, dioxane, THF, jetyl ether, disopropyl ether, benzene, toluene, xylene, Use ⁇ , ⁇ -dimethylimidazolidinone, ⁇ -methylpyrrolidone, sulfolane, a mixture of at least one solvent selected from these forces and water in an appropriate ratio between 100: 1 and 1: 100.
  • a 1: 2 mixture of water and dioxane can be used.
  • Examples of the base include pyridine, triethylamine, ⁇ ⁇ ⁇ -methylmorpholine, ⁇ -methylpiperidine, piperidine, piperazine, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, water Sodium oxide, lithium hydroxide, potassium hydroxide, potassium phosphate, sodium tert-butoxide, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), diisopropylethylamine, etc. can be used.
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • sodium carbonate can be used.
  • compound (VII) it is not necessary to use a base.
  • the palladium catalyst for example, palladium acetate, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium and its chloroformated carbonate can be used as the palladium source, and as the ligand, for example, Triphenylphosphine, ⁇ , -bis (diphenylphosphino) phenol, 0-tolylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3- (bisdiphenylphosphino) propane, 1,4 -Bis (diphenylphosphino) butane, di-tert-butyldiphenylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, etc.
  • the ligand for example, Triphenylphosphine, ⁇ , -bis (diphenylphosphino
  • ligand can be used. It is preferable to use 1 to 10 equivalents of the ligand with respect to palladium.
  • tetrakis triphenylphosphine
  • a ligand suitable for the reaction such as palladium, 1,1-bis (diphenylphosphino) phenol dichloropalladium-dichloromethane 1: 1, etc. is coordinated to palladium in advance.
  • the reaction is carried out at a temperature between the boiling points of the solvents used, preferably 100 ° C, for 5 minutes to 48 hours.
  • Compound (VI) and Compound (VII) may be obtained as commercially available products or by known methods [see, for example, Experimental Chemistry Course, 24 ⁇ , Japan Society of Health Sciences (1992)] or a method analogous thereto. I'll do it.
  • Compound (Id) is compound (VIII) with 1 to 100 equivalents of thiol compound, acid, trimethylsilyl iodide or sodium sulfite in a solvent at a temperature between -30 ° C and the boiling point of the solvent used. It can be produced by treating at a temperature of 5 minutes to 72 hours.
  • thiol compound for example, thiophenol, methanethiol, ethanethiol and the like can be used, and alkali metal salts thereof such as sodium thiophenoxide, sodium thiomethoxide, sodium thiooxide and the like can also be used. it can.
  • hydrogen bromide Z acetic acid for example, hydrogen bromide Z acetic acid, salt pyridinium, boron trifluoride, fluorine tribromide, trisalt bromine, aluminum bromide, salt bromide aluminum, etc. may be used. it can.
  • the solvent for example, dichloromethane, chloroform, 1,2-dichloroethane, DMF, N-methylpyrrolidone (NMP), jetyl ether, THF, a mixed solvent thereof or the like can be used.
  • R 4 is a chlorine atom, bromine atom or iodine atom (Ie) and a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic ring
  • the compound (If) as a group can be produced, for example, according to the following steps.
  • R 4e represents a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group
  • L 1 Represents a chlorine atom, a bromine atom or an iodine atom
  • Compound (X) is compound (IX), and when L 1 is a bromine atom, it can be synthesized according to Step 1-1 of Production Method 1, and when L 1 is an iodine atom, for example, methanol In the presence of sodium chlorite in a solvent such as ethanol, it can be synthesized by reacting a base such as sodium hydroxide or potassium hydroxide and sodium iodide.
  • L 1 is a chlorine atom
  • it can be synthesized by reacting chlorine or N-chlorosuccinimide in a solvent such as black mouth form or tetrasalt carbon.
  • Compound (IX) can be obtained, for example, by the method described in Production Method 1, 4 or 5, or a method analogous thereto.
  • Compound (XIV) can be synthesized according to Step 1 of Production Method 1.
  • Compounds (XI), (XII) and (XIII) can be obtained as commercial products.
  • Compounds (XI) and (XII) can be obtained by a known method such as “Experimental Chemistry Course, 24 ⁇ , Chemical Society of Japan (1992)”.
  • Compound) can be synthesized from compound (X) by, for example, step 1-4 of production method 1.
  • Compound (If) is synthesized from compound (XIV) by a method, for example, in steps 1 to 1 of production method 1. can do.
  • R 4 is carboxy (Ig) and CONR 9a R 9b (wherein R 9a and R 9b are as defined above), It can be manufactured according to the process.
  • R 9a , R % , R 3 °, X and L 1 are the same as defined above, and R 31 represents substituted or unsubstituted lower alkyl
  • Compound (XVI) is obtained by converting Compound (X) from 1 to 1000 equivalents of Compound (XV) in the presence of 0.0001 to 2 equivalents, preferably 0.01 to 0.1 equivalents of a palladium complex, 0.1 to 100 atm, preferably 1 to 0 to 250 in a carbon monoxide atmosphere at 10 atm, optionally in the presence of 1 to 100 equivalents of a base, in a solvent or without a solvent. It can be synthesized by reacting at C, preferably 20 to 150 ° C, for 5 minutes to 48 hours. Compound (XV) can also be used as a solvent.
  • Examples of the palladium complex include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [bis (1,2-diphenylphosphino) ethane] dichloropalladium, [1,1,1, -Bis (Diphenyl-phosphino) Phenocene] dichloropalladium etc.
  • a combination of a palladium precursor and a phosphine that forms a palladium complex in the reaction system can be used.
  • the palladium precursor for example, palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon and the like can be used.
  • phosphine include triphenylphosphine, 1,1, -bis (diphenylphosphino) ferrocene, bis (1,2-diphenylphosphino) ethane, bis (1,3-diphenylphosphino) propan, bis (1,4-diphenylphosphino) butane, 2,2, -bis (diphenylphosphino) -1,1, -binaphthyl, bis (1,4-dicyclohexylphosphino) butane and the like can be preferably used.
  • the combination of palladium acetate and bis (1,3-diphenylphosphino) propane and the combination of palladium carbon and bis (1,3-diphenylphosphino) propane can be preferably
  • an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, potassium acetate or the like, or an organic base such as pyridine or triethylamine, preferably carbonic acid can be used.
  • Carbonates such as potassium and cesium carbonate can be used.
  • the compound (XV) for example, methanol, ethanol, 1-propanol and 2-butanol are preferable.
  • Examples of the solvent include aliphatic hydrocarbon solvents such as pentane, hexane and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, methanol, ethanol, propanol and butanol.
  • Alcohol solvents tetralin, diphenyl ether, ethyl acetate, methylene chloride, chloroform, dichloroethane, carbon tetrachloride, pyridine, acetonitrile, DMF, DMA, 1-methyl-2-pyrrolidone, 1,3-dimethyl- 2-Imidazolidinone, DMSO, sulfolane, dimethyl sulfone, THF, dioxane, dimethoxyethane, a mixed solvent thereof and the like can be used.
  • Compound (XVIII) is obtained by reacting Compound (XVI) with 1 to 100 equivalents of Compound (XVII) in the presence of 1 to 100 equivalents, preferably 1 to 10 equivalents of a base, in a solvent or without solvent.
  • C force It can be synthesized by reacting at a temperature between the boiling points of the solvents used, preferably at -78 to 30 ° C for 5 minutes to 48 hours. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
  • butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide and the like can be used, and preferably butyl lithium is used.
  • the solvent for example, THF, jetyl ether, dioxane, diisopropyl ether, dimethoxyethane and the like can be used, and preferably THF can be used.
  • Compound (XVII) can be obtained as a commercially available product or by a known method [for example, the method described in Experimental Chemistry Course, 20 pp. 279, Maruzen (1992), etc.] or a method analogous thereto. it can.
  • Compound (Ig) can be synthesized from compound (XVI) by, for example, step 1 to step 1-4 of production method 1.
  • Compound (Ih) can be synthesized from compound (XVIII) by a method, for example, in Step 1-4 of Production Method 1.
  • Compound (I) can be produced, for example, according to the following steps.
  • Compound (XX) can be synthesized by subjecting compound (XIX) to a Sandmeyer reaction.
  • compound (XX) is obtained by combining compound (XIX) in a solvent in the presence of 1 to 100 equivalents of a nitrite compound and optionally 1 to 1000 equivalents of acid and 1 to 1000 equivalents of a halogen source. The reaction is allowed to proceed for 5 to 100 hours in a solvent-free environment at temperatures between -30 ° C and the boiling point of the solvent used. And can be synthesized.
  • nitrous acid compounds include nitrites such as nitrous acid and sodium nitrite, halogenated trosils such as -tosyl chloride, alkyl nitrites such as tert-butyl nitrite and isoamyl nitrite. Can be used.
  • Halogen sources include copper chloride (1), copper bromide (1), copper iodide (1), copper chloride (11), copper bromide (11), copper iodide (11), potassium iodide, Jodomethane or the like can be used.
  • solvent for example, alcohols such as methanol and ethanol, ethers such as THF and dioxane, acetone, DMSO, DMF, water, a mixed solvent thereof and the like can be used.
  • Compound (XXII) is a mixture of compound (XX) and 1 to 1000 equivalents of amine (XXI) in a solvent or non-solvent, optionally in the presence of 1 to 100 equivalents of a base, from 0 ° C. It can be synthesized by reacting at a temperature between the boiling points, preferably 0-100 ° C, for 5 minutes to 48 hours.
  • reaction can also be carried out in the presence of 0.0001 to 2 equivalents, preferably 0.01 to 0.1 equivalents of a palladium complex.
  • Examples of the palladium complex include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [bis (1,2-diphenylphosphino) ethane] dichloropalladium, [1,1, -bis ( Others such as diphenyl-phosphosino) weicene dichloropalladium
  • a combination of a palladium precursor and a phosphine that forms a palladium complex in the reaction system can be used.
  • the palladium precursor for example, palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon and the like can be used.
  • phosphine examples include triphenylphosphine, 1,1, -bis (diphenylphosphino) ferrocene, bis (1,2-diphenylphosphino) ethane, bis (1,3-diphenylphosphino) propan, bis (1,4-diphenylphosphino) butane, 2,2, -bis (diphenylphosphino) -1,1, -binaphthyl, bis (1,4-dicyclohexylphosphino) butane and the like can be used.
  • an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide or potassium acetate, or an organic base such as pyridine or triethylamine can be used.
  • the solvent examples include aliphatic hydrocarbon solvents such as pentane, hexane, and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and alcohol solvents such as methanol, ethanol, propanol, and butanol.
  • aliphatic hydrocarbon solvents such as pentane, hexane, and cyclohexane
  • aromatic hydrocarbon solvents such as benzene, toluene, and xylene
  • alcohol solvents such as methanol, ethanol, propanol, and butanol.
  • Compound (XXI) is obtained as a commercially available product or by a known method [for example, the method described in Experimental Chemistry Course, 20th page, page 279, Maruzen (1992), etc.] or the method described in Reference Examples. be able to.
  • Compound (I) can be synthesized from compound (XXII) by a method, for example, in Step 1-4 of Production Method 1.
  • R 7e represents a hydrogen atom or a substituted or unsubstituted lower alkyl
  • Compound (XXIII) uses Compound (Ilia), for example, Protective uroups in Organic Synthesis, third edition, TW Greene, John's It can be produced in accordance with the formyl protection method described in John Wiley & Sons Inc. (1999).
  • compound (XXIII) is obtained by mixing compound (Ilia) with 1 to 200 equivalents of compound (XV), in a solvent or without solvent, from a catalytic amount to 5 equivalents of acid and 1 to 10 equivalents of dehydrating agent. It can be synthesized by reacting for 5 to 48 hours at a temperature between -30 ° C and the boiling point of the solvent used.
  • P-toluenesulfonic acid can be used as the acid
  • examples of the dehydrating agent include For example, trimethyl orthoformate can be used.
  • the solvent for example, THF, 1,4-dioxane, a mixed solvent thereof or the like can be used.
  • Compound (XV) can be obtained as a commercial product.
  • diols such as ethylene glycol and 1,3-propylene glycol can also be used.
  • Compound (XXV) is obtained by treating Compound (XXIII) with 1 to 20 equivalents of base in a solvent at a temperature between ⁇ 100 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. It can be produced by reacting an equivalent amount of the compound (X XIV) at a temperature between ⁇ 100 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. If necessary, after treatment with a base, add 1 to 20 equivalents of salt or cerium, salt or triisopropoxytitanium at the same temperature, and then react with the compound (XXI V). You may let them. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
  • an inert gas atmosphere such as nitrogen or argon.
  • Compound (XXIV) can be obtained as a commercially available product, or by amidation of the corresponding carboxylic acid and amine (see, for example, Experimental Chemistry Course, Vol. 22, p. 258 (1992)). it can.
  • As the base for example, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium hexamethyldisilazide and the like can be used.
  • solvent for example, jetyl ether, THF, 1,2-dimethoxyethane (DME), 1,4-dioxane, n-hexane, toluene, a mixed solvent thereof or the like can be used.
  • Compound (XXVI) is treated with Compound (XXV) in a solvent or in the absence of water, in the presence of water, with a catalytic amount to 200 equivalents of acid at a temperature between 0 and 150 ° C for 5 minutes. Can be synthesized.
  • Examples of the acid include hydrochloric acid, sulfuric acid, 10-camphorsulfonic acid, trifluoroacetic acid, P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, titanium tetrachloride, boron trifluoride, and salt. ⁇ Aluminum or the like can be used.
  • solvent for example, THF, 1,4-dioxane, DME, a mixed solvent thereof or the like can be used.
  • Compound (XXVII) can be synthesized according to Step 1-2 of Compound (XXVI) Force Production Method 1.
  • Compound (Ii) can be synthesized from compound (XXVII) by, for example, the method described in Step 1-4 of Production Method 1.
  • a compound (I) having a desired functional group at a desired position can be obtained by appropriately combining the above methods.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • isomers such as tautomers may exist.
  • the present invention includes all possible isomers including these and mixtures in any ratio.
  • A), (IB), (IC), (ID), and (IE) are obtained in the form of a salt, they can be purified as they are. When they are obtained in a free form, they can be obtained by compound (1), ( IA), (IB) ⁇ (IC), (ID), and (IE) may be dissolved or suspended in a suitable solvent, and then isolated and purified by adding an acid or base.
  • the compounds (1), (IA), (IB), (IC), (ID) and (IE) and their pharmacologically acceptable salts are adducts with water or various solvents. These adducts are also encompassed by the present invention.
  • Test Example 1 Compound (I) in tissue and blood concentrations when administered locally to mouse pinna
  • the solution was prepared in accordance with conventional methods, and as an oral p38MAPK inhibitor BI RB796 [Nat. Struct. Biol., 9th, 268- 2 72 (2002)] was dissolved in acetone (Wako Pure Chemical Industries, Ltd.) and adjusted to the desired concentration.
  • acetone Waako Pure Chemical Industries, Ltd.
  • Compound 1 (1 w / v%) and BIRB796 (1 w / v%) dissolved in acetone were applied to the inside of the right auricle of mice in a volume of 20 ⁇ L / animal.
  • 30 minutes, 1 hour, 3 hours, 8 hours, and 24 hours after application blood was collected from the abdominal vena cava and the auricles were removed under anesthesia with ether.
  • a small amount of heline was added to the blood as an anticoagulant, and plasma was separated by centrifugation (600G, 10 minutes).
  • the tissue concentration AUC was 13200 ⁇ g'h / mL, and the plasma concentration AUC was 44.0 / z g'h / mL. It was found to be 300 times higher.
  • TPA Phorbol 12-myristate 13-acetate
  • Compound 1 0.01, 0.1, 1 w / v%) or BIRB796 (1) dissolved in the inner right mouse ear (same site as TPA application) 10 minutes before, 24 hours and 48 hours after TPA application w / v%) was applied at a volume of 20 L / animal.
  • a negative control group of mice was given the same volume of acetone instead of TPA.
  • acetone in the same volume was applied to mice in the negative control group and the positive control group. Each group used 5 or 6 mice. 72 hours after application of TPA, the thickness of the right auricle was measured using DIAL THI CKNESS GAUGE (model G, Ozaki Seisakusho) to examine the degree of auricular swelling.
  • Test Example 3 Glucuron due to in vitro metabolic evaluation system using human and mouse liver microsomes, this cattle.) ⁇ (I)
  • the reaction was stopped by stirring and stirring 100 ⁇ L of a acetonitrile solution containing 1 ⁇ g / mL of IS, to prepare a sample with a reaction time of 15 minutes.
  • 100 ⁇ L of a solution of acetonitrile containing nitrile was added to stop the reaction, and a sample having a reaction time of 0 minutes was used. Both samples were left on ice for about 10 minutes and then centrifuged. An equal amount of 10 mmol / L ammonium acetate was stirred in 100 ⁇ L of the supernatant after centrifugation to prepare an analytical sample.
  • the mass to charge ratio corresponding to the compound and its glucuronide conjugate (+176 Da) was measured by LC / MS / MS.
  • Residual rate (%) X 100 Peak height ratio with I.S. at 0 min reaction time
  • the survival rate after 15 minutes was 10% or less, and it was rapidly metabolized in the presence of UDPGA.
  • a peak corresponding to the glucuronic acid conjugate of Compound 1 was detected from the sample 15 minutes after the reaction. Based on the above, when Compound 1 enters the circulating blood stream, it is presumed that it undergoes inactivation and undergoes excretion promptly due to the metabolism of dalcronate conjugates in the liver.
  • the solution was prepared according to a conventional method.
  • Compound 34 was dissolved in acetone (Wako Pure Chemical Industries, Ltd.) to prepare the desired concentration.
  • Topical administration to the auricular skin dissolves in acetone inside the right auricle of mice.
  • Compound 34 (0.1 w / v%) was applied in a volume of 10 ⁇ L / animal.
  • 30 minutes, 1 hour, 2 hours, 9.5 hours, and 24.5 hours after application blood was collected from the thigh arteriovenous vein and the ears were removed under anesthesia with ether.
  • a small amount of heline was added to the blood as an anticoagulant, and the plasma was separated by centrifugation. Plasma pretreatment and concentration measurement were performed in the same manner as in Test Example 1.
  • Auricular homogenate, pretreatment and concentration measurement were performed in the same manner as in Test Example 1.
  • plasma concentration is below the lower limit of quantification «0.008 ⁇ L).
  • the tissue concentration was 5.40-9.51 / ⁇ ⁇ ⁇ 1 / ⁇ , and the local concentration was found to be 675 times higher than the plasma concentration.
  • Test Example 6 Confirmation of glucuronic acid binding and co-metabolism of compound (I) by in vitro metabolic evaluation system using human and mouse liver microsomes (2) Reaction solution containing 1 ⁇ mol / L compound 34, liver microsomes (human or mouse), 25 ⁇ g / mL alametasin, 3.5 mmol / L magnesium chloride and 100 mmol / L Tris-HCl buffer (pH 7.4) was preincubated at 37 ° C for 5 minutes. The protein concentration of micronome in the reaction solution was 0.05 mg / mL for humans and 0.025 mg / mL for mice. The reaction was started by adding UDPGA with a final concentration of 2 mmol / L to the reaction solution.
  • the final reaction volume was 50 ⁇ L. After incubation at 37 ° C, the reaction was stopped by adding 100 ⁇ L of acetonitrile solution containing 1 ⁇ g / mL IS and stirring, and used as the sample after the reaction. The incubation time was 30 minutes for humans and 20 minutes for mice. Pretreatment of the analysis sample, measurement, and calculation of the residual ratio were performed in the same manner as in Test Example 3. In an in vitro metabolic test using human liver microsomes, the survival rate of compound 34 was 63.5%. In an in vitro metabolic test using mouse liver microsomes, the residual ratio of Compound 34 was 86.4%. Based on the above, it was estimated that Compound 34, like Compound 1, was inactivated by glucuronidation metabolism in the liver and rapidly excreted when entering the circulating blood stream.
  • the activated human ⁇ 38 ⁇ was purchased from Upstate (Cat. No. ⁇ .14-251).
  • ⁇ 38 ⁇ kinase inhibitory activity was measured by the procedure shown below with reference to the method of Whitmarsh AJ and Davis RJ [Methods Enzymol., 332 ⁇ , .319-336 (2001)]. .
  • Myelin basic protein (catalog number: 133-13493, Wako Pure Chemical Industries, Ltd.) (20 ⁇ g / Atsusei) was used as the substrate to receive phosphate, and the reaction was performed using 3- [N-Morpholino] propanesulfonic acid ( MOPS) (20 mmol / L, pH 7.2), j8-Glycetophosphate (Sigma) (25 mmol / L), ethylenebis (oxyethylenenitrilo) tetraacetic acid (EGTA) (1 mmol / L), NaVO (Sigma-Aldrich) (1 mmol / L), dithiothreitol (DTT)
  • the topical administration agent of the present invention When administered locally, the topical administration agent of the present invention has a local concentration of 350 times or more, preferably 500 times or more, more preferably 1000 times or more, more preferably 2 000 times the plasma concentration.
  • a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof at a concentration of twice or more as it is it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
  • compositions according to the present invention may also be used as a mixture with any other therapeutically effective one or more other active ingredients.
  • these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmacologically acceptable carriers.
  • the administration route it is desirable to use the most effective one in the treatment, for example, local administration methods such as inhalation, transdermal, nasal drop, and eye drop.
  • local administration methods such as inhalation, transdermal, nasal drop, and eye drop.
  • Examples of the administration form include inhalants, external preparations, nasal drops, eye drops, injections and the like.
  • Inhalants are produced by formulating the active ingredient in powder, liquid or suspension, blending it into an inhalation propellant or carrier, and filling it into a suitable inhaler.
  • the active ingredient is powder
  • a normal mechanical powder inhaler can be used, and in the case of liquid or suspension, an inhaler such as a nebulizer can be used.
  • inhalable propellants such as Freon-11, Freon-12, Freon-21, Freon-22, Freon-113, Freon-114, Freon-123, Freon-142c, Freon- 134a, CFC-227, CFC-C318, 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227)
  • a fluorine-based compound such as propane, isobutane, hydrocarbons such as n-butane, ethers such as jetyl ether, compressed gas such as nitrogen gas and carbon dioxide, etc. May be added with a suspension aid such as sorbitan triorate.
  • Suitable dosage forms for external preparations are not particularly limited, and examples thereof include ointments and creams. These can be produced, for example, by dissolving or mixing the active ingredient in a base such as white petrolatum.
  • an active ingredient is added to sterilized purified water, and if necessary, an isotonic agent such as sodium chloride sodium salt, a preservative such as P-hydroxybenzoic acid ester, a buffering agent such as a phosphate buffer, etc. are used.
  • an isotonic agent such as sodium chloride sodium salt, a preservative such as P-hydroxybenzoic acid ester, a buffering agent such as a phosphate buffer, etc.
  • a buffering agent such as a phosphate buffer, etc.
  • buffering agents such as phosphate buffer and boric acid buffer, tonicity agents such as sodium chloride, preservatives such as salt benzalcoum, P-hydroxybenzoate, etc. are used. Can be manufactured.
  • the injection can be produced using a diluent or solvent such as a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
  • a diluent or solvent such as a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
  • excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, soybean lecithin, fatty acid ester
  • auxiliary components selected from surfactants such as surfactants and plasticizers such as glycerin can be added.
  • the dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration mode, patient age, body weight, nature or severity of symptoms to be treated, etc. 1 ⁇ g to 1000 mg, preferably 0.05 to 100 mg, more preferably 0.01 to 20 mg per person is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above. [0140] Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples. However, the present invention is not limited to these.
  • the organic layer is anhydrous Then, the residue was dried with glycine, and then the solvent was distilled off under reduced pressure to obtain a syrupy residue.
  • the residue was dissolved in acetone (20 mL), tosylic acid monohydrate (1.7 g, 8.9 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Saturated multistory water and ethyl acetate were added thereto, and the organic layer was separated and washed with saturated multistory water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained precipitate was dissolved in DMF (10 mL), and isopropylamine (0.88 mL, 10 mmol) and triethylamine (0.96 mL, 6.9 mmol) were added thereto and stirred at room temperature for 30 minutes. . Water and ethyl acetate were added thereto, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Compound 20 was obtained in the same manner as in Step 5 of Reference Example 16 using Compound A26.
  • Compound 21 was obtained in the same manner as in Step 1 of Reference Example 19 and Step 5 of Reference Example 16 using 3-methoxyphenylboric acid.
  • Compound 22 in which 3-methoxybenzoyl at the 6-position of quinazoline was converted to 3-hydroxybenzoyl was also obtained.
  • Compound 23 was obtained in the same manner as in Step 1 of Reference Example 19 and Step 5 of Reference Example 16 by using 3-chloro-4-fluorophenylboric acid.
  • Compound 24 was obtained in the same manner as in Step 1 of Reference Example 19 and Step 5 of Reference Example 16 using 3,5-dimethylphenolboric acid.
  • Compound 25 was obtained in the same manner as in Steps 3 and 4 of Reference Example 1 and Step 5 of Reference Example 16 using Compound A27 and 1- (methylsulfol) piperidin-4-ylamine.
  • Compound 26 was obtained in the same manner as in Steps 3 and 4 of Reference Example 1 and Step 5 of Reference Example 16 using Compound A27 and 4-aminotetrahydropyran.
  • Compound 27 was obtained in the same manner as in Steps 3 and 4 of Reference Example 1 and Step 5 of Reference Example 16 using Compound A27 and trans-1,4-diaminocyclohexane.
  • OUIUI 60 6S'0 Be ⁇ d fH , 3 ⁇ 4 I 0UIUI 6 -2 ⁇ 6) Be ⁇ / — Be; ⁇ fi
  • Compound 39 was obtained in the same manner as in Step 5 of Reference Example 1 and Step 2 of Reference Example 32 using Compound A36 and 1-naphthaleneboronic acid.
  • Compound 40 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A49.
  • 3-iodo-4-methylbenzoic acid (1.00 g, 3.89 mmol) was dissolved in chlorochloride (12.5 mL) and stirred at 80 ° C. for 1.75 hours, and then the salt was dissolved under reduced pressure.
  • the reaction mixture was dissolved in salt methylene (10.0 mL) and 5-amino-3-methyl-l- (p-tolyl) pyrazole (0.728 g, 3.89 mmol) and ⁇ , ⁇ -diisopropylethylamine (0.678) were dissolved. (mL, 3.89 mmol) in methylene chloride (10.0 mL) and then stirred overnight at room temperature.
  • Compound 45 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A55.
  • SV ⁇ ⁇ be fi, e [/ 3 ⁇ 4 / -tobe f (- ⁇ -Be ⁇ )-- ⁇ -9--, ⁇ : be: ⁇ - ⁇ 3 ⁇ 4 ⁇ ⁇ ) ⁇ ⁇ ; s3 ⁇ 4i fi fist ⁇ 3 ⁇ 4f 3 ⁇ 4, ⁇ XBe: ⁇ [— Be (— ⁇ —Be ⁇ ) — a— N—, E— ⁇ , ⁇ osv ⁇ ⁇

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Abstract

An agent for topical administration comprising a compound having a P38MAPK (Mitogen-Activated Protein Kinase) inhibitory effect or a pharmacologically salt thereof as an active ingredient, wherein, when the agent is administered topically, the concentration of the compound or salt at the topically administered site is 350 times or more higher than that in the blood plasma. In the agent for topical administration, the compound having the P38MAPK inhibitory effect may be, for example, a phenol derivative or a fused heterocyclic compound having a phenol structure in the fused ring system.

Description

局所投与剤  Topically administered
技術分野  Technical field
[0001] 本発明は、 p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有する化合 物またはその薬理学的に許容される塩を有効成分として含有する局所投与剤に関 する。  [0001] The present invention relates to a topical administration agent containing a compound having p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient.
背景技術  Background art
[0002] P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効成 分として含有する P38MAPK阻害剤（以下、 P38MAPK阻害剤という）は、炎症性疾患、 自己免疫疾患、癌等の治療に有用であることが知られており、例えば以下の報告が なされている。  [0002] P38MAPK inhibitors (hereinafter referred to as P38MAPK inhibitors) containing a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient are inflammatory diseases, autoimmune diseases, cancers, etc. It is known to be useful for treatment. For example, the following reports have been made.
(i) P38MAPK阻害剤は、ラットにおいてアジュバントで誘発される関節炎を抑制する [ ァルツライティス 'アンド'リウマチズム（Arthritis & Rheumatism)、第 43卷、 175- 183頁 (2000年）；バイオオーガニック 'アンド'メディシナル ·ケミストリ ~ ·レターズ（Bioorgani c & Medicinal Chemistry Letters)、第 8卷、 2689- 2694頁（1998年）]。また、 P38MAP K阻害剤は、ラットでの連鎖球菌細胞壁により誘発される関節炎を抑制する [バイオ オーガニック'アンド'メディシナル 'ケミストリ^ ~ ·レターズ（Bioorganic & Medicinal Che mistry Letters)、第 11卷、 693- 656頁（2001年）]。  (i) P38MAPK inhibitors suppress adjuvant-induced arthritis in rats [Arthritis & Rheumatism, 43, 175-183 (2000); bioorganic 'and' Medicinal Chemistry Letters, Vol. 8, pp. 2689-2694 (1998)]. In addition, P38MAP K inhibitors suppress arthritis induced by streptococcal cell walls in rats [Bioorganic & Medicinal Chemistry Letters, Vol. 11, 693- 656 (2001)].
(ii) P38MAPK阻害剤はリウマチ患者の症状を軽減する [アナルズ 'ォブ *ザ'リウマテ イツク*デイジージズ（Annals of the Rheumatic Diseases)、第 61卷（suppl. 1)、 A10018 頁 (2001年) ]。  (ii) P38MAPK inhibitors alleviate symptoms in patients with rheumatism [Annals of the Rheumatic Diseases, 61st (suppl. 1), A10018 (2001)] .
[0003] (iii) P38MAPK阻害剤は、マウスとモルモットにおいて抗原で誘発された好酸球浸潤 を抑制する [ジャーナル ·ォブ 'ファーマコロジ一'アンド ·ェクスペリメンタル ·セラピュ ~~アイツグス (Journal of Pharmacology and Experimental Therapeutics)、第 293卷、 281 -288頁（2000年）]。  [0003] (iii) P38MAPK inhibitors suppress antigen-induced eosinophil infiltration in mice and guinea pigs [Journal of 'Pharmacology 1' and Xperimental Therapeut Pharmacology and Experimental Therapeutics), 293, 281-288 (2000)].
(iv) P38MAPK阻害剤はリポポリサッカリドで誘発される肺での炎症性サイト力インの 産生と肺への好中球の浸潤を抑制する [アメリカン'ジャーナル ·ォブ ·フィジオロジー —ラング ·セノレラー ·アンド ·モレキュラー ·フィジオロジー (American Journal of Physiol ogy-Lung Cellular and Molecular Physiology),第 279卷、 L895- 902頁（2000年）]。 (iv) P38MAPK inhibitor suppresses lipopolysaccharide-induced inflammatory site force-in production in the lung and infiltration of neutrophils into the lung [American's Journal of Physiology —American Journal of Physiol ogy-Lung Cellular and Molecular Physiology, Vol. 279, L895-902 (2000)].
[0004] (v) P38MAPK阻害剤は、ヒトでリポポリサッカリドにより誘発される末梢血液中の好中 球数の増加やインターロイキン 6等のサイト力イン濃度の上昇を抑制する [ジャーナル 'ォブ 'ィムノロジー（Journal of Immunology)、第 168卷、 4070- 4077頁（2002年）]。 (vi) P38MAPK阻害剤はブレオマイシンで誘発される肺の線維化を抑制する [アメリカ ン ·ジャーナル ·ォブ ·フィジオロジ^——ラング ·セルラ^ ~ ·アンド ·モレキュラ^ ~ ·フイジ ォロン■ ~" (American Journal of Physiology- Lung Cellular ana Molecular Physiology) ^ 第 279卷、 L895-902頁（2000年）]。  [0004] (v) P38MAPK inhibitors suppress the increase in the number of neutrophils in the peripheral blood and the increase in the site force-in concentration such as interleukin 6 induced by lipopolysaccharide in humans [Journal 'Ob 'Journal of Immunology, 168, 4070-4077 (2002)]. (vi) P38MAPK inhibitor suppresses bleomycin-induced lung fibrosis [American Journal of Physiology ^ —— Lang Cellular ^ ~ and And Molecular ^ ~ American Journal of Physiology- Lung Cellular ana Molecular Physiology) ^ 279, L895-902 (2000)].
[0005] また、 P38MAPK阻害剤の副作用の懸念としては、以下の報告がなされている。  [0005] In addition, the following reports have been made regarding the side effects of P38MAPK inhibitors.
(i) P38MAPK阻害剤は CyP450を阻害し、肝臓への毒性を発現する [バイオオーガ- ック'アンド'メディシナル 'ケミストリー 'レターズ（Bioorganic & Medicinal Chemistry L etters)、第 8卷、 3111-3116頁（1998年）]。  (i) P38MAPK inhibitors inhibit CyP450 and develop liver toxicity [Bioorganic & Medicinal Chemistry Letters], VIII, pages 3111-3116 (1998)].
(ii) P38MAPK阻害剤は実験動物では長期間の投与により中枢性の毒性を発現する [バイオセンチユリ一（BioCentury)、第 12卷、 45号、 3- 4頁（2004年）]。  (ii) P38MAPK inhibitors develop central toxicity in experimental animals after long-term administration [BioCentury, No. 12, IV, 45, 3-4 (2004)].
(iii) P38MAPK aを欠損するマウスはエリスロポエチンを産生できずに貧血になる [セ ル（Cell)、第 102卷、 221- 231頁（2000年）]。  (iii) Mice deficient in P38MAPKa cannot produce erythropoietin and become anemic [Cell (cell), pp. 102, 221-231 (2000)].
[0006] 以上のことから、 P38MAPK阻害剤において、全身暴露による副作用と標的疾患部 位における薬理効果を分離することが望ま 、と認識されて!、る [ランセット (Lancet) 、第 364卷、 985-986頁（2004年）]。  [0006] Based on the above, it has been recognized that it is desirable to separate the side effects from systemic exposure and the pharmacological effects at the target disease site in P38MAPK inhibitors! [Lancet, 364, 985] -986 (2004)].
キナーゼ阻害剤にぉ 、て、阻害型式がァロステリック型式であることで作用の増強 及び持続性を持つものが以下の通り報告されている [ネーチヤ一'ストラクチャル 'バ ィォロジー（Nature Structural Biology)、第 9卷、 268- 272頁（2002年)；バイオオーガ ニック 'アンド'メディシナル 'ケミストリー 'レターズ（Bioorganic & Medicinal Chemistry Letters)、第 14卷、 5389-5394頁（2004年）；ネーチャ^ ~ ·ストラクチャル 'モレキュラ^ ~ · バイオロジー（Nature Structural Molecular Biology)、第 11卷、 1192- 1197頁（2004年 ) ]。  Among kinase inhibitors, the inhibition type is an allosteric type, and it has been reported that it has enhanced action and persistence as follows (Nature 1 Bistructural Nature). 9: 268-272 (2002); Bioorganic & Medicinal Chemistry Letters, 14: 5389-5394 (2004); Nature ^ ~ · Structural 'Molecular ^ ~ · Biology (Nature Structural Molecular Biology), 11th, pp. 192-1197 (2004)].
[0007] 一方、 P38MAPK阻害作用を有するキナゾリン誘導体が知られて 、る（特許文献 1及 び 2参照)。 [0007] On the other hand, quinazoline derivatives having a P38MAPK inhibitory action are known (Patent Documents 1 and 4). And 2).
特許文献 1：米国特許出願公開第 2004/0209904号明細書  Patent Document 1: US Patent Application Publication No. 2004/0209904
特許文献 2：国際公開第 04/092144号パンフレット  Patent Document 2: International Publication No. 04/092144 Pamphlet
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] 本発明の目的は、 P38MAPK阻害作用を有する化合物またはその薬理学的に許容 される塩を有効成分として含有し、かつ全身暴露による副作用と標的疾患部位にお ける薬理効果が分離された局所投与剤を提供することにある。 [0008] An object of the present invention is to contain a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient, and to separate side effects from systemic exposure and pharmacological effects at a target disease site. It is to provide a topical agent.
課題を解決するための手段  Means for solving the problem
[0009] 本発明は、以下の（1)〜（66)に関する。 [0009] The present invention relates to the following (1) to (66).
(1)局所投与された場合の P38MAPK (Mitogen- Activated Protein Kinase)阻害作用 を有する化合物またはその薬理学的に許容される塩の該局所における濃度が、その 血漿中濃度に対して 350倍以上となる該 p38MAPK阻害作用を有する化合物または その薬理学的に許容される塩を有効成分として含有する該局所投与剤。  (1) The local concentration of a compound having a P38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or its pharmacologically acceptable salt when administered locally is 350 times or more of its plasma concentration. The topical administration agent comprising, as an active ingredient, the compound having a p38MAPK inhibitory action or a pharmacologically acceptable salt thereof.
(2)局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的 に許容される塩の該局所における濃度が、その血漿中濃度に対して 500倍以上とな る該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効 成分として含有する該局所投与剤。  (2) The P38MAPK inhibitory action when the local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof is 500 times or more of the plasma concentration when administered locally. Or a pharmacologically acceptable salt thereof as an active ingredient.
[0010] (3)局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的 に許容される塩の該局所における濃度が、その血漿中濃度に対して 1000倍以上とな る該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効 成分として含有する該局所投与剤。  [0010] (3) The P38MAPK in which the local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is 1000 times or more of its plasma concentration The topical administration agent comprising a compound having an inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient.
(4)局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的 に許容される塩の該局所における濃度が、その血漿中濃度に対して 2000倍以上とな る該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効 成分として含有する該局所投与剤。  (4) The P38MAPK inhibitory action when the local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof is 2000 times or more the plasma concentration when administered locally. Or a pharmacologically acceptable salt thereof as an active ingredient.
[0011] (5) P38MAPK阻害作用を有する化合物力 フ ノール誘導体またはフ ノール構造 を縮環系に内包する縮環性複素環化合物である前記（1)〜 (4)の 、ずれかに記載の 局所投与剤。 [0011] (5) The compound power having a P38 MAPK inhibitory action A phenol derivative or a condensed heterocyclic compound encapsulating a phenol structure in a condensed ring system according to any one of (1) to (4) above Topically administered.
(6) P38MAPK阻害作用を有する化合物が、式 (I)  (6) A compound having P38MAPK inhibitory activity is represented by the formula (I)
[化 1]  [Chemical 1]
Figure imgf000005_0001
Figure imgf000005_0001
[0013] [式中、 R1及び R2は同一または異なって、水素原子、置換もしくは非置換の低級アル キル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキ-ル 、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケ-ル、置 換もしくは非置換の低級アルカノィル、置換もしくは非置換の低級シクロアルキル力 ルポニル、置換もしくは非置換のァリール、置換もしくは非置換の複素環基または CO NR5aR5b (式中、 R5a及び R5bは同一または異なって、水素原子または置換もしくは非置 換の低級アルキルを表す)を表し、 [Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkyl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower cycloalkyl force sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group Or CO NR 5a R 5b (wherein R 5a and R 5b are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl),
[0014] Xは結合、酸素原子、硫黄原子、 CR6aR6b (式中、 R6a及び R6bは同一または異なって、 水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキルまたは置換もし くは非置換の低級アルコキシを表す力、または R6a及び R6bが一緒になつて酸素原子を 表す)または NR7 (式中、 R7は水素原子、置換もしくは非置換の低級アルキルまたは 置換もしくは非置換の低級アルカノィルを表す)を表し、 [0014] X is a bond, oxygen atom, sulfur atom, CR 6a R 6b (wherein R 6a and R 6b are the same or different and are a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl or substituted Is a force representing unsubstituted lower alkoxy, or R 6a and R 6b together represent an oxygen atom) or NR 7 (wherein R 7 is a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or non-substituted) Represents a substituted lower alkanoyl),
Xが結合または CR6aR6b (式中、 R6a及び R6bはそれぞれ前記と同義である)である場合、 R3は置換もしくは非置換の低級アルコキシ、置換もしくは非置換のァリール、置換もし くは非置換の芳香族複素環基または NR8aR8b (式中、 R 及び R8bは同一または異なつ て、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アル ケ -ル、置換もしくは非置換の低級アルキ -ル、置換もしくは非置換のシクロアルキ ル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換のァリールまたは置 換もしくは非置換の複素環基を表すか、または R及び R8bが隣接する窒素原子と一 緒になって置換もしくは非置換の複素環基を形成する）を表し、 When X is a bond or CR 6a R 6b (wherein R 6a and R 6b are as defined above), R 3 is a substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted. Is an unsubstituted aromatic heterocyclic group or NR 8a R 8b (wherein R and R 8b are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl, Represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or R and R 8b together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocyclic group)
[0015] Xが酸素原子、硫黄原子または NR7 (式中、 R7は前記と同義である）である場合、 R3は 置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を表し、[0015] When X is an oxygen atom, a sulfur atom or NR 7 (wherein R 7 is as defined above), R 3 is Represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group,
R4は水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もし くは非置換の低級ァルケ-ル、置換もしくは非置換の低級アルコキシ、置換もしくは 非置換のァリール、置換もしくは非置換の複素環基、 CONR9aR9b (式中、 R9a及び R9bは それぞれ前記 R8a及び R8bと同義である）または COR1Q (式中、 R1Qは水素原子、ヒドロキ シ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級ァルケ-ル、置 換もしくは非置換の低級アルキ-ル、置換もしくは非置換のシクロアルキル、置換もし くは非置換の低級アルコキシ、置換もしくは非置換のァリールまたは置換もしくは非 置換の複素環基を表す)を表す]で表される 2-アミノキナゾリン誘導体またはその薬 理学的に許容される塩である前記（1)〜 (4)の 、ずれかに記載の局所投与剤。 R 4 is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Heterocyclic group, CONR 9a R 9b (wherein R 9a and R 9b are as defined above for R 8a and R 8b respectively) or COR 1Q (wherein R 1Q is a hydrogen atom, hydroxy, substituted or unsubstituted) Lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or The above-mentioned (1) to (4), which are 2-aminoquinazoline derivatives represented by the above or pharmaceutically acceptable salts thereof. Topical agents.
[0016] (7) R1が水素原子であり、 R2が置換もしくは非置換の低級アルキルである前記 (6)記 載の局所投与剤。 [0016] (7) The topical administration agent according to the above (6), wherein R 1 is a hydrogen atom, and R 2 is a substituted or unsubstituted lower alkyl.
(8) Xが結合である前記 (6)または（7)記載の局所投与剤。  (8) The topical administration agent according to (6) or (7), wherein X is a bond.
(9) Xが C=0である前記 (6)または（7)記載の局所投与剤。  (9) The topical administration agent according to (6) or (7), wherein X is C = 0.
(10) R3が置換もしくは非置換のァリールである前記 (6)〜（9)の 、ずれかに記載の局 所投与剤。 (10) The topical administration agent according to any one of (6) to (9), wherein R 3 is a substituted or unsubstituted aryl.
(11) R4が水素原子である前記 (6)〜（10)の 、ずれかに記載の局所投与剤。 (11) The topical administration agent according to any one of (6) to (10), wherein R 4 is a hydrogen atom.
(12) R4がハロゲンまたは置換もしくは非置換のァリールである前記 (6)〜（10)の 、ず れかに記載の局所投与剤。 (12) The topical administration agent according to any one of (6) to (10), wherein R 4 is halogen or a substituted or unsubstituted aryl.
(13) P38MAPK阻害作用を有する化合物力 式 (IA)  (13) P38MAPK inhibitory activity (IA)
[0017] [化 2] [0017] [Chemical 2]
Figure imgf000006_0001
Figure imgf000006_0001
{式中、 X、
Figure imgf000006_0002
R3及び R4はそれぞれ前記と同義であり、 {Where X,
Figure imgf000006_0002
R 3 and R 4 are as defined above,
R2aは置換もしくは非置換のァリール、置換もしくは非置換のァラルキル、置換もしくは 非置換の芳香族複素環基または CRUR12R13 [式中、 R11は水素原子または置換もしく は非置換の低級アルキルを表し、 R 2a is a substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic group or CR U R 12 R 13 [wherein R 11 is a hydrogen atom or substituted or unsubstituted Represents unsubstituted lower alkyl,
R12及び R13は同一または異なって、水素原子、置換もしくは非置換の低級アルキル、 OR14 (式中、 R14は水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置 換の低級アルケニル、置換もしくは非置換の低級アルキ-ル、置換もしくは非置換の シクロアルキル、置換もしくは非置換のァリールまたは置換もしくは非置換の複素環 基を表す)、 S(O) R14a (式中、 R1½は前記 R14と同義であり、 pは 0〜2の整数を表す)、 C R 12 and R 13 are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, OR 14 (wherein R 14 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl. , Substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group), S (O) R 14a (wherein R 1½ Is synonymous with R 14 above, p represents an integer of 0-2), C
P P
OR14b (式中、 R14bは前記 R14と同義である）、 CO R14e (式中、 ま前記 R14と同義である OR 14b (wherein, R 14b has the same meaning as the R 14), in CO R 14e (Formula have the same meanings as or said R 14
2  2
)、 CONR15aR15b (式中、 R15a及び R15bはそれぞれ前記 R及び R8bと同義である)または S( 0) NR15 15d (式中、 R15e及び R15dはそれぞれ前記 R 及び R8bと同義である)を表すか、), CONR 15a R 15b (wherein R 15a and R 15b are as defined above for R and R 8b ) or S (0) NR 15 15d (wherein R 15e and R 15d are the same as R and R respectively) Or the same as 8b )
2 2
または R12及び R13が隣接する炭素原子と一緒になつて置換もしくは非置換のシクロア ルキルまたは置換もしくは非置換の脂環式複素環基を形成する。ただし、 R11が水素 原子である場合、 R12及び R13は同時に水素原子にはならない]を表す }で表される 2- アミノキナゾリン誘導体またはその薬理学的に許容される塩である前記（1)〜 (4)の ヽ ずれかに記載の局所投与剤。 Or R 12 and R 13 together with the adjacent carbon atom form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted alicyclic heterocyclic group. However, when R 11 is a hydrogen atom, R 12 and R 13 are not hydrogen atoms at the same time.] Which is a 2-aminoquinazoline derivative represented by the above or a pharmacologically acceptable salt thereof ( The topical administration agent according to any one of 1) to (4).
[0019] (14) R1が水素原子である前記（13)記載の局所投与剤。 [0019] (14) The topical administration agent according to the above (13), wherein R 1 is a hydrogen atom.
(15) R2aが CRUaR12aR13a (式中、 RUaは水素原子または置換もしくは非置換の低級アル キルを表し、 (15) R 2a is CR Ua R 12a R 13a (wherein R Ua represents a hydrogen atom or a substituted or unsubstituted lower alkyl;
R12a及び R13aは同一または異なって、水素原子または置換もしくは非置換の低級アル キルを表すか、または R12a及び R13aが隣接する炭素原子と一緒になつて置換もしくは 非置換のシクロアルキルまたは置換もしくは非置換の脂環式複素環基を形成する。 ただし、 RUaが水素原子である場合、 R12a及び R13aは同時に水素原子にはならない)で ある前記（13)または（14)記載の局所投与剤。 R 12a and R 13a are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R 12a and R 13a together with an adjacent carbon atom are substituted or unsubstituted cycloalkyl or Forms a substituted or unsubstituted alicyclic heterocyclic group. However, when R Ua is a hydrogen atom, R 12a and R 13a are not hydrogen atoms at the same time.) The topical administration according to (13) or (14) above.
[0020] (16) Xが結合である前記（13)〜（15)の 、ずれかに記載の局所投与剤。 [0020] (16) The topical administration agent according to any one of (13) to (15), wherein X is a bond.
(17) Xが CR6aR6b (式中、 R6a及び R6bはそれぞれ前記と同義である）であり、 R3が置換も しくは非置換のァリールである前記（13)〜（15)の 、ずれかに記載の局所投与剤。(17) The above (13) to (15), wherein X is CR 6a R 6b (wherein R 6a and R 6b are as defined above), and R 3 is a substituted or unsubstituted aryl. The topical administration agent according to any one of the above.
(18) R6a及び R6bが一緒になつて酸素原子を表す前記 (17)記載の局所投与剤。 (18) The topical administration agent according to the above (17), wherein R 6a and R 6b together represent an oxygen atom.
(19) R4が水素原子である前記（13)〜（18)の 、ずれかに記載の局所投与剤。 (19) The topical administration agent according to any one of (13) to (18), wherein R 4 is a hydrogen atom.
(20) R4がハロゲンまたは置換もしくは非置換のァリールである前記（13)〜（18)の ヽ ずれかに記載の局所投与剤。 (20) In the above (13) to (18), R 4 is halogen or substituted or unsubstituted aryl. The topical administration agent according to any one of the above.
(21) P38MAPK阻害作用を有する化合物力 式 (IB)  (21) P38MAPK inhibitory activity (IB)
[化 3]  [Chemical 3]
Figure imgf000008_0001
Figure imgf000008_0001
[0022] 〈式中、 R4及び Xはそれぞれ前記と同義であり、 [Wherein, R 4 and X are as defined above, respectively]
qは 0または 1を表し、  q represents 0 or 1,
rは 0〜4の整数を表し、  r represents an integer from 0 to 4,
Yは酸素原子、 C=0、 NR17 (式中、 R17は水素原子、スルフィ入カルボキシ、置換もしく は非置換の低級アルキル、置換もしくは非置換の低級アルカノィル、置換もしくは非 置換の低級アルコキシカルボ-ルまたは置換もしくは非置換の低級アルキルスルホ -ルを表す)または CHR18{式中、 R18は水素原子、ヒドロキシ、アミ入カルボキシ、ス ルフィ入置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ 、モノもしくはジ (置換もしくは非置換の低級アルキル)アミ入置換もしくは非置換の低 級アルカノィル、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置 換の低級アルキルスルホ -ル、 NR19COR2° [式中、 R19は水素原子または置換もしくは 非置換の低級アルキルを表し、 R2°はァミノ、置換もしくは非置換の低級アルキル、置 換もしくは非置換の低級アルコキシまたはモノもしくはジ (置換もしくは非置換の低級 アルキル)アミノを表す]または NR19aS(0) R2°a (式中、 R19a及び R2°aはそれぞれ前記 R19 Y is an oxygen atom, C = 0, NR 17 (wherein R 17 is a hydrogen atom, sulfiated carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxy Carb or substituted or unsubstituted lower alkyl sulfol) or CHR 18 (wherein R 18 is a hydrogen atom, hydroxy, amino-substituted carboxy, sulfur-substituted substituted or unsubstituted lower alkyl, substituted or unsubstituted Substituted lower alkoxy, mono or di (substituted or unsubstituted lower alkyl) amino-substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkyl sulfol, NR 19 COR 2 ° [wherein, R 19 represents a hydrogen atom or a substituted or unsubstituted lower alkyl, R 2 ° is Amino, lay be substituted Unsubstituted lower alkyl, substitution or unsubstituted lower alkoxy or mono- or di represents an amino (substituted or unsubstituted lower alkyl) or NR 19a S (0) R 2 ° a ( wherein, R 19a and R 2 ° a is R 19
2  2
及び R2°と同義である）を表し }を表し、 And R 2 °).
[0023] R3aは置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を 表し、 [0023] R 3a represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group,
R16はァミノ、ヒドロキシ、スルフィ入カルボキシ、置換もしくは非置換の低級アルキル 、置換もしくは非置換の低級アルコキシ、モノもしくはジ (置換もしくは非置換の低級ァ ルキル)アミ入置換もしくは非置換の低級アルカノィル、置換もしくは非置換の低級ァ ルコキシカルボ-ル、置換もしくは非置換の低級アルキルスルホ -ル、 NR COR ( 式中、 R21a及び R22aはそれぞれ前記 R19及び R2°と同義である）または NR21bS(0) R22b (式 R 16 is amino, hydroxy, sulfi-substituted carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, mono- or di (substituted or unsubstituted lower alkyl) ami-substituted or unsubstituted lower alkanol, Substituted or unsubstituted lower Lucoxycarbol, substituted or unsubstituted lower alkyl sulfole, NR COR (wherein R 21a and R 22a are as defined above for R 19 and R 2 °) or NR 21b S (0) R 22b ( formula
2 中、 R21b及び R22bはそれぞれ前記 R19及び R2°と同義である）を表す。ただし、 rが 2〜4の 整数である場合は、それぞれの R16は同一でも異なって 、てもよ 、〉で表される 2-アミ ノキナゾリン誘導体またはその薬理学的に許容される塩である前記（1)〜 (4)の 、ず れかに記載の局所投与剤。 2, R 21b and R 22b are the same as R 19 and R 2 °, respectively. However, when r is an integer of 2 to 4, each R 16 may be the same or different, and is a 2-aminoquinazoline derivative represented by> or a pharmacologically acceptable salt thereof. The topical administration agent according to any one of (1) to (4).
[0024] (22) Xが結合である前記 (21)記載の局所投与剤。 [0024] (22) The topical administration agent according to the above (21), wherein X is a bond.
(23) R4が水素原子である前記 (21)または (22)記載の局所投与剤。 (23) The topical administration agent according to the above (21) or (22), wherein R 4 is a hydrogen atom.
(24)式 (IC)  (24) Formula (IC)
[0025] [化 4] [0025] [Chemical 4]
Figure imgf000009_0001
Figure imgf000009_0001
[0026] (式中、 Rla及び R2bは同一または異なって、水素原子、置換もしくは非置換の低級ァ ルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換のシクロアルキ ルまたは置換もしくは非置換のシクロアルケ-ルを表し、 [In the formula, R la and R 2b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted. Represents a cycloalkenyl of
R3bは置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を 表し、 R 3b represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group,
R4aは水素原子またはハロゲンを表し、 R 4a represents a hydrogen atom or halogen,
Xaは酸素原子または硫黄原子を表す)で表される 2_アミノキナゾリン誘導体またはそ の薬理学的に許容される塩。 2a -aminoquinazoline derivative represented by Xa represents an oxygen atom or a sulfur atom) or a pharmaceutically acceptable salt thereof.
(25) Rla及び R2bが同一または異なって水素原子または置換もしくは非置換の低級ァ ルキルである前記 (24)記載の 2-ァミノキナゾリン誘導体またはその薬理学的に許容 される塩。 (25) The 2-aminoquinazoline derivative or the pharmaceutically acceptable salt thereof according to the above (24), wherein R la and R 2b are the same or different and are a hydrogen atom or a substituted or unsubstituted lower alkyl.
[0027] (26) Rlaが水素原子であり、 R2bが置換もしくは非置換の低級アルキルである前記 (24) 記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 [0027] (26) The 2-aminoquinazoline derivative or the pharmaceutically acceptable salt thereof according to (24), wherein R la is a hydrogen atom, and R 2b is a substituted or unsubstituted lower alkyl.
(27) Rlaが水素原子であり、 R2bが 2-プロピルである前記 (24)記載の 2_アミノキナゾリン 誘導体またはその薬理学的に許容される塩。 (27) 2_aminoquinazoline according to the above (24), wherein R la is a hydrogen atom and R 2b is 2-propyl. A derivative or a pharmacologically acceptable salt thereof.
(28) R3bが置換もしくは非置換のァリールである前記 (24)〜（27)の 、ずれかに記載 の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 (28) The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (24) to (27), wherein R 3b is a substituted or unsubstituted aryl.
(29) ITがフエニルである前記（24)〜（27)の 、ずれかに記載の 2-アミノキナゾリン， 導体またはその薬理学的に許容される塩。  (29) The 2-aminoquinazoline, conductor or pharmacologically acceptable salt thereof according to any one of the above (24) to (27), wherein IT is phenyl.
(30) R½が水素原子である前記 (24)〜（29)の 、ずれかに記載の 2-アミ (30) The 2- amino group according to any one of (24) to (29), wherein R ½ is a hydrogen atom.
導体またはその薬理学的に許容される塩。  A conductor or a pharmacologically acceptable salt thereof.
(31) Xaが酸素原子である前記 (24)〜（30)の 、ずれかに記載の 2-アミ (31) The 2-amino group according to any one of (24) to (30), wherein X a is an oxygen atom.
導体またはその薬理学的に許容される塩。  A conductor or a pharmacologically acceptable salt thereof.
(32)式（ID)  (32) Expression (ID)
[0028] [化 5] [0028] [Chemical 5]
Figure imgf000010_0001
Figure imgf000010_0001
[0029] (式中、 R2a及び R3aはそれぞれ前記と同義である）で表される 2-アミノキナゾリン誘導 体またはその薬理学的に許容される塩。 [0029] A 2-aminoquinazoline derivative represented by the formula (wherein R 2a and R 3a are as defined above) or a pharmacologically acceptable salt thereof.
(33) R2aが CRUaR12aR13a (式中、 RUa、 R12a及び R13aはそれぞれ前記と同義である）である 前記 (32)記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。(33) R 2a is CR Ua R 12a R 13a (wherein R Ua , R 12a and R 13a are each as defined above) or the 2-aminoquinazoline derivative according to (32) or a pharmacological thereof Acceptable salt.
(34) R3aが置換もしくは非置換のァリールである前記 (32)または (33)記載の 2_ァミノ キナゾリン誘導体またはその薬理学的に許容される塩。 (34) The 2_aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the above (32) or (33), wherein R 3a is a substituted or unsubstituted aryl.
(35) R3aが置換もしくは非置換のフエ-ルである前記 (32)または (33)記載の 2_ァミノ キナゾリン誘導体またはその薬理学的に許容される塩。 (35) The 2_aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the above (32) or (33), wherein R 3a is a substituted or unsubstituted file.
(36) R3aが ( 36 ) R 3a
[0030] [化 6] [0030] [Chemical 6]
Figure imgf000010_0002
[0031] [式中、 sは 0〜4の整数を表し、
Figure imgf000010_0002
[0031] [wherein, s represents an integer of 0 to 4,
R23は水素原子、ハロゲンまたは低級アルキルを表し、 R 23 represents a hydrogen atom, halogen or lower alkyl,
R24は低級アルキル、シクロアルキル、低級アルコキシ、ァリール、置換基 A力 選ば れる 1つ〜置換可能な数の置換基で置換されたァリール、芳香族複素環基または置 換基 A力 選ばれる 1つ〜置換可能な数の置換基で置換された芳香族複素環基を表 す。ただし、 sが 2〜4の整数である場合は、それぞれの R23は同一でも異なっていても よい； R 24 is selected from lower alkyl, cycloalkyl, lower alkoxy, aryl, substituent A force selected from 1 to aryl substituted with a substitutable number of substituents, aromatic heterocyclic group or substituent A force 1 Represents an aromatic heterocyclic group substituted with one to a substitutable number of substituents. Provided that when s is an integer from 2 to 4, each R 23 may be the same or different;
置換基 A：ノヽロゲン、低級アルキル、ヒドロキシ低級アルキル、シクロアルキル、ァリー ル、 1つ〜置換可能な数のハロゲン及び Zもしくは 1つ〜置換可能な数の低級アルキ ルで置換されたァリール、 -NR25aR25b (式中、 R25a及び R25bは同一または異なって水素 原子、低級アルキルまたはシクロアルキルを表す力、または R25a及び R25bが隣接する 窒素原子と一緒になつて脂環式複素環基または 1つ〜置換可能な数の低級アルキ ルで置換された脂環式複素環基を形成する） ]である前記 (32)または (33)記載の 2- アミノキナゾリン誘導体またはその薬理学的に許容される塩。 Substituent A: neurogen, lower alkyl, hydroxy lower alkyl, cycloalkyl, aryl, 1 to substitutable number of halogens and Z or 1 to substitutable number of lower alkyl substituted with- NR 25a R 25b (wherein R 25a and R 25b are the same or different and represent a hydrogen atom, lower alkyl or cycloalkyl, or R 25a and R 25b together with the adjacent nitrogen atom are cycloaliphatic The 2-aminoquinazoline derivative or the pharmacology thereof according to the above (32) or (33), which is a cyclic group or an alicyclic heterocyclic group substituted with 1 to a substitutable number of lower alkyl) Acceptable salt.
[0032] (37) R24が- NR25aR25b (式中、 R25a及び R25bはそれぞれ前記と同義である)で置換された フエ-ルまたは- NR25aR25b (式中、 R25a及び R25bはそれぞれ前記と同義である)で置換さ れたピリジルである前記 (36)記載の 2-アミノキナゾリン誘導体またはその薬理学的に 許容される塩。 [0032] (37) R 24 is - (wherein, R 25a and R 25b have the same meanings as defined above) NR 25a R 25b is substituted with Hue - le or - NR 25a R 25b (wherein, R 25a And R 25b is as defined above, and the 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to (36), which is pyridyl substituted with
(38) R24が 1つ〜置換可能な数のハロゲン及び Zもしくは 1つ〜置換可能な数の低級 アルキルで置換されたフエ-ルで置換されたフエ-ル、または 1つ〜置換可能な数の ハロゲン及び Zもしくは 1つ〜置換可能な数の低級アルキルで置換されたフエ-ルで 置換されたピリジルである前記 (36)記載の 2-アミノキナゾリン誘導体またはその薬理 学的に許容される塩。 (38) R 24 is a one or more substitutable number substituted with a halogen substituted with one to substitutable number of halogens and Z or one to substitutable number of lower alkyl, or one to substitutable The 2-aminoquinazoline derivative or the pharmacologically acceptable salt thereof according to (36), which is pyridyl substituted with a halogen substituted with a number of halogens and Z or 1 to a substitutable number of lower alkyl. salt.
(39) R3aが (39) R 3a
[0033] [化 7]
Figure imgf000012_0001
[0033] [Chemical 7]
Figure imgf000012_0001
[0034] (式中、 s、 R23及び R24はそれぞれ前記と同義である）である前記 (32)または（33)記載 の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 [0034] The 2-aminoquinazoline derivative or the pharmaceutically acceptable salt thereof according to the above (32) or (33), wherein s, R 23 and R 24 are as defined above.
(40) sが 1であり、 R23が低級アルキルであり、 R24がシクロアルキルである前記（39)記載 の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 (40) The 2-aminoquinazoline derivative or the pharmaceutically acceptable salt thereof according to (39), wherein s is 1, R 23 is lower alkyl, and R 24 is cycloalkyl.
(41)式 (IE)  (41) (IE)
[0035] [化 8] [0035] [Chemical 8]
Figure imgf000012_0002
Figure imgf000012_0002
[0036] (式中、 Rla、 R2a及び R3aはそれぞれ前記と同義であり、 (Wherein R la , R 2a and R 3a are as defined above, respectively)
R4bは置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を 表す)で表される 2-ァミノキナゾリン誘導体またはその薬理学的に許容される塩。 (42) Rlaが水素原子であり、 R2aが CRUaR12aR13a (式中、 Rn R12a及び R13aはそれぞれ前 記と同義である）である前記 (41)記載の 2-アミノキナゾリン誘導体またはその薬理学 的に許容される塩。 R 4b represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group) or a pharmacologically acceptable salt thereof. (42) R la is a hydrogen atom, and R 2a is CR Ua R 12a R 13a (wherein R n R 12a and R 13a have the same meanings as defined above), An aminoquinazoline derivative or a pharmacologically acceptable salt thereof.
[0037] (43) R3aが置換もしくは非置換のァリールである前記 (41)または (42)記載の 2-ァミノ キナゾリン誘導体またはその薬理学的に許容される塩。 [0037] (43) The 2-amino quinazoline derivative or a pharmaceutically acceptable salt thereof according to (41) or (42), wherein R 3a is a substituted or unsubstituted aryl.
(44) R3aが置換もしくは非置換のフエ-ルである前記 (41)または (42)記載の 2-ァミノ キナゾリン誘導体またはその薬理学的に許容される塩。 (44) The 2-amino quinazoline derivative or a pharmaceutically acceptable salt thereof according to (41) or (42), wherein R 3a is a substituted or unsubstituted file.
(45) R4bが置換もしくは非置換のァリールである前記 (41)〜 (44)の 、ずれかに記載 の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 (45) The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (41) to (44), wherein R 4b is a substituted or unsubstituted aryl.
(46) R4bが置換もしくは非置換のフエ-ルである前記 (41)〜 (44)の 、ずれかに記載 の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 (46) The above (41) to (44), wherein R 4b is a substituted or unsubstituted file. 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof.
(47) R4bが置換もしくは非置換の芳香族複素環基である前記 (41)〜 (44)の 、ずれか に記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 (47) The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (41) to (44), wherein R 4b is a substituted or unsubstituted aromatic heterocyclic group.
(48) R4bが置換もしくは非置換のピリジルである前記 (41)〜 (44)の 、ずれかに記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 (48) The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of (41) to (44), wherein R 4b is substituted or unsubstituted pyridyl.
[0038] (49) p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有する化合物が、前 記 (24)〜 (48)の 、ずれかに記載の 2-アミノキナゾリン誘導体またはその薬理学的に 許容される塩である前記（1)〜 (4)の 、ずれかに記載の局所投与剤。  [0038] (49) A compound having a p38MAPK (Mitogen-Activated Protein Kinase) inhibitory activity is any one of the 2-aminoquinazoline derivatives described in any one of (24) to (48) above or a pharmacologically acceptable salt thereof. The topical administration agent according to any one of the above (1) to (4), which is a salt.
(50) p38MAPK (Mitogen- Activated Protein Kinase)阻害作用がァロステリック阻害に 基づく作用であることを特徴とする、前記（1)〜（23)及び (49)のいずれかに記載の局 所投与剤。  (50) The locally administered agent according to any one of (1) to (23) and (49) above, wherein the p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action is an action based on allosteric inhibition.
(51)局所投与された場合の p38MAPK (Mitogen- Activated Protein Kinase)阻害作用 を有する化合物またはその薬理学的に許容される塩の該局所における濃度が、その 血漿中濃度に対して 350倍以上となる該 p38MAPK阻害作用を有する化合物または その薬理学的に許容される塩の有効量を投与する工程を含む、該局所投与による 疾患の治療方法。  (51) The local concentration of a compound having p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof when administered locally is 350 times or more of its plasma concentration. A method for treating a disease by local administration, comprising a step of administering an effective amount of the compound having a p38MAPK inhibitory action or a pharmacologically acceptable salt thereof.
(52)局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学 的に許容される塩の該局所における濃度が、その血漿中濃度に対して 500倍以上と なる該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩の有 効量を投与する工程を含む、該局所投与による疾患の治療方法。  (52) Having a P38 MAPK inhibitory action when the local concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof is 500 times or more of its plasma concentration when administered locally A method for treating a disease by local administration, comprising a step of administering an effective amount of a compound or a pharmaceutically acceptable salt thereof.
[0039] (53)局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学 的に許容される塩の該局所における濃度が、その血漿中濃度に対して 1000倍以上と なる該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩の有 効量を投与する工程を含む、該局所投与による疾患の治療方法。  [0039] (53) The P38MAPK inhibition wherein the local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered locally is 1000 times or more the plasma concentration thereof A method for treating a disease by local administration, comprising a step of administering an effective amount of a compound having an action or a pharmacologically acceptable salt thereof.
(54)局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学 的に許容される塩の該局所における濃度が、その血漿中濃度に対して 2000倍以上と なる該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩の有 効量を投与する工程を含む、該局所投与による疾患の治療方法。 (55) P38MAPK阻害作用を有する化合物力 フ ノール誘導体またはフ ノール構造 を縮環系に内包する縮環性複素環化合物である前記 (51)〜（54)の 、ずれかに記 載の治療方法。 (54) Having a P38 MAPK inhibitory action when the local concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof is 2000 times or more of its plasma concentration when administered locally A method for treating a disease by local administration, comprising a step of administering an effective amount of a compound or a pharmaceutically acceptable salt thereof. (55) Compound power having P38MAPK inhibitory action The therapeutic method according to any one of (51) to (54) above, which is a condensed heterocyclic compound containing a phenol derivative or a phenol structure in a condensed ring system .
[0040] (56) P38MAPK阻害作用を有する化合物力 前記（6)〜（23)のいずれかに記載の 2- アミノキナゾリン誘導体またはその薬理学的に許容される塩である前記 (51)〜 (54) の!、ずれかに記載の治療方法。  [0040] (56) Compound power having P38MAPK inhibitory action The above-mentioned (51) to (51) which is the 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to any one of (6) to (23). 54) No !, The treatment method described in any one of them.
(57) P38MAPK阻害作用を有する化合物力 前記（24)〜（48)の 、ずれかに記載の 2 -ァミノキナゾリン誘導体またはその薬理学的に許容される塩である前記 (51)〜 (54) の!、ずれかに記載の治療方法。  (57) Compound power having P38MAPK inhibitory activity The above-mentioned (51) to (54) which is the 2-aminoquinazoline derivative or the pharmaceutically acceptable salt thereof according to any one of (24) to (48) above. ) No !, the treatment method described in any one.
(58) p38MAPK (Mitogen- Activated Protein Kinase)阻害作用がァロステリック阻害に 基づく作用であることを特徴とする、前記 (51)〜 (57)記載の治療方法。  (58) The treatment method according to any one of (51) to (57) above, wherein the p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action is an action based on allosteric inhibition.
(59)局所投与剤の製造のための、局所投与された場合の p38MAPK(Mitogen-Activ ated Protein Kinase)阻害作用を有する化合物またはその薬理学的に許容される塩 の該局所における濃度が、その血漿中濃度に対して 350倍以上となる該 p38MAPK阻 害作用を有する化合物またはその薬理学的に許容される塩の使用。  (59) The concentration of a compound having a p38 MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof when locally administered for the production of a topical administration agent Use of a compound having a p38 MAPK inhibitory action or a pharmacologically acceptable salt thereof that is 350 times or more of the plasma concentration.
[0041] (60)局所投与剤の製造のための、局所投与された場合の P38MAPK阻害作用を有 する化合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿 中濃度に対して 500倍以上となる該 P38MAPK阻害作用を有する化合物またはその 薬理学的に許容される塩の使用。  [60] (60) For the production of a topical preparation, the local concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is the plasma concentration. Use of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof that is 500 times or more of the amount.
(61)局所投与剤の製造のための、局所投与された場合の P38MAPK阻害作用を有 する化合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿 中濃度に対して 1000倍以上となる該 P38MAPK阻害作用を有する化合物またはその 薬理学的に許容される塩の使用。  (61) For the production of a topical preparation, the local concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is 1000 with respect to its plasma concentration. Use of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof that is twice or more.
(62)局所投与剤の製造のための、局所投与された場合の P38MAPK阻害作用を有 する化合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿 中濃度に対して 2000倍以上となる該 P38MAPK阻害作用を有する化合物またはその 薬理学的に許容される塩の使用。  (62) The concentration of a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically for the production of a topical agent is 2000 with respect to its plasma concentration. Use of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof that is twice or more.
[0042] (63) P38MAPK阻害作用を有する化合物力 フ ノール誘導体またはフ ノール構造 を縮環系に内包する縮環性複素環化合物である前記 (59)〜（62)の 、ずれかに記 載の使用。 [0042] (63) Compound power having P38MAPK inhibitory activity Phenolic derivatives or phenol structures The use according to any one of (59) to (62), which is a condensed heterocyclic compound encapsulating in a condensed ring system.
(64) P38MAPK阻害作用を有する化合物力 前記（6)〜（23)の 、ずれかに記載の 2- アミノキナゾリン誘導体またはその薬理学的に許容される塩である前記 (59)〜（62) のいずれかに記載の使用。  (64) Compound power having P38MAPK inhibitory activity The above-mentioned (6) to (23), which is the 2-aminoquinazoline derivative or pharmacologically acceptable salt thereof according to any one of the above (59) to (62) Use as described in any of the above.
(65) P38MAPK阻害作用を有する化合物力 前記（24)〜（48)の 、ずれかに記載の 2 -ァミノキナゾリン誘導体またはその薬理学的に許容される塩である前記 (59)〜（62) のいずれかに記載の使用。  (65) Compound power having P38MAPK inhibitory activity The above-mentioned (24) to (48), which is the 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to any one of the above (59) to (62 ) Use as described in any of the above.
(66) p38MAPK (Mitogen- Activated Protein Kinase)阻害作用がァロステリック阻害に 基づく作用であることを特徴とする、前記 (59)〜（65)記載の使用。  (66) The use according to (59) to (65) above, wherein the p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action is an action based on allosteric inhibition.
発明の効果  The invention's effect
[0043] 本発明により、 p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有する化 合物またはその薬理学的に許容される塩を有効成分として含有する局所投与剤等 が提供される。  [0043] According to the present invention, a topical administration agent or the like containing a compound having a p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient is provided.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0044] 本明細書にぉ 、て、局所とは、患部を意味し、具体的には、例えば眼球及びその 周辺組織、呼吸器 (より具体的には、鼻腔、副鼻腔、口腔、咽頭、扁桃、気管、気管 支、肺胞等)、消化器、皮膚、脊髄等が挙げられる。また、疾患組織、例えば、良性及 び悪性の腫瘍組織、ポリープ、膿瘍、のう胞等が包含される。それらに付随する近傍 の血管系も包含される。 [0044] As used herein, local means the affected area, specifically, for example, the eyeball and surrounding tissues, respiratory organs (more specifically, nasal cavity, sinuses, oral cavity, pharynx, Tonsils, trachea, trachea, alveoli, etc.), digestive organs, skin, spinal cord and the like. Also included are diseased tissues such as benign and malignant tumor tissues, polyps, abscesses, cysts and the like. The nearby vasculature associated with them is also included.
[0045] 本発明の局所投与剤により例えば呼吸器疾患の治療が可能であり、該呼吸器疾患 の例としては、例えば気管支平滑筋の収縮を伴う呼吸器疾患、気道血管系収縮を伴 う呼吸器疾患、炎症を伴う呼吸器疾患、粘液分泌を伴う呼吸器疾患、気道壁の可逆 的または不可逆的な組織的変性を伴う呼吸器疾患、気道血管系の可逆的または不 可逆的な組織的変性を伴う呼吸器疾患、肺胞の可逆的または不可逆的な変性を伴 う呼吸器疾患、鼻腔の可逆的または不可逆的な組織的変性を伴う呼吸器疾患、副 鼻腔の可逆的または不可逆的な組織的変性を伴う呼吸器疾患等が挙げられ、より具 体的には、気管支喘息、慢性閉塞性肺疾患 (COPD)、肺気腫、慢性気管支炎、肺繊 維症、肺高血圧症、好酸球性肺炎、アレルギー性鼻炎、好酸球性副鼻腔炎、鼻ポリ ープ症、慢性または急性副鼻腔炎、咽頭炎、扁桃炎、肺癌等が挙げられる。 [0045] The topical administration agent of the present invention can be used to treat, for example, respiratory diseases. Examples of the respiratory diseases include respiratory diseases accompanied by contraction of bronchial smooth muscle, respiratory diseases involving airway vasculature contraction, and the like. Respiratory disease with inflammation, respiratory disease with mucus secretion, respiratory disease with reversible or irreversible systemic degeneration of airway wall, reversible or irreversible systemic degeneration of airway vasculature Respiratory disease with reversible, respiratory disease with reversible or irreversible degeneration of the alveoli, respiratory disease with reversible or irreversible tissue degeneration of the nasal cavity, reversible or irreversible tissue of the sinuses Respiratory diseases with mechanical degeneration, and more specifically, bronchial asthma, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, pulmonary fibrosis Examples include fibrosis, pulmonary hypertension, eosinophilic pneumonia, allergic rhinitis, eosinophilic sinusitis, nasal polyposis, chronic or acute sinusitis, pharyngitis, tonsillitis, and lung cancer.
[0046] また、本発明の局所投与剤により例えば皮膚疾患の治療が可能であり、該皮膚疾 患の例としては、例えば炎症を伴う皮膚疾患、皮膚組織の可逆的または不可逆的な 組織的変性を伴う皮膚疾患、皮膚血管系の可逆的または不可逆的な組織的変性を 伴う皮膚疾患等が挙げられ、より具体的には、アトピー性皮膚炎、接触性皮膚炎、尊 麻疹、にきび、乾癬、湿疹、掌躕膿疱症、強皮症、類てんぽうそう、悪性黒色腫等が 挙げられる。  [0046] Further, for example, skin diseases can be treated with the topical administration agent of the present invention. Examples of the skin diseases include skin diseases accompanied by inflammation, reversible or irreversible tissue degeneration of skin tissues, and the like. Skin diseases accompanied by reversible or irreversible systemic degeneration of the skin vasculature, and more specifically, atopic dermatitis, contact dermatitis, measles, acne, psoriasis, Examples include eczema, palmoplantar pustulosis, scleroderma, epilepsy, and malignant melanoma.
[0047] また、本発明の局所投与剤により例えば眼疾患の治療が可能であり、該眼疾患の 例としては、例えば炎症を伴う眼疾患、眼球及びその周辺組織の可逆的または不可 逆的な組織的変性を伴う眼疾患、眼球周辺血管系の可逆的または不可逆的な組織 的変性を伴う眼疾患等が挙げられ、より具体的には、アレルギー性結膜炎、ブドウ膜 炎、白内障、緑内障、網膜剥離、黄斑変性症、ドライアイ等が挙げられる。  [0047] The topical administration agent of the present invention can treat, for example, eye diseases. Examples of the eye diseases include, for example, eye diseases accompanied by inflammation, reversible or irreversible of the eyeball and surrounding tissues. Ocular diseases with systemic degeneration, ocular diseases with reversible or irreversible systemic degeneration of the peripheral vasculature, and more specifically, allergic conjunctivitis, uveitis, cataract, glaucoma, retina Examples include exfoliation, macular degeneration, and dry eye.
[0048] また、本発明の局所投与剤により例えば消ィ匕器疾患の治療が可能であり、該消化 器疾患の例としては、例えば炎症を伴う消化器疾患、粘液分泌を伴う消化器疾患、 消化器の可逆的または不可逆的な組織的変性を伴う消化器疾患、消化器周辺血管 系の可逆的または不可逆的な組織的変性を伴う消化器疾患等が挙げられ、より具体 的には、炎症性大腸炎、クローン病、口内炎、過敏性大腸炎、大腸癌、直腸癌、結腸 癌等が挙げられる。  [0048] Further, for example, it is possible to treat gastrointestinal diseases with the topical administration agent of the present invention. Examples of the digestive diseases include digestive diseases with inflammation, digestive diseases with mucus secretion, Digestive tract diseases with reversible or irreversible systemic degeneration of the digestive tract, digestive tract diseases with reversible or irreversible systemic degeneration of the peripheral GI system, and more specifically inflammation Examples include ulcerative colitis, Crohn's disease, stomatitis, irritable colitis, colon cancer, rectal cancer, and colon cancer.
[0049] さらに、本発明の局所投与剤により、例えば中枢神経系疾患の治療が可能であり、 該中枢神経系疾患の例としては、例えば炎症を伴う中枢神経系疾患、神経の可逆的 または不可逆的な組織的変性を伴う中枢神経系疾患、神経周辺血管系の可逆的ま たは不可逆的な組織的変性を伴う中枢神経系疾患等が挙げられ、より具体的には、 アルツハイマー病、パーキンソン氏病、多発性硬化症、筋萎縮性側索硬化症 (ALS) 、神経因性疼痛等が挙げられる。  [0049] Further, for example, central nervous system diseases can be treated with the topical administration agent of the present invention. Examples of the central nervous system diseases include, for example, central nervous system diseases accompanied by inflammation, reversible or irreversible nerves. Central nervous system disease with general tissue degeneration, central nervous system disease with reversible or irreversible systemic degeneration of the peripheral nerve vasculature, and more specifically, Alzheimer's disease, Parkinson Disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), neuropathic pain and the like.
[0050] 本発明の局所投与剤の投与方法としては、例えば局所注入、局所吸入、局所塗付 等が挙げられる。  [0050] Examples of the method for administering the topical administration agent of the present invention include local injection, local inhalation, and topical application.
本発明の局所投与剤の有効成分として用いられる物質は、後述の試験例 1に記載 の方法により、 BALB/c系マウスに P38MAPK阻害作用を有する化合物またはその薬 理学的に許容される塩（lw/v%、 20 L)を局所投与し、局所及び血漿中の各 AUC ( それぞれ局所及び血漿中濃度一時間曲線下面積)を測定した場合、その局所 AUC (局所濃度）が血漿中 AUC (血漿中濃度）に対して 350倍以上となる P38MAPK阻害作 用を有する化合物またはその薬理学的に許容される塩であれば 、ずれでもよぐ好 ましくは 500倍以上、より好ましくは 1000倍以上、さらに好ましくは 2000倍以上の濃度 となる該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩が 挙げられる。 Substances used as active ingredients of the topical administration agent of the present invention are described in Test Example 1 described later. Using this method, BALB / c mice were topically administered with a compound having P38 MAPK inhibitory activity or a pharmaceutically acceptable salt thereof (lw / v%, 20 L), and each AUC (locally and plasma) was locally administered. And the area under the plasma concentration hour curve), the compound having a P38MAPK inhibitory action, or its pharmacology, whose local AUC (local concentration) is 350 times or more that of plasma AUC (plasma concentration) As long as the salt is acceptable, the compound having the P38MAPK inhibitory action or its pharmacology at a concentration of 500 times or more, more preferably 1000 times or more, and even more preferably 2000 times or more is acceptable. Salts that are acceptable.
[0051] 本発明の局所投与剤の有効成分として用いられる物質のより具体的な例として、以 下のような性質を有する物質が挙げられるが、本発明の局所投与剤の有効成分とし て用いられる物質はこれらに限定されるものではない。なお、ここでは P38MAPK阻害 作用を有する化合物またはその薬理学的に許容される塩を総称して物質とする。 局所投与された物質の投与部位からの吸収が極めて緩やかであり、かつ循環血に 移行した後、速やかに肝代謝を受けて不活性化され、一方消化管に遺漏した物質が 腸管力も吸収された後、肝臓で同様に速やかに代謝不活性化されるもの。  [0051] More specific examples of the substance used as the active ingredient of the topical administration agent of the present invention include substances having the following properties, which are used as the active ingredient of the topical administration agent of the present invention. The material to be used is not limited to these. Here, P38MAPK inhibitory compounds or pharmacologically acceptable salts are collectively referred to as substances. Absorption of locally administered substances from the administration site was very slow, and after transferring to circulating blood, it was quickly inactivated by hepatic metabolism, while substances leaked in the digestive tract also absorbed intestinal force. Later, it is also metabolically inactivated in the liver as quickly.
[0052] 局所投与された物質の結晶が非常にゆっくりと溶解し、さらに投与部位力もの吸収 が極めて緩やかであり、一方消化管に遺漏した物質が腸管から吸収されず、そのま ま糞中に排泄されるもの。  [0052] Crystals of locally administered substances dissolve very slowly, and absorption at the site of administration is very slow, while substances leaked into the digestive tract are not absorbed from the intestinal tract and remain in the feces. What is excreted.
局所投与された物質の投与部位からの吸収が極めて緩やかであり、かつ循環血に 移行した後、速やかに抱合体を形成し排泄されるもの。  Absorption of locally administered substances from the site of administration is very gradual, and after transferring to circulating blood, conjugates are rapidly formed and excreted.
[0053] 局所投与された物質の投与部位からの吸収が極めて緩やかであり、かつ循環血に 移行した後、速やかに血中酵素で代謝不活性化されるもの。 [0053] Absorption from a site of administration of a locally administered substance is extremely slow, and after being transferred to circulating blood, it is rapidly metabolically inactivated by enzymes in the blood.
以下、式 (1)、（IA)、 (IB) , (IC)、（ID)及び (IE)で表される化合物を、それぞれ化合 物（1)、（IA)、 (IB) , (IC)、（ID)及び (IE)という。他の式番号で表される化合物につい ても同様である。  Hereinafter, the compounds represented by the formulas (1), (IA), (IB), (IC), (ID) and (IE) are represented by the compounds (1), (IA), (IB), (IC ), (ID) and (IE). The same applies to the compounds represented by other formula numbers.
[0054] 化合物（I)、 (IA)、 (IB)、 (IC)、（ID)及び (IE)の各基の定義にお!、て、  [0054] In the definition of each group of compounds (I), (IA), (IB), (IC), (ID) and (IE),
低級アルキル、低級アルコキシ、低級アルコキシカルボ-ル、モノもしくはジ低級アル キルアミノ及び低級アルキルスルホニルの低級アルキル部分としては、例えば直鎖ま たは分枝状の炭素数 1〜10のアルキル、より具体的にはメチル、ェチル、プロピル、ィ ソプロピル、ブチル、イソブチル、 sec-ブチル、 tert-ブチル、ペンチル、イソペンチル 、ネオペンチル、へキシル、ヘプチル、ォクチル、ノニル、デシル等が挙げられる。ジ 低級アルキルァミノの 2つの低級アルキル部分は、同一でも異なって 、てもよ 、。 The lower alkyl part of lower alkyl, lower alkoxy, lower alkoxy carbo, mono- or di-lower alkylamino and lower alkylsulfonyl includes, for example, linear or Or branched alkyl having 1 to 10 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl , Octyl, nonyl, decyl and the like. The two lower alkyl moieties of the di-lower alkylamino may be the same or different.
[0055] ヒドロキシ低級アルキルのアルキレン部分は前記低級アルキル力 水素原子を 1つ 除いたものと同義である。  [0055] The alkylene part of hydroxy lower alkyl has the same meaning as that obtained by removing one hydrogen atom from the lower alkyl force.
低級ァルケ-ルとしては、例えば直鎖または分枝状の炭素数 2〜10のァルケ-ル、 より具体的にはビニル、ァリル、 1-プロぺニル、メタクリル、クロチル、 1-ブテニル、 3- ブテュル、 2-ペンテ-ル、 4-ペンテ-ル、 2-へキセ -ル、 5-へキセ -ル、 2-ヘプテ- ル、 2-オタテュル、 2-ノネ-ル、 2-デセ-ル等が挙げられる。  Examples of the lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms, more specifically vinyl, allyl, 1-propenyl, methacryl, crotyl, 1-butenyl, 3- Butyl, 2-Pentel, 4-Pentel, 2-Hexel, 5-Hexel, 2-Heptel, 2-Otatur, 2-Nonele, 2-Deseal Etc.
[0056] 低級アルキニルとしては、例えば直鎖または分枝状の炭素数 2〜10のアルキニル、 より具体的にはェチュル、 2-プロビュル、 2-ブチュル、 2-ペンチ-ル、 2-へキシュル 、 2-ヘプチュル、 2-ォクチ-ル、 2-ノ二-ル、 2-デシ-ル等が挙げられる。  [0056] Examples of the lower alkynyl include straight-chain or branched alkynyl having 2 to 10 carbon atoms, more specifically, etul, 2-probule, 2-butyur, 2-pentyl, 2-hexyl, Examples include 2-heptur, 2-octyl, 2-nonyl, and 2-decyl.
シクロアルキルとしては、例えば炭素数 3〜8のシクロアルキル、より具体的にはシク 口プロピノレ、シクロブチノレ、シクロペンチノレ、シクロへキシノレ、シクロへプチノレ、シクロ ォクチル等が挙げられる。  Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and more specifically cyclopropynole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like.
[0057] シクロアルケ-ルとしては、例えば炭素数 3〜8のシクロアルケ-ル、より具体的には シクロプロぺニノレ、シクロブテニノレ、シクロペンテ二ノレ、シクロへキセニノレ、シクロヘプ テニル、シクロオタテュル等が挙げられる。  [0057] The cycloalkenyl includes, for example, a cycloalkenyl having 3 to 8 carbon atoms, more specifically, cyclopropeninole, cyclobuteninole, cyclopenteninole, cyclohexenole, cycloheptenyl, cyclootatur and the like.
低級アルカノィルとしては、例えば直鎖または分枝状の炭素数 1〜8のアルカノィル 、より具体的にはホルミル、ァセチル、プロピオニル、ブチリル、イソブチリル、バレリル 、イソバレリル、ビバロイル、へキサノィル、ヘプタノィル、オタタノィル等が挙げられる  Examples of the lower alkanoyl include linear or branched alkanoyl having 1 to 8 carbon atoms, more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, heptanoyl, otatanyl and the like. Be mentioned
[0058] シクロアルキルカルボ-ルにおけるシクロアルキル部分は、前記シクロアルキルと同 義である。 [0058] The cycloalkyl moiety in the cycloalkyl carbocycle has the same meaning as the above cycloalkyl.
ァリールとしては、例えば炭素数 6〜14のァリール、より具体的にはフエ-ル、ナフ チル、アントリル等が挙げられる。  Examples of aryl include aryl having 6 to 14 carbon atoms, and more specifically, ferrule, naphthyl, and anthryl.
ァラルキルとしては、例えば炭素数？〜 15のァラルキル、より具体的にはベンジル、 フエネチル、ベンズヒドリル、ナフチルメチル等が挙げられる。 As aralkyl, for example, carbon number? ~ 15 aralkyl, more specifically benzyl, Examples include phenethyl, benzhydryl, naphthylmethyl, and the like.
[0059] 芳香族複素環基としては、例えば窒素原子、酸素原子及び硫黄原子から選ばれる 少なくとも 1個の原子を含む 5員または 6員の単環性芳香族複素環基、 3〜8員の環が 縮合した二環または三環性で窒素原子、酸素原子及び硫黄原子から選ばれる少な くとも 1個の原子を含む縮環性芳香族複素環基等が挙げられ、より具体的にはピリジ ル (該ピリジルの窒素原子が酸化されてできる基も本発明に包含される）、ピラジュル 、ピリミジニル、ピリダジニル、キノリル、イソキノリル、フタラジニル、キナゾリニル、キノ キサリニル、ナフチリジニル、シンノリニル、ピロリル、ピラゾリル、イミダゾリル、トリァゾ リル、テトラゾリル、チェニル、フリル、チアゾリル、ォキサゾリル、インドリル、インダゾリ ル、ベンゾイミダゾリル、ベンゾトリァゾリル、ベンゾチアゾリル、ベンゾォキサゾリル、プ リニル等が挙げられる。  [0059] Examples of the aromatic heterocyclic group include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, Examples include condensed bicyclic or tricyclic condensed rings containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. (A group formed by oxidation of the nitrogen atom of the pyridyl is also encompassed in the present invention), pyraduryl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazol Ril, tetrazolyl, chenyl, furyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, ben Examples include zotriazolyl, benzothiazolyl, benzoxazolyl, purinyl and the like.
[0060] 複素環基としては、例えば前記芳香族複素環基、脂環式複素環基等が挙げられる 脂環式複素環基としては、例えば窒素原子、酸素原子及び硫黄原子から選ばれる 少なくとも 1個の原子を含む 5員または 6員の単環性脂環式複素環基、 3〜8員の環が 縮合した二環または三環性で窒素原子、酸素原子及び硫黄原子から選ばれる少な くとも 1個の原子を含む縮環性脂環式複素環基等が挙げられ、より具体的にはピロリ ジニル、ピペリジル、ピペラジニル、モルホリニル、チオモルホリニル、ホモピペリジル 、ホモピぺラジュル、テトラヒドロピリジニル、テトラヒドロキノリル、テトラヒドロイソキノリ ル、テトラヒドロフラ -ル、テトラヒドロビラ-ル、ジヒドロべンゾフラ-ル等が挙げられる  [0060] Examples of the heterocyclic group include the aromatic heterocyclic group and the alicyclic heterocyclic group. Examples of the alicyclic heterocyclic group include at least one selected from a nitrogen atom, an oxygen atom, and a sulfur atom. 5- or 6-membered monocyclic alicyclic heterocyclic group containing a single atom, a bicyclic or tricyclic condensed 3- to 8-membered ring, and at least a nitrogen atom, an oxygen atom and a sulfur atom Examples thereof include condensed alicyclic heterocyclic groups containing one atom, and more specifically pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidyl, homopiperadil, tetrahydropyridinyl, tetrahydro Examples include quinolyl, tetrahydroisoquinol, tetrahydrofural, tetrahydrobiral, and dihydrobenzofural.
[0061] 隣接する窒素原子と一緒になつて形成される複素環基としては、例えば少なくとも 1 個の窒素原子を含む 5員または 6員の単環性複素環基 (該単環性複素環基は、他の 窒素原子、酸素原子または硫黄原子を含んでいてもよい）、 3〜8員の環が縮合した 二環または三環性で少なくとも 1個の窒素原子を含む縮環性複素環基 (該縮環性複 素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい)等が挙げ られ、より具体的にはピロリジ -ル、ピペリジ入ピペラジ -ル、モルホリノ、チオモルホ リ入ホモピベリジ入ホモピぺラジュル、テトラヒドロピリジル、テトラヒドロキノリル、テト ラヒドロイソキノリル等が挙げられる。 [0061] Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group). May contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed ring-containing heterocyclic group containing 3 to 8 membered rings and containing at least one nitrogen atom (The condensed polycyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, pyrrolidyl, piperidyl-containing piperazil, morpholino, Homopiperadil with thiomorpholine, tetrahydropyridyl, tetrahydroquinolyl, teto And lahydroisoquinolyl.
[0062] 隣接する炭素原子と一緒になつて形成されるシクロアルキルは、前記シクロアルキ ルと同義である。  [0062] The cycloalkyl formed together with the adjacent carbon atoms has the same meaning as the above cycloalkyl.
隣接する炭素原子と一緒になつて形成される脂環式複素環基は、前記脂環式複素 環基と同義である。  The alicyclic heterocyclic group formed together with adjacent carbon atoms has the same meaning as the alicyclic heterocyclic group.
ハロゲンは、フッ素、塩素、臭素、ヨウ素の各原子を意味する。  Halogen means each atom of fluorine, chlorine, bromine and iodine.
[0063] 置換低級アルキル、置換低級アルコキシ、置換低級ァルケ-ル、置換低級アルキ -ル、置換シクロアルキル、置換シクロアルケ-ル、モノもしくはジ (置換低級アルキル[0063] Substituted lower alkyl, substituted lower alkoxy, substituted lower alkyl, substituted lower alkyl, substituted cycloalkyl, substituted cycloalkenyl, mono or di (substituted lower alkyl
)ァミノ、置換低級アルカノィル、置換シクロアルキルカルボ-ル、置換低級アルコキ シカルボニル、置換低級アルキルスルホ-ル及び隣接する炭素原子と一緒になつて 形成される置換シクロアルキルにおける置換基 (置換基 a)としては、例えば同一また は異なって、置換数 1〜3の、より具体的にはハロゲン、ヒドロキシイミ入低級アルコキ シィミノ、シァ入シクロアルキル、低級アルカノィルォキシ、置換もしくは非置換のァリ ール (該置換ァリールにおける置換基としては、例えば同一または異なって置換数 1 〜3の、より具体的にはハロゲン、アミ入ヒドロキシ、シァ入カルボキシ、低級アルキ ル、低級アルコキシ、低級アルカノィル、モノもしくはジ低級アルキルアミ入複素環基 等が挙げられる）、置換もしくは非置換の複素環基 (該置換複素環基における置換基 としては、例えば同一または異なって置換数 1〜3の、より具体的にはハロゲン、ァミノ 、ヒドロキシ、シァ入カルボキシ、低級アルキル、低級アルコキシ、低級アルカノィル 、低級アルキルスルホ-ル等が挙げられる）、 CONR26aR26b〈式中、 R26a及び R26bは同一 または異なって水素原子、置換もしくは非置換の低級アルキル (該置換低級アルキ ルにおける置換基としては、例えば同一または異なって置換数 1〜3の、より具体的に はハロゲン、ヒドロキシ、低級アルコキシ、ァリール等が挙げられる）、置換もしくは非 置換の低級アルケニル (該置換低級アルケニルにおける置換基としては、例えば同 一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルコキ シ等が挙げられる）、置換もしくは非置換の低級アルキニル (該置換低級アルキニル における置換基としては、例えば同一または異なって置換数 1〜3の、より具体的には ハロゲン、ヒドロキシ、低級アルコキシ等が挙げられる）、置換もしくは非置換のシクロ アルキル (該置換シクロアルキルにおける置換基としては、例えば同一または異なつ て置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルキル、低級アルコキ シ等が挙げられる）、置換もしくは非置換のシクロアルケニル (該置換シクロアルケ- ルにおける置換基としては、例えば同一または異なって置換数 1〜3の、より具体的に はハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）、置換もしく は非置換の低級アルコキシ (該置換低級アルコキシにおける置換基としては、例えば 同一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルコ キシ等が挙げられる）、置換もしくは非置換のァリール [該置換ァリールにおける置換 基としては、例えば同一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒド 口キシ、置換もしくは非置換の低級アルキル (該置換低級アルキルにおける置換基と しては、例えば同一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキ シ、低級アルコキシ等が挙げられる）、置換もしくは非置換の低級アルコキシ (該置換 低級アルコキシにおける置換基としては、例えば同一または異なって置換数 1〜3の 、より具体的にはハロゲン、ヒドロキシ、低級アルコキシ等が挙げられる）、置換もしく は非置換のァリール (該置換ァリールにおける置換基としては、例えば同一または異 なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルキル、低級アル コキシ等が挙げられる）、置換もしくは非置換の複素環基 (該置換複素環基における 置換基としては、例えば同一または異なって置換数 1〜3の、より具体的にはハロゲン 、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）、低級アルキルスルホ ニルァミノ等が挙げられる]、置換もしくは非置換の複素環基 [該置換複素環基にお ける置換基としては、例えば同一または異なって置換数 1〜3の、より具体的にはハロ ゲン、ヒドロキシ、低級アルキル、低級アルコキシ、置換もしくは非置換のァリール (該 置換ァリールにおける置換基としては、例えば同一または異なって置換数 1〜3の、よ り具体的にはハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）、 置換もしくは非置換の複素環基 (該置換複素環基における置換基としては、例えば 同一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルキ ル、低級アルコキシ等が挙げられる）等が挙げられる]、 COR27{式中、 R27は水素原子 、置換もしくは非置換の低級アルキル (該置換低級アルキルにおける置換基としては 、例えば同一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低 級アルコキシ等が挙げられる）、置換もしくは非置換のシクロアルキル (該置換シクロ アルキルにおける置換基としては、例えば同一または異なって置換数 1〜3の、より具 体的にはハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）、置 換もしくは非置換の低級アルコキシ (該置換低級アルコキシにおける置換基としては 、例えば同一または異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低 級アルコキシ等が挙げられる）、置換もしくは非置換のァリール [該置換ァリールにお ける置換基としては、例えば同一または異なって置換数 1〜3の、より具体的にはハロ ゲン、アミ入ヒドロキシ、置換もしくは非置換の低級アルキル (該置換低級アルキルに おける置換基としては、例えば同一または異なって置換数 1〜3の、より具体的にはハ ロゲン、ヒドロキシ、低級アルコキシ等が挙げられる）、置換もしくは非置換の低級アル コキシ (該置換低級アルコキシにおける置換基としては、例えば同一または異なって 置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルコキシ等が挙げられる )、モノもしくはジ低級アルキルアミ入置換もしくは非置換のァリール (該置換ァリー ルにおける置換基としては、例えば同一または異なって置換数 1〜3の、より具体的に はハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）、置換もしく は非置換の複素環基 (該置換複素環基における置換基としては、例えば同一または 異なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルキル、低級ァ ルコキシ等が挙げられる)等が挙げられる]または置換もしくは非置換の芳香族複素 環基 [該置換芳香族複素環基における置換基としては、例えば同一または異なって 置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ 、モノもしくはジ低級アルキルアミ入置換もしくは非置換のァリール (該置換ァリール における置換基としては、例えば同一または異なって置換数 1〜3の、より具体的には ハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）、置換もしくは 非置換の複素環基 (該置換複素環基における置換基としては、例えば同一または異 なって置換数 1〜3の、より具体的にはハロゲン、ヒドロキシ、低級アルキル、低級アル コキシ等が挙げられる)等が挙げられる]を表すほたは S(O) R27a (式中、 R27aは前記 R27 ) Substituent in substituted cycloalkyl formed with amino, substituted lower alkanol, substituted cycloalkyl carbo yl, substituted lower alkoxycarbonyl, substituted lower alkyl sulphone and adjacent carbon atom (substituent a) As, for example, the same or different, and having 1 to 3 substitutions, more specifically, halogen, hydroxyimine-containing lower alkoximino, sia-containing cycloalkyl, lower alkanoyloxy, substituted or unsubstituted aryl. (Substituents in the substituted aryl are, for example, the same or different and having 1 to 3 substituents, more specifically, halogen, amino-containing hydroxy, cyanated carboxy, lower alkyl, lower alkoxy, lower alkanol, mono or Di-lower alkylamino-containing heterocyclic groups, etc.), substituted or unsubstituted heterocyclic groups (including Examples of the substituent in the substituted heterocyclic group include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, amino, hydroxy, carboxy-containing, lower alkyl, lower alkoxy, lower alkanol, lower alkylsulfo- CONR 26a R 26b wherein R 26a and R 26b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, the same or different Differently substituted 1 to 3, more specifically, halogen, hydroxy, lower alkoxy, aryl and the like), substituted or unsubstituted lower alkenyl (substituents in the substituted lower alkenyl are, for example, the same or Differently having 1 to 3 substitutions, and more specifically, halogen, hydroxy, lower alkoxy and the like. Substituted or unsubstituted lower alkynyl (substituents in the substituted lower alkynyl include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkoxy and the like), substituted or unsubstituted Substituted cyclo Alkyl (substituents in the substituted cycloalkyl include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, etc.), substituted or unsubstituted (The substituents in the substituted cycloalkenyl include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, etc.) Is an unsubstituted lower alkoxy (substituents in the substituted lower alkoxy are, for example, the same or different and have 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkoxy, etc.), substituted or non-substituted Substituted aryl [substituents in the substituted aryl include, for example, the same or different, 3, more specifically, halogen, hydroxy, substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, the same or different, more specifically 1 to 3 substituents, more specifically, Are halogen, hydroxy, lower alkoxy and the like), substituted or unsubstituted lower alkoxy (substituents in the substituted lower alkoxy are, for example, the same or different, and having 1 to 3 substituents, more specifically halogen , Hydroxy, lower alkoxy, etc.), substituted or unsubstituted aryl (substituents in the substituted aryl include, for example, the same or different substituents having 1 to 3 substituents, more specifically halogen, hydroxy , Lower alkyl, lower alkyl, etc.), substituted or unsubstituted heterocyclic groups (substituents in the substituted heterocyclic groups include For example, halogen, hydroxy, lower alkyl, lower alkoxy, etc.), lower alkylsulfonylamino, etc.], substituted or unsubstituted heterocyclic groups [Substituents in the substituted heterocyclic group are, for example, the same or different and having 1 to 3 substitutions, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, substituted or unsubstituted aryl ( Examples of the substituent in the substituted aryl include the same or different substituents having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, etc.), substituted or unsubstituted heterocyclic groups ( Examples of the substituent in the substituted heterocyclic group include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, hydro Shi, lower alkyl, lower alkoxy, etc.) and the like], in the COR 27 {wherein, R 27 is a hydrogen atom, a substituted or unsubstituted lower alkyl (the substituent in said substituted lower alkyl is , For example, the same or different and having 1 to 3 substituents, more specifically halogen, hydroxy, lower alkoxy, etc.), substituted or unsubstituted cycloalkyl (substituents in the substituted cycloalkyl include, for example, The same or different and having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy and the like), substituted or unsubstituted lower alkoxy (substituents in the substituted lower alkoxy include For example, the same or different and having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkoxy, etc.), substituted or unsubstituted aryl [the substituent in the substituted aryl is, for example, Identical or different and having 1 to 3 substitutions, more specifically halogen, amino-substituted hydroxy, substituted or unsubstituted Secondary alkyl (substituents in the substituted lower alkyl are, for example, the same or different and have 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkoxy, etc.), substituted or unsubstituted lower Alkoxy (substituents in the substituted lower alkoxy include, for example, the same or different substituents having 1 to 3 substituents, more specifically halogen, hydroxy, lower alkoxy and the like), mono- or di-lower alkylamino-substituted or Unsubstituted aryl (substituents in the substituted aryl include, for example, the same or different substituents having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, etc.), substituted or Is an unsubstituted heterocyclic group (the substituents in the substituted heterocyclic group are, for example, the same or different 1-3, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy and the like)] or a substituted or unsubstituted aromatic heterocyclic group [in the substituted aromatic heterocyclic group Examples of the substituent include, for example, the same or different, the number of substitutions 1 to 3, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, mono- or di-lower alkylamido substituted or unsubstituted aryl (the substitution in the substituted aryl) Examples of the group are the same or different and having 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl, lower alkoxy, etc.), substituted or unsubstituted heterocyclic group (the substituted heterocyclic group) Examples of the substituents in FIG. 1 are the same or different and have 1 to 3 substituents, more specifically, halogen, hydroxy, lower alkyl. And the like are represented by S (O) R 27a (wherein R 27a represents R 27
2  2
と同義である)を表すか、または R26a及び R26bが隣接する窒素原子と一緒になつて置換 もしくは非置換の複素環基 (該隣接する窒素原子と一緒になつて形成される置換複 素環基における置換基としては、例えば同一または異なって置換数 1〜3の、より具 体的にはハロゲン、ヒドロキシ、低級アルキル、低級アルコキシ等が挙げられる）を形 成する〉、 NR26 26d (式中、 R26e及び R26dはそれぞれ前記 R26a及び R26bと同義である）、 0 R27b (式中、 R は前記 R27と同義である）、 COR27e (式中、 R27eは前記 R27と同義である)、 CO R27d (式中、 R™は前記 R27と同義である）、 S(O) R27e (式中、 piは 0〜2の整数を表 Or R 26a and R 26b are substituted together with the adjacent nitrogen atom Or an unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group formed together with the adjacent nitrogen atom is, for example, the same or different, the number of substitution is 1 to 3, more specifically, NR 26 26d (wherein R 26e and R 26d have the same meanings as R 26a and R 26b , respectively), 0 R 27b ( In the formula, R is as defined above for R 27 ), COR 27e (where R 27e is as defined above for R 27 ), CO R 27d (wherein R ™ is as defined above for R 27 ) , S (O) R 27e (where pi represents an integer from 0 to 2)
2 pi  2 pi
し、 R27eは前記 R27と同義である）、 SO NR26 26f (式中、 R26e及び R26fはそれぞれ前記 R26a R 27e has the same meaning as R 27 ), SO NR 26 26f (wherein R 26e and R 26f are each R 26a
2  2
及び R26bと同義である）等が挙げられる。置換シクロアルキル及び置換シクロアルケ- ルにおける置換基は上記の置換基に加え、置換もしくは非置換の低級アルキル (該 置換低級アルキルにおける置換基としては、例えば同一または異なって置換数 1〜3 の、より具体的にはハロゲン、ヒドロキシ、低級アルコキシ等が挙げられる）であっても よい。 And R 26b ). Substituents in substituted cycloalkyl and substituted cycloalkenyl are substituted or unsubstituted lower alkyl in addition to the above-mentioned substituents (substituents in the substituted lower alkyl are, for example, the same or different, having 1 to 3 substitutions, Specific examples thereof include halogen, hydroxy, lower alkoxy and the like.
[0064] ここで、ハロゲン、低級アルキル、低級アルコキシ、低級アルキルスルホニル及びモ ノもしくはジ低級アルキルァミノの低級アルキル部分、低級ァルケ-ル、低級アルキ -ル、シクロアルキル、シクロアルケ-ル、低級アルカノィル及び低級アルカノィルォ キシの低級アルカノィル部分、ァリール、芳香族複素環基、複素環基及び隣接する 窒素原子と一緒になつて形成される複素環基はそれぞれ前記と同義であり、低級ァ ルコキシィミノ及び低級アルキルスルホ -ルァミノの低級アルキル部分は前記低級ァ ルキルと同義である。  [0064] Here, halogen, lower alkyl, lower alkoxy, lower alkylsulfonyl and lower alkyl part of mono- or di-lower alkylamino, lower alkyl, lower alkyl, cycloalkyl, cycloalkenyl, lower alkanol and lower The lower alkanoyl moiety of alkanoyloxy, aryl, aromatic heterocyclic group, heterocyclic group and heterocyclic group formed together with the adjacent nitrogen atom are as defined above, respectively, lower alkyloximino and lower alkylsulfo- The lower alkyl part of luamino has the same meaning as the lower alkyl.
[0065] 置換ァリール、置換フエニル、置換ァラルキル、置換芳香族複素環基、置換複素環 基、隣接する窒素原子と一緒になつて形成される置換複素環基及び隣接する炭素 原子と一緒になつて形成される置換脂環式複素環基における置換基としては、例え ば同一または異なって置換数 1〜3の、より具体的にはハロゲン、ニトロ、ヒドロキシ、 シァ入カルボキシ、低級アルカノィルォキシ、置換もしくは非置換の低級アルキル（ 該置換低級アルキルにおける置換基は、前記置換基 aと同義である）、置換もしくは 非置換の低級アルコキシ (該置換低級アルコキシにおける置換基は、前記置換基 aと 同義である）、置換もしくは非置換の低級アルカノィル (該置換低級アルカノィルにお ける置換基は、前記置換基 aと同義である）、置換もしくは非置換の低級アルコキシ力 ルポニル (該置換低級アルコキシカルボニルにおける置換基は、前記置換基 aと同義 である）、置換もしくは非置換の低級アルキルスルホニル (該置換低級アルキルスル ホ-ルにおける置換基は、前記置換基 aと同義である）、 CONR28aR28b (式中、 R2 及び R28bはそれぞれ前記 R26a及び R26bと同義である）、 NR28 28d (式中、 R28e及び R28dはそれ ぞれ前記 R26a及び R26bと同義である）、 NR29CONR28eR28f [式中、 R28e及び R28fはそれぞれ 前記 R26a及び R26bと同義であり、 R29は水素原子または置換もしくは非置換の低級アル キル (該置換低級アルキルにおける置換基は、前記置換基 aと同義である）を表す] 等が挙げられる。 [0065] Substituted aryl, substituted phenyl, substituted aralkyl, substituted aromatic heterocyclic group, substituted heterocyclic group, substituted heterocyclic group formed together with adjacent nitrogen atom, and adjacent carbon atom Examples of the substituent in the formed substituted alicyclic heterocyclic group include, for example, the same or different and the number of substitutions of 1 to 3, more specifically, halogen, nitro, hydroxy, carboxy-substituted, lower alkanoyloxy, Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl has the same meaning as the substituent a), substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy has the same meaning as the substituent a) A substituted or unsubstituted lower alkanol (the substituent in the substituted lower alkanol is as defined above for the substituent a), substituted or non-substituted Lower alkoxy power of substitution Luponyl (the substituent in the substituted lower alkoxycarbonyl has the same meaning as the substituent a), substituted or unsubstituted lower alkylsulfonyl (the substituent in the substituted lower alkylsulfonyl has the same meaning as the substituent a) CONR 28a R 28b (wherein R 2 and R 28b have the same meanings as R 26a and R 26b , respectively), NR 28 28d (wherein R 28e and R 28d are the same as R 26a, respectively) and R 26b is as defined above), in NR 29 CONR 28e R 28f [wherein, R 28e and R 28f are respectively the same as the aforementioned R 26a and R 26b, R 29 is a hydrogen atom or a substituted or unsubstituted lower Al Kill (the substituent in the substituted lower alkyl represents the same as the substituent a)] and the like.
[0066] ここで、ハロゲン、低級アルキル、低級アルコキシ、低級アルコキシカルボニル及び 低級アルキルスルホ -ルの低級アルキル部分、低級アルカノィル及び低級アルカノ ィルォキシの低級アルカノィル部分はそれぞれ前記と同義である。  [0066] Here, the lower alkyl part of halogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl and lower alkylsulfol, and the lower alkanol part of lower alkanoyloxy and lower alkanoyloxy are as defined above.
P38MAPK阻害作用を有する化合物の薬理学的に許容される塩は、薬理学的に許 容される酸付加塩、金属塩、アンモニゥム塩、有機アミン付加塩、アミノ酸付加塩等を 包含する。  The pharmacologically acceptable salts of the compound having P38MAPK inhibitory activity include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
[0067] P38MAPK阻害作用を有する化合物の薬理学的に許容される酸付加塩としては、 塩酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩、酢酸塩、マレイン酸塩、フマル酸 塩、クェン酸塩等の有機酸塩が挙げられ、薬理学的に許容される金属塩としては、 ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアル カリ土類金属塩、アルミニウム塩、亜鉛塩等が挙げられ、薬理学的に許容されるアン モ -ゥム塩としては、アンモ-ゥム、テトラメチルアンモ -ゥム等の塩が挙げられ、薬理 学的に許容される有機アミン付加塩としては、モルホリン、ピぺリジン等の付加塩が挙 げられ、薬理学的に許容されるアミノ酸付加塩としては、グリシン、フエ-ルァラニン、 リジン、ァスパラギン酸、グルタミン酸等の付加塩が挙げられる。  [0067] Pharmacologically acceptable acid addition salts of compounds having P38MAPK inhibitory action include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, acetate, maleate, and fumarate. And organic acid salts such as citrate, and pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, Aluminum salts, zinc salts, etc. can be mentioned, and pharmacologically acceptable ammonium salts include ammonium salts, tetramethyl ammonium salts, etc., which are pharmacologically acceptable. Examples of organic amine addition salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include addition of glycine, ferrolanine, lysine, aspartic acid, glutamic acid and the like. Salt I can get lost.
[0068] 本発明で用いられる 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩 、及び本発明の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩は例え ば下記のキナーゼの阻害剤として用いることもできる。 [0068] The 2-aminoquinazoline derivative or pharmacologically acceptable salt thereof used in the present invention and the 2-aminoquinazoline derivative or pharmacologically acceptable salt thereof of the present invention include, for example, the following kinases: It can also be used as an inhibitor.
KINASE INSERT DOMAIN RECEPTOR (KDR)、 ABELSON MURINE LEUKEMIA VI RAL ONCOGENE HOMOLOG 1 (ABLl)、 ACTIVATED P21CDC42HS KINASE (A CK)、 TYR03 PROTEIN TYROSINE KINASE (TYR03)、 CYTOPLASMIC TYROSIN E KINASE (CSK)、 EPHRIN RECEPTOR EphA2 (EPHA2)、 EPHRIN RECEPTOR Ep hB4 (EPHB4)、 PROTEIN- TYROSINE KINASE, CYTOPLASMIC (FAK)、 FIBROBL AST GROWTH FACTOR RECEPTOR 1 (FGFRl)、 INSULIN-LIKE GROWTH FAC TOR I RECEPTOR (IGFIR)、 JANUS KINASE 3 (JAK3)、 MET PROTOONCOGENEKINASE INSERT DOMAIN RECEPTOR (KDR), ABELSON MURINE LEUKEMIA VI RAL ONCOGENE HOMOLOG 1 (ABLl), ACTIVATED P21CDC42HS KINASE (A CK), TYR03 PROTEIN TYROSINE KINASE (TYR03), CYTOPLASMIC TYROSIN E KINASE (CSK), EPHRIN RECEPTOR EphA2 (EPHA2), EPHRIN RECEPTOR Ep hB4 (EPHB4), PROTEIN- TYROSINE KINASE, CYTOPLASMIC B (FGFRl), INSULIN-LIKE GROWTH FAC TOR I RECEPTOR (IGFIR), JANUS KINASE 3 (JAK3), MET PROTOONCOGENE
(MET)、 FMS— RELATED TYROSINE KINASE 3 (FLT3)、 PLATELET-DERIVED G ROWTH FACTOR RECEPTOR ALPHA (PDGFR a )、 V- SRC AVIAN SARCOMA (S CHMIDT— RUPPIN A— 2) VIRAL ONCOGENE (SRC)、 PROTEIN— TYROSINE KINAS E SYK (SYK)、 TEC PROTEIN TYROSINE KINASE (TEC)、 TEK TYROSINE KINAS E, ENDOTHELIAL (TIE2)、 NEUROTROPHIC TYROSINE KINASE, RECEPTOR, T YPE 1 (TRKA)、 PYRUVATE DEHYDROGENASE KINASE, ISOENZYME 1 (PDKl) 、 RIBOSOMAL PROTEIN S6 KINASE, 90— KD, 3 (RSK2)、 CALCIUM/CALMODULI N— DEPENDENT PROTEIN KINASE IV (CaMK4)、 CALCIUM/CALMODULIN— DEP ENDENT PROTEIN KINASE Π- ALPHA (CaMK2 a )、 CHECKPOINT, S. POMBE, HOMOLOG OF, 1 (CHKl)、 DEATH-ASSOCIATED PROTEIN KINASE 1 (DAPKl) 、 MITOGEN— ACTIVATED PROTEIN KINASE— ACTIVATED PROTEIN KINASE 2 ( MAPKAPK2)、 ONCOGENE PIM 1 (PIMl)、 CHECKPOINT KINASE 2, S. POMBE, HOMOLOG OF (CHK2)、 CYCUN- DEPENDENT KINASE 2 (CDK2)、 GLYCOGEN(MET), FMS— RELATED TYROSINE KINASE 3 (FLT3), PLATELET-DERIVED G ROWTH FACTOR RECEPTOR ALPHA (PDGFR a), V- SRC AVIAN SARCOMA (S CHMIDT— RUPPIN A— 2) VIRAL ONCOGENE (SRC), PROTEIN— TYROSINE KINAS E SYK (SYK), TEC PROTEIN TYROSINE KINASE (TEC), TEK TYROSINE KINAS E, ENDOTHELIAL (TIE2), NEUROTROPHIC TYROSINE KINASE, RECEPTOR, T YPE 1 (TRKA), PYRUVATE DEHYDEROZY, BOZ S6 KINASE, 90— KD, 3 (RSK2), CALCIUM / CALMODULI N— DEPENDENT PROTEIN KINASE IV (CaMK4), CALCIUM / CALMODULIN— DEP ENDENT PROTEIN KINASE Π-ALPHA (CaMK2 a), CHECKPOINT, S. POMBE, HOMOLOG OF, 1 (CHKl), DEATH-ASSOCIATED PROTEIN KINASE 1 (DAPKl), MITOGEN— ACTIVATED PROTEIN KINASE— ACTIVATED PROTEIN KINASE 2 (MAPKAPK2), ONCOGENE PIM 1 (PIMl), CHECKPOINT KINASE 2, S. POMBE, HOMOLOG OF (K) CYCUN- DEPENDENT KINASE 2 (CDK2), GLYCOGEN
SYNTHASE KINASE 3- BETA (GSK3 β )、 MITOGEN- ACTIVATED PROTEIN KIN ASE 1 (Erk2)、 MITOGEN— ACTIVATED PROTEIN KINASE 8 (JNKI)、 MITOGEN— ACTIVATED PROTEIN KINASE 14 (p38 a )、 PROTEIN KINASE, SERINE/ARGINI NE— SPECIFIC, 1 (SRPKl)、 AURORA KINASE A (AurA)、 INHIBITOR OF KAPPA L IGHT CHAIN GENE ENHANCER IN B CELLS, KINASE OF, BETA (IKK β )、 NEV ER IN MITOSIS GENE A- RELATED KINASE 2 (NEK2)、 TTK PROTEIN KINASE (T TK)、 V- RAF- 1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 (RAFl)、 MITOGEN- ACTIVATED PROTEIN KINASE KINASE KINASE 5 (MAP3K5)、 INTER LEUKIN 1 RECEPTOR-ASSOCIATED KINASE 4 (IRAK4)、 PHOSPHORYLASE KI NASE, MUSCLE, GAMMA- 1 (PHKGl)、 CASEIN KINASE I, DELTA (CKl δ )、 PRO TEIN KINASE D2 (PKD2) SYNTHASE KINASE 3- BETA (GSK3 β), MITOGEN- ACTIVATED PROTEIN KIN ASE 1 (Erk2), MITOGEN— ACTIVATED PROTEIN KINASE 8 (JNKI), MITOGEN— ACTIVATED PROTEIN KINASE 14 (p38 a), PROTEIN KINASE, SERINE / ARGINI NE— SPECIFIC, 1 (SRPKl), AURORA KINASE A (AurA), INHIBITOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS, KINASE OF, BETA (IKK β), NEV ER IN MITOSIS GENE A- RELATED KINASE 2 (NEK2), TTK PROTEIN KINASE (T TK), V- RAF- 1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 (RAFl), MITOGEN- ACTIVATED PROTEIN KINASE KINASE KINASE 5 (MAP3K5), INTER LEUKIN 1 RECEPTOR-ASSOCIATED KINASE 4 (IRAKRY), PHOSPE MUSCLE, GAMMA-1 (PHKGl), CASEIN KINASE I, DELTA (CKl δ), PRO TEIN KINASE D2 (PKD2)
次に、化合物 (I)の製造法について説明する。  Next, a method for producing compound (I) will be described.
[0069] なお、以下に示す製造法において、定義した基が該製造法の条件下で変化するか 、または方法を実施するのに不適切な場合、有機合成化学で常用される方法、例え ば官能基の保護、脱保護 [例えば、プロテクティブ'グループス'イン'オーガニック' ンンセンス弟二版 (Protective uroups in Organic Synthesis, third edition)、クリ' ~~ン、 T. W. Greene)著、ジョン'ワイリ^ ~ ·アンド'サンズ 'インコーポレイテッド（John Wiley & Sons Inc.) (1999年) ]等の手段を用いることにより目的化合物を製造することができ る。また、必要に応じて置換基導入等の反応工程の順序を変えることもできる。  [0069] In the production methods shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the method, a method commonly used in organic synthetic chemistry, for example, Functional group protection, deprotection [eg, Protective uroups in Organic Synthesis, third edition, Protective uroups in Organic Synthesis, third edition, by TW Greene, John Wylly · The target compound can be produced by using means such as “John Wiley & Sons Inc. (1999)”. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
[0070] 化合物（I)は、例えば公知の方法（US2004/0209904、 WO04/092144)により製造す ることがでさる。  [0070] Compound (I) can be produced, for example, by a known method (US2004 / 0209904, WO04 / 092144).
また、化合物（I)は、例えば以下の工程によっても製造することができる。 製造法 1  Compound (I) can also be produced, for example, by the following steps. Manufacturing method 1
化合物（I)のうち、 Xが結合であり、 R3が置換もしくは非置換のァリールまたは置換も しくは非置換の芳香族複素環基である化合物 (Id)は、例えば以下の工程に従い製 造することができる。 Among compounds (I), a compound (Id) in which X is a bond and R 3 is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group is produced, for example, according to the following steps. can do.
[0071] [化 9] [0071] [Chemical 9]
Figure imgf000026_0001
Figure imgf000026_0001
(式中、
Figure imgf000026_0002
R2、 R3a及び R4はそれぞれ前記と同義であり、 R3°は置換もしくは非置換の 低級アルキルを表す） (Where
Figure imgf000026_0002
R 2 , R 3a and R 4 are as defined above, and R 3 ° represents a substituted or unsubstituted lower alkyl)
工程ト 1  Process 1
化合物（III)は、化合物（II)を溶媒中、 1〜20当量の臭素と反応させることにより得る ことができる。 [0073] 溶媒としては、例えば酢酸、四塩化炭素、クロ口ホルム、ジクロロメタン、 1,2-ジクロロ ェタン、ジォキサン、テトラヒドロフラン (THF)、酢酸ェチル等を用いることができ、好 ましくは酢酸を用いることができる。 Compound (III) can be obtained by reacting Compound (II) with 1 to 20 equivalents of bromine in a solvent. [0073] As the solvent, for example, acetic acid, carbon tetrachloride, chloroform, formaldehyde, dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran (THF), ethyl acetate, etc. can be used, and preferably acetic acid is used. be able to.
反応は 0 °Cから用いる溶媒の沸点の間の温度、好ましくは 60 °Cにおいて 5分間から 48時間程度行われる。  The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably 60 ° C. for about 5 minutes to 48 hours.
[0074] 臭素の代わりに、例えば N-ブロモこはく酸イミド、ピロリドントリプロミド、臭化第一銅 、ピリジ-ゥムトリブ口ミド等を用いることもできる。この場合、溶媒としては、例えばァセ トニトリノレ、メタノール、エタノール、ジクロロメタン、 1,2 -ジクロロェタン、クロロホノレム、 ジメトキシェタン、 Ν,Ν-ジメチルホルムアミド（DMF)、ジォキサン、 THF、ジェチルェ 一テル、ジイソプロピルエーテル、 Ν,Ν-ジメチルイミダゾリジノン、 Ν-メチルピロリドン、 スルホラン等を用いることができ、好ましくは DMFを用いることができる。  [0074] Instead of bromine, for example, N-bromosuccinimide, pyrrolidone tripromide, cuprous bromide, pyridinium mutobide amide and the like can be used. In this case, examples of the solvent include acetonitrile, methanol, ethanol, dichloromethane, 1,2-dichloroethane, chlorohonolem, dimethoxyethane, Ν, Ν-dimethylformamide (DMF), dioxane, THF, jetyl ether, diisopropyl ether. Ν, Ν-dimethylimidazolidinone, 、 -methylpyrrolidone, sulfolane and the like can be used, and preferably DMF can be used.
[0075] 化合物（II)は市販品として、またはフルォロベンゼン誘導体より、公知の方法 {フル ォロベンゼン誘導体を、リチォ化 [例えば、ケミカル 'レビュー（Chemical Reviews)、 90 卷、 879頁（1990年)等参照]次いでホルミル化 [例えば、実験化学講座、第 21卷、 30 頁（1991年)等参照]に付す方法等 }もしくはそれに準じた方法により得ることができる 工程ト 2  [0075] Compound (II) is a commercially available product or a known method from a fluorobenzene derivative {referred to fluorination of a fluorobenzene derivative [for example, see Chemical Reviews, 90 pp. 879 (1990), etc.] ] Then, formylation [see, for example, Experimental Chemistry Course, page 21, page 30 (1991), etc.] etc.} or a method analogous thereto can be obtained.
化合物 (V)は、公知の方法 [例えば、ジャーナル ·ォブ ·ヘテロサイクリック 'ケミストリ 一（Journal of Heterocyclic Chemistry)、 34卷、 385頁（1997年）参照]またはそれに準 じた方法によって、化合物（III)を溶媒中、 1〜20当量の塩基存在下、 1〜20当量の化 合物 (IV)と反応させること〖こより得ることができる。  Compound (V) can be obtained by known methods [for example, see Journal of Heterocyclic Chemistry, 34, 385 (1997)] or a method analogous thereto. It can be obtained by reacting (III) with 1 to 20 equivalents of compound (IV) in a solvent in the presence of 1 to 20 equivalents of a base.
[0076] 溶媒としては、例えば Ν,Ν-ジメチルァセトアミド（DMA)、 DMF, N-メチルピロリドン、 ジメチルスルホキシド（DMSO)等を用いることができ、好ましくは DMAを用いることが できる。 As the solvent, for example, Ν, Ν-dimethylacetamide (DMA), DMF, N-methylpyrrolidone, dimethyl sulfoxide (DMSO) and the like can be used, and DMA can be preferably used.
塩基としては、例えば炭酸カリウム、炭酸セシウム、ナトリウムメトキシド、カリウム tert -ブトキシド等を用いることができ、好ましくは炭酸カリウムまたは炭酸セシウムを用い ることがでさる。  As the base, for example, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide and the like can be used, and potassium carbonate or cesium carbonate is preferably used.
[0077] 反応は室温から 180 °Cの間の温度、好ましくは 160 °Cにおいて、 5分間力も 48時間 程度行われる。 [0077] The reaction is carried out at a temperature between room temperature and 180 ° C, preferably at 160 ° C, for 5 minutes and for 48 hours. Done about.
化合物（IV)は市販品として、または公知の方法 [例えば、ジャーナル'ォブ 'オーガ ニック'ケミストリー（Journal of Organic Chemistry)、 57卷、 2497頁（1992年）参照]もし くはそれに準じた方法により得ることができる。  Compound (IV) is a commercially available product or a known method [see, for example, Journal of Organic Chemistry, page 57, page 2497 (1992)] or a method equivalent thereto. Can be obtained.
工程ト 3  Process 3
化合物（VIII)は、化合物（V)を溶媒中、 0.1〜10当量の塩基及び 0.001〜1当量の パラジウム触媒存在下、 1〜20当量の化合物 (VI)または (VII)と反応させることにより 得ることができる。  Compound (VIII) is obtained by reacting Compound (V) with 1 to 20 equivalents of Compound (VI) or (VII) in the presence of 0.1 to 10 equivalents of base and 0.001 to 1 equivalents of palladium catalyst in a solvent. be able to.
[0078] 溶媒としては、例えばァセトニトリル、メタノール、エタノール、ジクロロメタン、 1,2-ジ クロロェタン、クロ口ホルム、 DMA, DMF、ジォキサン、 THF、ジェチルエーテル、ジィ ソプロピルエーテル、ベンゼン、トルエン、キシレン、 Ν,Ν-ジメチルイミダゾリジノン、 Ν -メチルピロリドン、スルホラン、これら力も選ばれる少なくとも 1つの溶媒と水を 100対 1 から 1対 100までの間の適切な比率で混合した混合液等を用いることができ、好ましく は水とジォキサンの 1対 2混合液を用いることができる。  [0078] Examples of the solvent include acetonitrile, methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform, DMA, DMF, dioxane, THF, jetyl ether, disopropyl ether, benzene, toluene, xylene, Use 液, Ν-dimethylimidazolidinone, Ν-methylpyrrolidone, sulfolane, a mixture of at least one solvent selected from these forces and water in an appropriate ratio between 100: 1 and 1: 100. Preferably, a 1: 2 mixture of water and dioxane can be used.
[0079] 塩基としては、例えばピリジン、トリェチルァミン、 Ν-メチルモルホリン、 Ν-メチルピぺ リジン、ピぺリジン、ピぺラジン、酢酸カリウム、炭酸カリウム、炭酸セシウム、炭酸ナトリ ゥム、炭酸水素ナトリウム、水酸化ナトリウム、水酸化リチウム、水酸ィ匕カリウム、リン酸 カリウム、ナトリウム tert-ブトキシド、 1,8-ジァザビシクロ [5.4.0]-7-ゥンデセン（DBU)、 ジイソプロピルェチルアミン等を用いることができ、好ましくは炭酸ナトリウムを用いる ことができる。なお、化合物 (VII)を用いる場合は、塩基を用いなくてもよい。  [0079] Examples of the base include pyridine, triethylamine, メ チ ル -methylmorpholine, Ν-methylpiperidine, piperidine, piperazine, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, water Sodium oxide, lithium hydroxide, potassium hydroxide, potassium phosphate, sodium tert-butoxide, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), diisopropylethylamine, etc. can be used. Preferably, sodium carbonate can be used. In addition, when using compound (VII), it is not necessary to use a base.
[0080] パラジウム触媒としては、パラジウム源として、例えば酢酸パラジウム、トリフルォロ酢 酸パラジウム、トリス (ジベンジリデンアセトン)ジパラジウム及びそのクロ口ホルム付カロ 物等を用いることができ、配位子として、例えばトリフエ-ルホスフィン、 Ι, -ビス (ジフ ェ-ルホスフイノ)フエ口セン、 0-トリルホスフィン、 1,2-ビス (ジフエ-ルホスフイノ)ェタン 、 1,3- (ビスジフエ-ルホスフイノ)プロパン、 1,4-ビス（ジフエ-ルホスフイノ）ブタン、ジ- tert-ブチルジフエ-ルホスフィン、 2- (ジ -tert-ブチルホスフイノ)ビフエ-ル、 2- (ジシク 口へキシルホスフイノ)ビフエ-ル等を用いることができ、これら配位子をパラジウムに 対して 1〜10当量用いるのが好ましい。なお、例えばテトラキス (トリフエニルホスフィン) パラジウム、 1 , 1-ビス (ジフエ-ルホスフイノ)フエ口センジクロロパラジウム ·ジクロロメタ ン 1： 1付加物等の、反応を行うのに適切な配位子が予めパラジウムに配位した巿販 試薬を用いることもできる。 [0080] As the palladium catalyst, for example, palladium acetate, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium and its chloroformated carbonate can be used as the palladium source, and as the ligand, for example, Triphenylphosphine, Ι, -bis (diphenylphosphino) phenol, 0-tolylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3- (bisdiphenylphosphino) propane, 1,4 -Bis (diphenylphosphino) butane, di-tert-butyldiphenylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, etc. can be used. It is preferable to use 1 to 10 equivalents of the ligand with respect to palladium. For example, tetrakis (triphenylphosphine) Use a commercially available reagent in which a ligand suitable for the reaction, such as palladium, 1,1-bis (diphenylphosphino) phenol dichloropalladium-dichloromethane 1: 1, etc. is coordinated to palladium in advance. You can also
[0081] 反応は、室温力 用いる溶媒の沸点の間の温度、好ましくは 100 °Cにおいて、 5分 間から 48時間程度行われる。  [0081] The reaction is carried out at a temperature between the boiling points of the solvents used, preferably 100 ° C, for 5 minutes to 48 hours.
化合物 (VI)及び化合物 (VII)は市販品として、または公知の方法 [例えば、実験化 学講座、 24卷、 日本ィ匕学会（1992年)等参照]もしくはそれに準じた方法により得るこ とがでさる。  Compound (VI) and Compound (VII) may be obtained as commercially available products or by known methods [see, for example, Experimental Chemistry Course, 24 卷, Japan Society of Health Sciences (1992)] or a method analogous thereto. I'll do it.
工程ト4  Process 4
化合物（Id)は、化合物 (VIII)を、 1〜100当量のチオールィ匕合物、酸、ヨウ化トリメチ ルシリルまたは硫ィ匕ナトリウムで、溶媒中、 -30 °C力 用いる溶媒の沸点の間の温度 で 5分間から 72時間処理することにより製造することができる。  Compound (Id) is compound (VIII) with 1 to 100 equivalents of thiol compound, acid, trimethylsilyl iodide or sodium sulfite in a solvent at a temperature between -30 ° C and the boiling point of the solvent used. It can be produced by treating at a temperature of 5 minutes to 72 hours.
[0082] チオール化合物としては、例えばチオフヱノール、メタンチオール、エタンチオール 等を用いることができ、これらのアルカリ金属塩、例えばナトリウムチオフエノキシド、 ナトリウムチオメトキシド、ナトリウムチォェトキシド等も用いることができる。 As the thiol compound, for example, thiophenol, methanethiol, ethanethiol and the like can be used, and alkali metal salts thereof such as sodium thiophenoxide, sodium thiomethoxide, sodium thiooxide and the like can also be used. it can.
酸としては、例えば臭化水素 Z酢酸、塩ィ匕ピリジ-ゥム、三フッ化ホウ素、三臭化ホ ゥ素、三塩ィ匕ホウ素、臭化アルミニウム、塩ィ匕アルミニウム等を用いることができる。  As the acid, for example, hydrogen bromide Z acetic acid, salt pyridinium, boron trifluoride, fluorine tribromide, trisalt bromine, aluminum bromide, salt bromide aluminum, etc. may be used. it can.
[0083] 溶媒としては、例えばジクロロメタン、クロ口ホルム、 1,2-ジクロロェタン、 DMF、 N-メ チルピロリドン（NMP)、ジェチルエーテル、 THF、これらの混合溶媒等を用いることが できる。 [0083] As the solvent, for example, dichloromethane, chloroform, 1,2-dichloroethane, DMF, N-methylpyrrolidone (NMP), jetyl ether, THF, a mixed solvent thereof or the like can be used.
製造法 2  Production method 2
化合物 (I)のうち、 R4が塩素原子、臭素原子またはヨウ素原子である化合物 (Ie)及 び置換もしくは非置換の低級ァルケ-ル、置換もしくは非置換のァリールまたは置換 もしくは非置換の複素環基である化合物 (If)は、例えば以下の工程に従い製造する ことができる。 Of the compounds (I), R 4 is a chlorine atom, bromine atom or iodine atom (Ie) and a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic ring The compound (If) as a group can be produced, for example, according to the following steps.
[0084] [化 10]
Figure imgf000030_0001
[0084] [Chemical 10]
Figure imgf000030_0001
(式中、
Figure imgf000030_0002
R2、 R3、 R3°及び Xはそれぞれ前記と同義であり、 R4eは置換もしくは非置換 の低級アルケニル、置換もしくは非置換のァリールまたは置換もしくは非置換の複素 環基を表し、 L1は塩素原子、臭素原子またはヨウ素原子を表す） (Where
Figure imgf000030_0002
R 2 , R 3 , R 3 ° and X are as defined above, R 4e represents a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, L 1 Represents a chlorine atom, a bromine atom or an iodine atom)
工程 2-1 Process 2-1
化合物 (X)は、化合物 (IX)を用い、 L1が臭素原子の場合は、製造法 1の工程 1-1に 準じて合成することができ、 L1がヨウ素原子の場合は、例えばメタノール、エタノール 等の溶媒中、亜塩素酸ナトリウム存在下、例えば水酸ィ匕ナトリウム、水酸化カリウム等 の塩基及びヨウ化ナトリウムを作用させることにより合成することができ、 L1が塩素原子 の場合は、例えばクロ口ホルム、四塩ィ匕炭素等の溶媒中、塩素または N-クロロコハク 酸イミドを作用させることにより合成することができる。 Compound (X) is compound (IX), and when L 1 is a bromine atom, it can be synthesized according to Step 1-1 of Production Method 1, and when L 1 is an iodine atom, for example, methanol In the presence of sodium chlorite in a solvent such as ethanol, it can be synthesized by reacting a base such as sodium hydroxide or potassium hydroxide and sodium iodide. When L 1 is a chlorine atom For example, it can be synthesized by reacting chlorine or N-chlorosuccinimide in a solvent such as black mouth form or tetrasalt carbon.
化合物（IX)は、例えば製造法 1、 4もしくは 5記載の方法またはそれに準じた方法で 得られる。  Compound (IX) can be obtained, for example, by the method described in Production Method 1, 4 or 5, or a method analogous thereto.
工程 2- 2 Process 2-2
化合物 (XIV)は、製造法 1の工程ト 3に準じて合成することができる。  Compound (XIV) can be synthesized according to Step 1 of Production Method 1.
化合物 (XI)、 (XII)及び (XIII)は市販品として得ることができる。また化合物 (XI)及 び (XII)は公知の方法「例えば、実験化学講座、 24卷、 日本化学会（1992年)等参照 Compounds (XI), (XII) and (XIII) can be obtained as commercial products. Compounds (XI) and (XII) can be obtained by a known method such as “Experimental Chemistry Course, 24 卷, Chemical Society of Japan (1992)”.
」もしくはそれに準じた方法により得ることもできる。 It can also be obtained by a method analogous thereto.
工程 2- 3 Process 2-3
化合物 ）は、化合物 (X)から、例えば製造法 1の工程 1-4に方法によって合成す ることがでさる。  Compound) can be synthesized from compound (X) by, for example, step 1-4 of production method 1.
工程 2- 4 Process 2-4
化合物（If)は、化合物 (XIV)から、例えば製造法 1の工程 1-4に方法によって合成 することができる。 Compound (If) is synthesized from compound (XIV) by a method, for example, in steps 1 to 1 of production method 1. can do.
製造法 3  Production method 3
化合物 (I)のうち、 R4がカルボキシである化合物 (Ig)及び CONR9aR9b (式中、 R9a及び R9bはそれぞれ前記と同義である）である化合物 (Ih)は、例えば以下の工程に従い製 造することができる。 Among the compounds (I), R 4 is carboxy (Ig) and CONR 9a R 9b (wherein R 9a and R 9b are as defined above), It can be manufactured according to the process.
[0087] [化 11]  [0087] [Chemical 11]
Figure imgf000031_0001
Figure imgf000031_0001
(式中、
Figure imgf000031_0002
R9a、 R%、 R3°、 X及び L1はそれぞれ前記と同義であり、 R31は置換も しくは非置換の低級アルキルを表す） (Where
Figure imgf000031_0002
R 9a , R % , R 3 °, X and L 1 are the same as defined above, and R 31 represents substituted or unsubstituted lower alkyl)
工程 3-1  Process 3-1
化合物（XVI)は、化合物（X)を、 1〜1000当量の化合物（XV)と、 0.0001〜2当量、 好ましくは 0.01〜0.1当量のパラジウム錯体の存在下、 0.1〜100気圧、好ましくは 1〜1 0気圧の一酸化炭素雰囲気下、必要に応じて 1〜100当量の塩基存在下、溶媒中ま たは無溶媒で、 0〜250。C、好ましくは 20〜150 °Cで、 5分間から 48時間反応させるこ とにより合成することができる。化合物 (XV)は、溶媒を兼ねて使用することもできる。  Compound (XVI) is obtained by converting Compound (X) from 1 to 1000 equivalents of Compound (XV) in the presence of 0.0001 to 2 equivalents, preferably 0.01 to 0.1 equivalents of a palladium complex, 0.1 to 100 atm, preferably 1 to 0 to 250 in a carbon monoxide atmosphere at 10 atm, optionally in the presence of 1 to 100 equivalents of a base, in a solvent or without a solvent. It can be synthesized by reacting at C, preferably 20 to 150 ° C, for 5 minutes to 48 hours. Compound (XV) can also be used as a solvent.
[0089] パラジウム錯体としては、例えばテトラキス (トリフエニルホスフィン)パラジウム、ジクロ 口ビス (トリフエ-ルホスフィン)パラジウム、 [ビス (1 ,2-ジフエ-ルホスフイノ)ェタン]ジク ロロパラジウム、 [1 , 1，-ビス (ジフエ-ルホスフイノ)フエ口セン]ジクロロパラジウム等の他[0089] Examples of the palladium complex include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [bis (1,2-diphenylphosphino) ethane] dichloropalladium, [1,1,1, -Bis (Diphenyl-phosphino) Phenocene] dichloropalladium etc.
、反応系中でパラジウム錯体を形成させるパラジウム前駆体とホスフィンの組み合わ せを用いることができる。 A combination of a palladium precursor and a phosphine that forms a palladium complex in the reaction system can be used.
[0090] パラジウム前駆体としては、例えば酢酸パラジウム、塩化パラジウム、トリス (ジべンジ リデンアセトン)ジパラジウム、パラジウム炭素等を用いることができる。 ホスフィンとしては、例えばトリフエ-ルホスフィン、 1,1，-ビス (ジフエ-ルホスフイノ)フ エロセン、ビス (1,2-ジフエ-ルホスフイノ)ェタン、ビス (1,3-ジフエ-ルホスフイノ)プロパ ン、ビス (1 ,4-ジフエ-ルホスフイノ)ブタン、 2,2， -ビス (ジフエ-ルホスフイノ) -1 , 1， -ビナ フチル、ビス (1,4-ジシクロへキシルホスフイノ)ブタン等を用いることができ、好ましくは 酢酸パラジウムとビス (1,3-ジフヱ-ルホスフイノ)プロパンの組み合わせ及びパラジゥ ム炭素とビス (1,3-ジフエ-ルホスフイノ)プロパンの組み合わせを用いることができる。 [0090] As the palladium precursor, for example, palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon and the like can be used. Examples of phosphine include triphenylphosphine, 1,1, -bis (diphenylphosphino) ferrocene, bis (1,2-diphenylphosphino) ethane, bis (1,3-diphenylphosphino) propan, bis (1,4-diphenylphosphino) butane, 2,2, -bis (diphenylphosphino) -1,1, -binaphthyl, bis (1,4-dicyclohexylphosphino) butane and the like can be preferably used. The combination of palladium acetate and bis (1,3-diphenylphosphino) propane and the combination of palladium carbon and bis (1,3-diphenylphosphino) propane can be used.
[0091] 塩基としては、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、リン酸カリウム、 水酸ィ匕カリウム、酢酸カリウム等の無機塩基、ピリジン、トリェチルァミン等の有機塩基 を用いることができ、好ましくは炭酸カリウム、炭酸セシウム等の炭酸塩を用いることが できる。 [0091] As the base, for example, an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, potassium acetate or the like, or an organic base such as pyridine or triethylamine, preferably carbonic acid can be used. Carbonates such as potassium and cesium carbonate can be used.
化合物（XV)としては、例えばメタノール、エタノール、 1-プロパノール、 2-ブタノー ルが好ましい。  As the compound (XV), for example, methanol, ethanol, 1-propanol and 2-butanol are preferable.
[0092] 溶媒としては、例えばペンタン、へキサン、シクロへキサン等の脂肪族炭化水素系 溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、メタノール、ェタノ ール、プロパノール、ブタノール等のアルコール系溶媒、テトラリン、ジフエ-ルエー テル、酢酸ェチル、塩化メチレン、クロ口ホルム、ジクロロェタン、四塩化炭素、ピリジ ン、ァセトニトリル、 DMF、 DMA, 1-メチル -2-ピロリドン、 1,3-ジメチル- 2-イミダゾリジ ノン、 DMSO、スルホラン、ジメチルスルホン、 THF、ジォキサン、ジメトキシェタン、こ れらの混合溶媒等を用いることができる。  [0092] Examples of the solvent include aliphatic hydrocarbon solvents such as pentane, hexane and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, methanol, ethanol, propanol and butanol. Alcohol solvents, tetralin, diphenyl ether, ethyl acetate, methylene chloride, chloroform, dichloroethane, carbon tetrachloride, pyridine, acetonitrile, DMF, DMA, 1-methyl-2-pyrrolidone, 1,3-dimethyl- 2-Imidazolidinone, DMSO, sulfolane, dimethyl sulfone, THF, dioxane, dimethoxyethane, a mixed solvent thereof and the like can be used.
工程 3- 2  Process 3-2
化合物（XVIII)は、化合物（XVI)を、 1〜 100当量の化合物（XVII)と、 1〜100当量、 好ましくは 1〜10当量の塩基の存在下、溶媒中または無溶媒で、 -78 °C力 用いる溶 媒の沸点の間の温度で、好ましくは- 78〜30 °Cで、 5分間から 48時間反応させること により合成することができる。なお、反応は窒素、アルゴン等の不活性気体雰囲気下 で実施することが好ましい。  Compound (XVIII) is obtained by reacting Compound (XVI) with 1 to 100 equivalents of Compound (XVII) in the presence of 1 to 100 equivalents, preferably 1 to 10 equivalents of a base, in a solvent or without solvent. C force It can be synthesized by reacting at a temperature between the boiling points of the solvents used, preferably at -78 to 30 ° C for 5 minutes to 48 hours. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
[0093] 塩基としては、例えばブチルリチウム、 sec-ブチルリチウム、 tert-ブチルリチウム、リ チウムジイソプロピルアミド等を用いることができ、好ましくはブチルリチウムを用いるこ とがでさる。 溶媒としては、例えば THF、ジェチルエーテル、ジォキサン、ジイソプロピルエーテ ル、ジメトキシェタン等を用いることができ、好ましくは THFを用いることができる。 [0093] As the base, for example, butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide and the like can be used, and preferably butyl lithium is used. As the solvent, for example, THF, jetyl ether, dioxane, diisopropyl ether, dimethoxyethane and the like can be used, and preferably THF can be used.
[0094] 化合物 (XVII)は、市販品として、または公知の方法 [例えば、実験化学講座、 20卷 、 279頁、丸善（1992年)等に記載の方法]もしくはそれに準じた方法により得ることが できる。 [0094] Compound (XVII) can be obtained as a commercially available product or by a known method [for example, the method described in Experimental Chemistry Course, 20 pp. 279, Maruzen (1992), etc.] or a method analogous thereto. it can.
工程 3- 3  Process 3-3
化合物（Ig)は、化合物 (XVI)から、例えば製造法 1の工程 1-4に方法によって合成 することができる。  Compound (Ig) can be synthesized from compound (XVI) by, for example, step 1 to step 1-4 of production method 1.
工程 3- 4  Process 3-4
化合物（Ih)は、化合物 (XVIII)から、例えば製造法 1の工程 1-4に方法によって合成 することができる。  Compound (Ih) can be synthesized from compound (XVIII) by a method, for example, in Step 1-4 of Production Method 1.
製造法 4  Manufacturing method 4
化合物 (I)は、例えば以下の工程に従い製造することができる。  Compound (I) can be produced, for example, according to the following steps.
[0095] [化 12] [0095] [Chemical 12]
Figure imgf000033_0001
Figure imgf000033_0001
(XXII) (I)  (XXII) (I)
[0096] (式中、
Figure imgf000033_0002
R4、 R3°、 X及び L1はそれぞれ前記と同義である） [0096] (wherein
Figure imgf000033_0002
R 4 , R 3 °, X and L 1 are as defined above)
工程 4-1  Process 4-1
化合物 (XX)は、化合物 (XIX)をザンドマイヤー反応に付すことにより合成すること ができる。  Compound (XX) can be synthesized by subjecting compound (XIX) to a Sandmeyer reaction.
すなわち化合物 (XX)は、化合物 (XIX)を、 1〜100当量の亜硝酸ィ匕合物と必要に 応じて 1〜1000当量の酸、 1〜1000当量のハロゲン源の存在下、溶媒中または無溶 媒で、 -30 °Cから用いる溶媒の沸点の間の温度で、 5分間から 100時間反応させるこ とにより合成することができる。 That is, compound (XX) is obtained by combining compound (XIX) in a solvent in the presence of 1 to 100 equivalents of a nitrite compound and optionally 1 to 1000 equivalents of acid and 1 to 1000 equivalents of a halogen source. The reaction is allowed to proceed for 5 to 100 hours in a solvent-free environment at temperatures between -30 ° C and the boiling point of the solvent used. And can be synthesized.
[0097] 亜硝酸ィ匕合物としては、例えば亜硝酸、亜硝酸ナトリウム等の亜硝酸塩、塩化-ト ロシル等のハロゲン化-トロシル、亜硝酸 tert-ブチル、亜硝酸イソアミル等の亜硝酸 アルキルを用いることができる。  [0097] Examples of nitrous acid compounds include nitrites such as nitrous acid and sodium nitrite, halogenated trosils such as -tosyl chloride, alkyl nitrites such as tert-butyl nitrite and isoamyl nitrite. Can be used.
酸としては、例えばヨウ化水素酸、臭化水素酸、塩酸等を用いることができる。 ハロゲン源としては、塩化銅 (1)、臭化銅 (1)、ヨウ化銅 (1)、塩化銅 (11)、臭化銅 (11)、ヨウ ィ匕銅 (11)、ヨウ化カリウム、ジョードメタン等を用いることができる。  As the acid, for example, hydroiodic acid, hydrobromic acid, hydrochloric acid and the like can be used. Halogen sources include copper chloride (1), copper bromide (1), copper iodide (1), copper chloride (11), copper bromide (11), copper iodide (11), potassium iodide, Jodomethane or the like can be used.
[0098] 溶媒としては、例えばメタノール、エタノール等のアルコール類、 THF、ジォキサン 等のエーテル類、アセトン、 DMSO、 DMF、水、これらの混合溶媒等を用いることがで きる。 As the solvent, for example, alcohols such as methanol and ethanol, ethers such as THF and dioxane, acetone, DMSO, DMF, water, a mixed solvent thereof and the like can be used.
工程 4- 2  Process 4-2
化合物（XXII)は、化合物（XX)と 1〜1000当量のァミン (XXI)を溶媒中または無溶 媒で、必要に応じて 1〜100当量の塩基の存在下、 0 °Cから用いる溶媒の沸点の間の 温度で、好ましくは 0〜100 °Cで、 5分間から 48時間反応させることにより、合成するこ とがでさる。  Compound (XXII) is a mixture of compound (XX) and 1 to 1000 equivalents of amine (XXI) in a solvent or non-solvent, optionally in the presence of 1 to 100 equivalents of a base, from 0 ° C. It can be synthesized by reacting at a temperature between the boiling points, preferably 0-100 ° C, for 5 minutes to 48 hours.
[0099] また必要に応じて、 0.0001〜2当量、好ましくは 0.01〜0.1当量のパラジウム錯体の 存在下、反応を行うこともできる。  [0099] If necessary, the reaction can also be carried out in the presence of 0.0001 to 2 equivalents, preferably 0.01 to 0.1 equivalents of a palladium complex.
パラジウム錯体としては、例えばテトラキス (トリフエニルホスフィン)パラジウム、ジクロ 口ビス (トリフエ-ルホスフィン)パラジウム、 [ビス (1 ,2-ジフエ-ルホスフイノ)ェタン]ジク ロロパラジウム、 [1,1，-ビス (ジフエ-ルホスフイノ)フエ口セン]ジクロロパラジウム等の他 Examples of the palladium complex include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [bis (1,2-diphenylphosphino) ethane] dichloropalladium, [1,1, -bis ( Others such as diphenyl-phosphosino) weicene dichloropalladium
、反応系中でパラジウム錯体を形成させるパラジウム前駆体とホスフィンの組み合わ せを用いることができる。 A combination of a palladium precursor and a phosphine that forms a palladium complex in the reaction system can be used.
[0100] パラジウム前駆体としては、例えば酢酸パラジウム、塩化パラジウム、トリス (ジべンジ リデンアセトン)ジパラジウム、パラジウム炭素等を用いることができる。 [0100] As the palladium precursor, for example, palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon and the like can be used.
ホスフィンとしては、例えばトリフエ-ルホスフィン、 1,1，-ビス (ジフエ-ルホスフイノ)フ エロセン、ビス (1,2-ジフエ-ルホスフイノ)ェタン、ビス (1,3-ジフエ-ルホスフイノ)プロパ ン、ビス (1 ,4-ジフエ-ルホスフイノ)ブタン、 2,2， -ビス (ジフエ-ルホスフイノ) -1 , 1， -ビナ フチル、ビス (1,4-ジシクロへキシルホスフイノ)ブタン等を用いることができる。 [0101] 塩基としては、例えば炭酸カリウム、炭酸ナトリウム、炭酸セシウム、リン酸カリウム、 水酸ィ匕カリウム、酢酸カリウム等の無機塩基、ピリジン、トリェチルァミン等の有機塩基 を用いることができる。 Examples of phosphine include triphenylphosphine, 1,1, -bis (diphenylphosphino) ferrocene, bis (1,2-diphenylphosphino) ethane, bis (1,3-diphenylphosphino) propan, bis (1,4-diphenylphosphino) butane, 2,2, -bis (diphenylphosphino) -1,1, -binaphthyl, bis (1,4-dicyclohexylphosphino) butane and the like can be used. [0101] As the base, for example, an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide or potassium acetate, or an organic base such as pyridine or triethylamine can be used.
溶媒としては、例えばペンタン、へキサン、シクロへキサン等の脂肪族炭化水素系 溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、メタノール、ェタノ ール、プロパノール、ブタノール等のアルコール系溶媒、テトラリン、ジフエ-ルエー テル、酢酸ェチル、塩化メチレン、クロ口ホルム、ジクロロェタン、四塩化炭素、ピリジ ン、ァセトニトリル、 DMF、 DMA, 1-メチル -2-ピロリドン、 1,3-ジメチル- 2-イミダゾリジ ノン、 DMSO、スルホラン、ジメチルスルホン、 THF、ジォキサン、ジメトキシェタン、こ れらの混合溶媒等を用いることができる。  Examples of the solvent include aliphatic hydrocarbon solvents such as pentane, hexane, and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and alcohol solvents such as methanol, ethanol, propanol, and butanol. , Tetralin, Diphenyl ether, Ethyl acetate, Methylene chloride, Chloroform, Dichloroethane, Carbon tetrachloride, Pyridine, Acetonitrile, DMF, DMA, 1-Methyl-2-pyrrolidone, 1,3-Dimethyl-2-imidazolide Non, DMSO, sulfolane, dimethyl sulfone, THF, dioxane, dimethoxyethane, a mixed solvent thereof or the like can be used.
[0102] 化合物 (XXI)は、市販品として、または公知の方法 [例えば、実験化学講座、 20卷 、 279頁、丸善（1992年)等に記載の方法]もしくは参考例に記載の方法により得ること ができる。 [0102] Compound (XXI) is obtained as a commercially available product or by a known method [for example, the method described in Experimental Chemistry Course, 20th page, page 279, Maruzen (1992), etc.] or the method described in Reference Examples. be able to.
工程 4- 3  Process 4-3
化合物（I)は、化合物 (XXII)から、例えば製造法 1の工程 1-4に方法によって合成 することができる。  Compound (I) can be synthesized from compound (XXII) by a method, for example, in Step 1-4 of Production Method 1.
製造法 5  Manufacturing method 5
化合物 (I)のうち、 Xが C(=0)または C(OH)R7e (式中、 R7 ま水素原子または置換もし くは非置換の低級アルキルを表す)である化合物（Ii)は、例えば以下の工程に従 ヽ 製造することができる。 Among the compounds (I), the compound (Ii) in which X is C (= 0) or C (OH) R 7e (wherein R 7 represents a hydrogen atom or a substituted or unsubstituted lower alkyl) For example, it can be produced according to the following steps.
[0103] [化 13] [0103] [Chemical 13]
Figure imgf000036_0001
Figure imgf000036_0001
(li)  (li)
[0104] [式中、
Figure imgf000036_0002
R3Q及び R31はそれぞれ前記と同義であり、 Xbは C(=0)または C(OH) R7e (式中、 R7 ま前記と同義である)を表し、 R4dは水素原子、ハロゲン、ヒドロキシ、置 換もしくは非置換の低級アルキル、置換もしくは非置換の低級ァルケ-ル、置換もし くは非置換の低級アルコキシ、置換もしくは非置換のァリールまたは置換もしくは非 置換の複素環基を表し、 R32は水素原子、置換もしくは非置換の低級アルキルまたは NR33aR33b (式中、 R33a及び R33bは同一または異なって、水素、置換もしくは非置換の低 級アルキルまたは置換もしくは非置換の低級アルコキシを表す）を表す] [0104] [where
Figure imgf000036_0002
R 3Q and R 31 are each as defined above, X b represents C (= 0) or C (OH) R 7e (wherein R 7 is as defined above), R 4d is a hydrogen atom, Represents halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group , R 32 is a hydrogen atom, substituted or unsubstituted lower alkyl or NR 33a R 33b (wherein R 33a and R 33b are the same or different, hydrogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted Represents lower alkoxy)]
工程 5-1  Process 5-1
化合物（XXIII)は、化合物（Ilia)を用い、例えばプロテクティブ ·グループス 'イン 'ォ ~~ ニック'シンセンス弟二版 (Protective uroups in Organic Synthesis, third edition )、グリーン（T. W. Greene)著、ジョン'ワイリ一'アンド'サンズ 'インコーポレイテッド (J ohn Wiley & Sons Inc.) (1999年）等に記載のホルミルの保護法に準じて製造すること ができる。  Compound (XXIII) uses Compound (Ilia), for example, Protective uroups in Organic Synthesis, third edition, TW Greene, John's It can be produced in accordance with the formyl protection method described in John Wiley & Sons Inc. (1999).
[0105] すなわち、化合物（XXIII)は、化合物（Ilia)を、 1〜200当量の化合物（XV)と、溶媒 中または無溶媒で、触媒量から 5当量の酸及び 1〜10当量の脱水剤の存在下、 -30 °Cから用いる溶媒の沸点の間の温度で 5分間から 48時間反応させることにより合成す ることがでさる。  [0105] That is, compound (XXIII) is obtained by mixing compound (Ilia) with 1 to 200 equivalents of compound (XV), in a solvent or without solvent, from a catalytic amount to 5 equivalents of acid and 1 to 10 equivalents of dehydrating agent. It can be synthesized by reacting for 5 to 48 hours at a temperature between -30 ° C and the boiling point of the solvent used.
酸としては、例えば P-トルエンスルホン酸等を用いることができ、脱水剤としては、例 えばオルトギ酸トリメチル等を用いることができる。 For example, P-toluenesulfonic acid can be used as the acid, and examples of the dehydrating agent include For example, trimethyl orthoformate can be used.
[0106] 溶媒としては、例えば THF、 1,4-ジォキサン、これらの混合溶媒等を用いることがで きる。  [0106] As the solvent, for example, THF, 1,4-dioxane, a mixed solvent thereof or the like can be used.
化合物 (XV)は市販品として得ることができる。なお、化合物 (XV)の代わりに、ェチ レングリコール、 1,3-プロピレングリコール等のジオールを用いることもできる。  Compound (XV) can be obtained as a commercial product. In place of compound (XV), diols such as ethylene glycol and 1,3-propylene glycol can also be used.
工程 5- 2  Process 5-2
化合物（XXV)は、化合物（XXIII)を、溶媒中、 1〜20当量の塩基で、 -100 °Cから用 いる溶媒の沸点の間の温度で 5分間から 48時間処理した後、 1〜20当量の化合物 (X XIV)と、 -100 °Cから用いる溶媒の沸点の間の温度で 5分間から 48時間反応させるこ とにより製造することができる。また、必要に応じ、塩基で処理した後に、同温度で 1〜 20当量の塩ィ匕セリウム、塩ィ匕トリイソプロポキシチタン等を添カ卩し、次いでィ匕合物（XXI V)と反応させてもよい。また、反応は窒素、アルゴン等の不活性気体雰囲気下で実 施することが好ましい。  Compound (XXV) is obtained by treating Compound (XXIII) with 1 to 20 equivalents of base in a solvent at a temperature between −100 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. It can be produced by reacting an equivalent amount of the compound (X XIV) at a temperature between −100 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. If necessary, after treatment with a base, add 1 to 20 equivalents of salt or cerium, salt or triisopropoxytitanium at the same temperature, and then react with the compound (XXI V). You may let them. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
[0107] 化合物 (XXIV)は、市販品として、または対応するカルボン酸とァミンのアミド化 [例 えば、実験化学講座、第 22卷、 p.258 (1992年)等参照]等によって得ることができる。 塩基としては、例えば n-ブチルリチウム、 sec-ブチルリチウム、 tert-ブチルリチウム、 リチウムへキサメチルジシラジド等を用いることができる。  [0107] Compound (XXIV) can be obtained as a commercially available product, or by amidation of the corresponding carboxylic acid and amine (see, for example, Experimental Chemistry Course, Vol. 22, p. 258 (1992)). it can. As the base, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium hexamethyldisilazide and the like can be used.
溶媒としては、例えばジェチルエーテル、 THF、 1,2-ジメトキシェタン（DME)、 1,4- ジォキサン、 n-へキサン、トルエン、これらの混合溶媒等を用いることができる。  As the solvent, for example, jetyl ether, THF, 1,2-dimethoxyethane (DME), 1,4-dioxane, n-hexane, toluene, a mixed solvent thereof or the like can be used.
工程 5- 3  Process 5-3
化合物 (XXVI)は、化合物 (XXV)を、溶媒中または無溶媒で、水の存在下、触媒 量から 200当量の酸で、 0〜150 °Cの間の温度で 5分間力 48時間処理することにより 合成することができる。  Compound (XXVI) is treated with Compound (XXV) in a solvent or in the absence of water, in the presence of water, with a catalytic amount to 200 equivalents of acid at a temperature between 0 and 150 ° C for 5 minutes. Can be synthesized.
[0108] 酸としては、例えば塩酸、硫酸、 10-カンファースルホン酸、トリフルォロ酢酸、 P-トル エンスルホン酸、メタンスルホン酸、トリフルォロメタンスルホン酸、四塩化チタン、三フ ッ化ホウ素、塩ィ匕アルミニウム等を用いることができる。  [0108] Examples of the acid include hydrochloric acid, sulfuric acid, 10-camphorsulfonic acid, trifluoroacetic acid, P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, titanium tetrachloride, boron trifluoride, and salt.匕 Aluminum or the like can be used.
溶媒としては、例えば THF、 1,4-ジォキサン、 DME、これらの混合溶媒等を用いるこ とがでさる。 工程 5- 4 As the solvent, for example, THF, 1,4-dioxane, DME, a mixed solvent thereof or the like can be used. Process 5-4
化合物（XXVII)は、化合物（XXVI)力 製造法 1の工程 1-2に準じて合成することが できる。  Compound (XXVII) can be synthesized according to Step 1-2 of Compound (XXVI) Force Production Method 1.
工程 5- 5  Process 5-5
化合物（Ii)は、化合物 (XXVII)から、例えば製造法 1の工程 1-4記載の方法によつ て合成することができる。  Compound (Ii) can be synthesized from compound (XXVII) by, for example, the method described in Step 1-4 of Production Method 1.
[0109] 上記の方法を適宜組み合わせて実施することにより、所望の位置に所望の官能基 を有する化合物（I)を得ることができる。 [0109] A compound (I) having a desired functional group at a desired position can be obtained by appropriately combining the above methods.
上記各製造法における中間体及び目的化合物は、有機合成化学で常用される分 離精製法、例えば、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー 等に付して単離精製することができる。また、中間体においては特に精製することなく 次の反応に供することも可能である。  The intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. In addition, the intermediate can be subjected to the next reaction without any particular purification.
[0110] 化合物（1)、（IA)、 (IB) , (IC)、（ID)及び (IE)の中には、幾何異性体、光学異性体[0110] Among compounds (1), (IA), (IB), (IC), (ID) and (IE), there are geometric isomers, optical isomers
、互変異性体等の異性体が存在し得るものもある力 本発明は、これらを含め、全て の可能な異性体及びそれらの任意の比率の混合物を包含する。 In some cases, isomers such as tautomers may exist. The present invention includes all possible isomers including these and mixtures in any ratio.
化合物（1)、（IA)、 (IB)ゝ (IC)、（ID)及び (IE)の塩を取得したいとき、化合物（I)、（I When it is desired to obtain salts of the compounds (1), (IA), (IB) ゝ (IC), (ID) and (IE), the compounds (I), (I
A)、 (IB) , (IC)、（ID)及び (IE)が塩の形で得られるときはそのまま精製すればよぐ また、遊離の形で得られるときは、化合物 (1)、（IA)、 (IB)ゝ (IC)、（ID)及び (IE)を適 当な溶媒に溶解または懸濁し、酸または塩基を加えて単離、精製すればよい。 When A), (IB), (IC), (ID), and (IE) are obtained in the form of a salt, they can be purified as they are. When they are obtained in a free form, they can be obtained by compound (1), ( IA), (IB) ゝ (IC), (ID), and (IE) may be dissolved or suspended in a suitable solvent, and then isolated and purified by adding an acid or base.
[0111] また、化合物 (1)、（IA)、 (IB) , (IC)、（ID)及び (IE)及びそれらの薬理学的に許容 される塩は、水あるいは各種溶媒との付加物の形で存在することもある力 これらの 付加物も本発明に包含される。 [0111] The compounds (1), (IA), (IB), (IC), (ID) and (IE) and their pharmacologically acceptable salts are adducts with water or various solvents. These adducts are also encompassed by the present invention.
本発明で使用される化合物（I)の具体例を表 1及び 2に示す。なお、表 1及び 2にお いて、 Me、 Pr及び i-Prは、それぞれメチル、プロピル及びイソプロピルを表す。  Specific examples of the compound (I) used in the present invention are shown in Tables 1 and 2. In Tables 1 and 2, Me, Pr and i-Pr represent methyl, propyl and isopropyl, respectively.
[0112] [表 1-1] 表 1 -1[0112] [Table 1-1] Table 1 -1
Figure imgf000039_0001
Figure imgf000039_0001
化合物番号 NR1R£ X Compound Number NR 1 R £ X
Figure imgf000039_0002
Figure imgf000039_0002
CI CI
NHi-Pr 4 NHi-Pr 4
ipp CONMe(OMe)  ipp CONMe (OMe)
Figure imgf000039_0003
-2]
Figure imgf000039_0003
-2]
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
[0114] [表 1-3] [0114] [Table 1-3]
Figure imgf000041_0001
Figure imgf000041_0001
[0115] [表 1-4] [0115] [Table 1-4]
Figure imgf000042_0001
Figure imgf000042_0001
[0116] [表 1-5] 42 [0116] [Table 1-5] 42
Figure imgf000043_0001
[0117] 次に、本発明の局所投与剤の効果について、試験例により具体的に説明する。 試験例 1：化合物 (I)の、マウス耳介へ局所投与した きの組織中及び血 中濃度の 驢 ω
Figure imgf000043_0001
[0117] Next, the effects of the topical administration agent of the present invention will be specifically described with reference to test examples. Test Example 1: Compound (I) in tissue and blood concentrations when administered locally to mouse pinna
実験には 7週齢の雌性 BALB/cマウス（日本チヤ一ルスリバ一）を使用した。なお、マ ウスは室温 19〜25 °C、湿度 30〜70%、 1日 12時間照明（午前 7時〜午後 7時）の飼育 室にて、プラスチックケージに 6匹ずつ収容し、市販の固形飼料と水を自由に摂取さ せて飼育した。実験例数は各時点 n=2で行った。  For the experiment, 7-week-old female BALB / c mice (Nippon Chirusuriba) were used. In addition, 6 mice are housed in a plastic cage in a breeding room with a room temperature of 19-25 ° C, humidity of 30-70%, and 12 hours a day (7 am-7pm). The animals were reared with free access to feed and water. The number of experiments was performed at each time point n = 2.
[0118] 溶液の調製は常法に従い、化合物 1または対照薬として経口の p38MAPK阻害剤 BI RB796 [ネーチャ^ ~ ·ストラクチャ^ ~ ·バイオロジー（Nat. Struct. Biol.)、第 9卷、 268-2 72頁 (2002年)]をアセトン (和光純薬工業）に溶解し、 目的の濃度に調製した。耳介 皮膚への局所投与はマウスの右耳介内側へアセトンに溶解した化合物 1 (1 w/v%)及 び BIRB796 (1 w/v%)を 20 μ L/匹の容量で塗布した。塗布後、 30分、 1時間、 3時間、 8時間、 24時間経過後に、エーテルで麻酔下、腹部大静脈からの採血と耳介の摘出 をした。抗凝固剤として血液に少量のへノ リンを添加し、遠心操作 (600G、 10分間） により血漿を分離した。 [0118] The solution was prepared in accordance with conventional methods, and as an oral p38MAPK inhibitor BI RB796 [Nat. Struct. Biol., 9th, 268- 2 72 (2002)] was dissolved in acetone (Wako Pure Chemical Industries, Ltd.) and adjusted to the desired concentration. For topical administration to the auricle skin, Compound 1 (1 w / v%) and BIRB796 (1 w / v%) dissolved in acetone were applied to the inside of the right auricle of mice in a volume of 20 μL / animal. 30 minutes, 1 hour, 3 hours, 8 hours, and 24 hours after application, blood was collected from the abdominal vena cava and the auricles were removed under anesthesia with ether. A small amount of heline was added to the blood as an anticoagulant, and plasma was separated by centrifugation (600G, 10 minutes).
[0119] 上記で採取した血漿 50 Lに、 1 μ g/mLの内部標準物質 (I.S.)を含むァセトニトリ ル溶液 100 μ Lを加え攪拌し、氷上で約 10分間放置した後、遠心分離した。その上 清 100 μ Lに等量の 10 mmol/L酢酸アンモ-ゥムをカ卩ぇ攪拌し、血漿サンプルとした 。血漿サンプル中の化合物 1及び BIRB796の濃度を高速液体クロマトグラム 質量分 析装置 (LC/MS/MS)を用いて測定した。  [0119] To 50 L of the plasma collected above, 100 μL of a acetonitrile solution containing 1 μg / mL internal standard substance (I.S.) was added, stirred, allowed to stand on ice for about 10 minutes, and then centrifuged. Further, 100 μL of the supernatant was stirred with an equal amount of 10 mmol / L ammonium acetate to obtain a plasma sample. The concentrations of Compound 1 and BIRB796 in the plasma sample were measured using a high performance liquid chromatogram mass spectrometer (LC / MS / MS).
[0120] 採取した耳介を秤量後、ファルコンチューブ（15 mL容、 Becton Dickinson, NJ、 US A)中で、 2 mLの注射用蒸留水（大塚製薬工場、徳島）を添加し、ハンドホモジナイザ 一（MH-1000、ァズワン、大阪）でホモジナイズした。さらに、 8 mLのメタノールを添カロ し、再度ハンドホモジナイザーでホモジナイズした。耳ホモジネート 50 μ Lに、 1 μ g/ mLの I.S.を含むァセトニトリル溶液 100 μ Lをカ卩ぇ攪拌し、氷上で約 10分間放置した 後、遠心分離した。その上清 100 μ Lに等量の 10 mmol/L酢酸アンモ-ゥムを加え 攪拌し、耳ホモジネートサンプルとした。耳ホモジネートサンプル中の化合物 1及び BI RB796の濃度を LC/MS/MSを用いて測定した。 [0121] 化合物 1を耳に塗布投与した場合、組織内濃度一時間曲線下面積 (組織内濃度の AUC)は 8690 μ g'h/mL、血漿中濃度一時間曲線下面積 (血漿中濃度の AUC)は 0. 00489 /z g'h/mLであり、局所濃度が血漿中濃度に比べ 1780000倍高いことが判明し た。 [0120] After weighing the collected auricles, add 2 mL of distilled water for injection (Otsuka Pharmaceutical Factory, Tokushima) in a Falcon tube (15 mL, Becton Dickinson, NJ, USA). Homogenized at (MH-1000, As One, Osaka). Further, 8 mL of methanol was added and homogenized again with a hand homogenizer. A 50 μL ear homogenate was stirred with 100 μL of a acetonitrile solution containing 1 μg / mL IS, allowed to stand on ice for about 10 minutes, and then centrifuged. An equal volume of 10 mmol / L ammonium acetate was added to 100 μL of the supernatant and stirred to obtain an ear homogenate sample. The concentrations of Compound 1 and BI RB796 in the ear homogenate sample were measured using LC / MS / MS. [0121] When Compound 1 was applied to the ear, the area under the tissue concentration hour curve (AUC of tissue concentration) was 8690 μg'h / mL, and the area under the plasma concentration hour curve (plasma concentration AUC) was 0.0000489 / z g'h / mL, and the local concentration was found to be 1.78 million times higher than the plasma concentration.
一方、 BIRB796を耳に塗布投与した場合、組織内濃度の AUCは 13200 μ g'h/mL、 血漿中濃度の AUCは 44.0 /z g'h/mLであり、局所濃度が血漿中濃度に比べ 300倍高 いことが判明した。  On the other hand, when BIRB796 was applied to the ear, the tissue concentration AUC was 13200 μg'h / mL, and the plasma concentration AUC was 44.0 / z g'h / mL. It was found to be 300 times higher.
試験例 2：マウスの TPA誘発皮膚炎モデルでの化合物 (I)の浮腈抑制効 (1) 実験には 7週齢の雌性 BALB/cマウス（日本チヤ一ルスリバ一）を使用した。なお、マ ウスは試験例 1と同様の方法で飼育した。試験化合物の投与用溶液の調製及び皮膚 への局所投与は試験例 1と同様の方法で実施した。実験例数は各群 n=6で行った。  Test Example 2: Anti-buoyant effect of Compound (I) in a mouse TPA-induced dermatitis model (1) Seven-week-old female BALB / c mice (Japanese chili sliver) were used in the experiment. The mice were raised in the same manner as in Test Example 1. Preparation of test compound solution for administration and topical administration to the skin were carried out in the same manner as in Test Example 1. The number of experiments was performed in each group n = 6.
[0122] マウスの右耳介内側へアセトンに溶解した 0.06 w/v%の Phorbol 12-myristate 13-ac etate (以下 TPAと略す、 Sigma-Aldrich)を 10 μ L/匹の容量で塗布した。 TPA塗布の 1 0分前、 24時間後及び 48時間後に、マウス右耳介内側 (TPA塗布と同部位)ヘアセト ンに溶解した化合物 1 (0.01、 0.1、 1 w/v%)または BIRB796 (1 w/v%)を 20 L/匹の容 量で塗布した。陰性対照群のマウスには TPAの代わりにアセトンを同容量塗布した。 陰性対照群及び陽性対照群のマウスには、化合物 1の代わりにアセトンを同容量塗 布した。なお、各群 5あるいは 6匹のマウスを用いた。 TPA塗布 72時間後に DIAL THI CKNESS GAUGE (model G、尾崎製作所）を用いて右耳介の厚さを測定し、耳介腫 脹の程度を調べた。 [0122] 0.06 w / v% Phorbol 12-myristate 13-acetate (hereinafter abbreviated as TPA, Sigma-Aldrich) dissolved in acetone was applied to the inside of the right auricle of the mouse at a volume of 10 μL / mouse. Compound 1 (0.01, 0.1, 1 w / v%) or BIRB796 (1) dissolved in the inner right mouse ear (same site as TPA application) 10 minutes before, 24 hours and 48 hours after TPA application w / v%) was applied at a volume of 20 L / animal. A negative control group of mice was given the same volume of acetone instead of TPA. Instead of Compound 1, acetone in the same volume was applied to mice in the negative control group and the positive control group. Each group used 5 or 6 mice. 72 hours after application of TPA, the thickness of the right auricle was measured using DIAL THI CKNESS GAUGE (model G, Ozaki Seisakusho) to examine the degree of auricular swelling.
[0123] その結果マウス耳介を 0.01、 0.1、 1 w/v%の化合物 1で処置した場合、 TPA誘発によ る耳介腫脹がそれぞれ 21.0%、 38.3%、 54.3%抑制されることが判明した。一方、 1 w/v% の BIRB796処置時の抑制率は 44.4%であった。本評価系は、表皮肥厚や炎症性細胞 浸潤、炎症性サイト力イン産生等、ヒトの乾癬における病態の一部と類似するもので あることから、化合物 1はヒトの乾癬に有効である可能性が推察された。  [0123] As a result, it was found that treatment of mouse auricles with 0.01, 0.1, 1 w / v% of Compound 1 suppressed TPA-induced auricular swelling by 21.0%, 38.3%, and 54.3%, respectively. did. On the other hand, the inhibition rate after treatment with BIRB796 at 1 w / v% was 44.4%. Since this evaluation system is similar to some of the pathologies in human psoriasis, such as epidermal thickening, inflammatory cell infiltration, and production of inflammatory site force in, compound 1 may be effective in human psoriasis Was inferred.
試験例 3：ヒト及びマウス肝ミクロソームを用いた in vitro代謝評価系によるグルクロン 拘, 本牛.)^の (i)  Test Example 3: Glucuron due to in vitro metabolic evaluation system using human and mouse liver microsomes, this cattle.) ^ (I)
1 μ mol/Lの化合物 1、 0.5 mg/mLヒトあるいはマウス肝ミクロノーム、 30 μ g/mLァ ラメタシン、 3.5 mmol/L塩化マグネシウム及び 100 mmol/Lトリス—塩酸緩衝液（pH 7. 4)を含有する反応液を 37 °Cで 5分間プレインキュペートした。反応液に最終濃度 2 m mol/Lゥリジン- 5' -二リン酸グルクロン酸 (UDPGA)を添加することにより、反応を開 始した。最終的な反応液の容量は 50 μ Lであった。 37 °Cで 15分間インキュベーショ ン後、 1 μ g/mLの I.S.を含むァセトニトリル溶液 100 μ Lをカロえ攪拌することにより反 応を停止し、反応時間 15分の試料とした。 UDPGAを添加する前に、 I.S.を含むァセト 二トリル溶液 100 μ Lを添加し反応を停止したものを、反応時間 0分の試料とした。両 試料ともに、氷上で約 10分間放置した後、遠心分離した。遠心分離後の上清 100 μ Lに等量の 10 mmol/L酢酸アンモ-ゥムをカ卩ぇ攪拌し、分析試料とした。 LC/MS/MS により、化合物及びそのグルクロン酸抱合体 (+176Da)に相当する質量電荷比を測定 した。 1 μmol / L Compound 1, 0.5 mg / mL human or mouse liver micronome, 30 μg / mL A reaction solution containing lametacin, 3.5 mmol / L magnesium chloride and 100 mmol / L Tris-HCl buffer (pH 7.4) was preincubated at 37 ° C for 5 minutes. The reaction was started by adding a final concentration of 2 mmol / L uridine-5′-diphosphate glucuronic acid (UDPGA) to the reaction solution. The final reaction volume was 50 μL. After incubation at 37 ° C for 15 minutes, the reaction was stopped by stirring and stirring 100 μL of a acetonitrile solution containing 1 μg / mL of IS, to prepare a sample with a reaction time of 15 minutes. Before adding UDPGA, 100 μL of a solution of acetonitrile containing nitrile was added to stop the reaction, and a sample having a reaction time of 0 minutes was used. Both samples were left on ice for about 10 minutes and then centrifuged. An equal amount of 10 mmol / L ammonium acetate was stirred in 100 μL of the supernatant after centrifugation to prepare an analytical sample. The mass to charge ratio corresponding to the compound and its glucuronide conjugate (+176 Da) was measured by LC / MS / MS.
[0124] 反応時間 0分における I.S.とのピーク高さ比と反応時間 15分における I.S.とのピーク 高さ比を用いて、下式に従って残存率 (%)を算出した。  [0124] Using the peak height ratio with I.S. at a reaction time of 0 minutes and the peak height ratio with I.S. at a reaction time of 15 minutes, the residual ratio (%) was calculated according to the following formula.
[0125] [数 1] 反応時間 15分における I.S.とのピーク高さ比 [0125] [Equation 1] Peak height ratio with I.S. at 15 min reaction time
残存率 (％) = X 100 反応時間 0分における I. S.とのピーク高さ比  Residual rate (%) = X 100 Peak height ratio with I.S. at 0 min reaction time
[0126] ヒト及びマウス肝ミクロソームを用いた in vitro代謝評価系にお 、て、化合物 1の反応 [0126] Reaction of Compound 1 in an in vitro metabolic evaluation system using human and mouse liver microsomes
15分後の残存率はいずれも 10%以下であり、 UDPGA存在下で速やかに代謝された。 また、反応 15分後のサンプルより、化合物 1のグルクロン酸抱合体に相当するピーク が検出された。以上のことから、化合物 1は循環血流中に入った場合、肝臓でダルク ロン酸抱合代謝を受け不活ィ匕し、速やかに排泄を受けることが推測される。  The survival rate after 15 minutes was 10% or less, and it was rapidly metabolized in the presence of UDPGA. In addition, a peak corresponding to the glucuronic acid conjugate of Compound 1 was detected from the sample 15 minutes after the reaction. Based on the above, when Compound 1 enters the circulating blood stream, it is presumed that it undergoes inactivation and undergoes excretion promptly due to the metabolism of dalcronate conjugates in the liver.
試験例 4:化合物 (I)のマウス耳介へ局所投与した きの組織中及び血 中濃度の椎 実験には 7週齢の雌性 BALB/cマウス（日本チヤ一ルスリバ一）を使用した。なお、マ ウスは試験例 1と同様の方法で飼育した。実験例数は各時点 n = 3で行った。  Test Example 4: 7-week-old female BALB / c mice (Japanese chili sliver) were used in the vertebral experiments with tissue and blood concentrations when compound (I) was locally administered to the mouse pinna. The mice were raised in the same manner as in Test Example 1. The number of experiments was performed at each time point n = 3.
[0127] 溶液の調製は常法に従!、、化合物 34をアセトン (和光純薬工業）に溶解し、 目的の 濃度に調製した。耳介皮膚への局所投与はマウスの右耳介内側へアセトンに溶解し た化合物 34 (0.1 w/v%)を 10 μ L/匹の容量で塗布した。塗布後、 30分、 1時間、 2時 間、 9.5時間、 24.5時間経過後に、エーテルで麻酔下、大腿部動静脈からの採血と耳 介の摘出をした。抗凝固剤として血液に少量のへノ リンを添加し、遠心操作により血 漿を分離した。血漿の前処理及び濃度測定は試験例 1と同様の方法で行った。 [0127] The solution was prepared according to a conventional method. Compound 34 was dissolved in acetone (Wako Pure Chemical Industries, Ltd.) to prepare the desired concentration. Topical administration to the auricular skin dissolves in acetone inside the right auricle of mice. Compound 34 (0.1 w / v%) was applied in a volume of 10 μL / animal. 30 minutes, 1 hour, 2 hours, 9.5 hours, and 24.5 hours after application, blood was collected from the thigh arteriovenous vein and the ears were removed under anesthesia with ether. A small amount of heline was added to the blood as an anticoagulant, and the plasma was separated by centrifugation. Plasma pretreatment and concentration measurement were performed in the same manner as in Test Example 1.
[0128] 採取した耳介をテープストリツビングし、投与部位の角質層を除去した。 [0128] The collected pinna was tape stripped to remove the stratum corneum at the administration site.
耳介のホモジネート、前処理及び濃度測定は試験例 1と同様の方法で行った。 化合物 34を耳に塗布投与した場合、血漿中濃度は定量下限未満 « 0.008 μ
Figure imgf000047_0001
L)であった。組織内濃度 5.40〜9.51 /ζ πιΟ1/ίであり、局所濃度が血漿中濃度に比べ 675倍以上高いことが判明した。 Auricular homogenate, pretreatment and concentration measurement were performed in the same manner as in Test Example 1. When compound 34 is applied to the ear, plasma concentration is below the lower limit of quantification «0.008 μ
Figure imgf000047_0001
L). The tissue concentration was 5.40-9.51 / ζ πι Ο 1 / ί, and the local concentration was found to be 675 times higher than the plasma concentration.
試,験例 5：マウスの ΤΡΑ謙発皮膚炎モデルでの化合物 (1)の浮 fl重 ¾制効 (2) 実験には 7週齢の雌性 BALB/cマウス（日本チヤ一ルスリバ一）を使用した。なお、マ ウスは試験例 1と同様の方法で飼育した。試験化合物の投与用溶液の調製及び皮膚 への局所投与は試験例 1と同様の方法で実施した。実験例数は各群 n= 6で行った。  Test, Test Example 5: Floating weight of compound (1) in mouse model of humility dermatitis ¾ efficacy (2) 7 weeks old female BALB / c mice (Japanese chili slivers) were used in the experiment. used. The mice were raised in the same manner as in Test Example 1. Preparation of test compound solution for administration and topical administration to the skin were carried out in the same manner as in Test Example 1. The number of experiments was performed in each group n = 6.
[0129] マウスの右耳介内側へアセトンに溶解した 0.06 w/v%の TPA (Sigma-Aldrich)を 10 μ L/匹の容量で塗布した。 ΤΡΑ塗布の 10分前、 24時間後及び 48時間後に、マウス右 耳介内側 (ΤΡΑ塗布と同部位)へアセトンに溶解したィ匕合物 34 (0.01、 0.1 w/v%)を 10 μ L/匹の容量で塗布した。陰性対照群のマウスには、 ΤΡΑの代わりにアセトンを同容 量塗布した。陰性対照群及び陽性対照群のマウスには、化合物 34の代わりにァセト ンを同容量塗布した。なお、各群 5あるいは 6匹のマウスを用いた。 ΤΡΑ塗布 72時間後 に DIAL THICKNESS GAUGE (model G、尾崎製作所）を用いて右耳介の厚さを測定 し、耳介腫脹の程度を調べた。  [0129] 0.06 w / v% TPA (Sigma-Aldrich) dissolved in acetone was applied to the inside of the right auricle of the mouse in a volume of 10 μL / mouse. 10 μL of the mixture 34 (0.01, 0.1 w / v%) dissolved in acetone 10 minutes before, 24 hours and 48 hours after application Applied in a volume of / animal. A negative control group of mice was given the same volume of acetone instead of sputum. In the negative control group and the positive control group, the same volume of vaccine was applied instead of compound 34. Each group used 5 or 6 mice. 72 hours after application of acupuncture, the thickness of the right auricle was measured using DIAL THICKNESS GAUGE (model G, Ozaki Seisakusho) to examine the extent of auricular swelling.
[0130] その結果マウス耳介を 0.01及び 0.1 w/v%の化合物 34で処置した場合、 TPA誘発に よる耳介腫脹がそれぞれ 42.0%及び 61.9%抑制されることが判明した。本評価系は、表 皮肥厚や炎症性細胞浸潤、炎症性サイト力イン産生等、ヒトの乾癬における病態の 一部と類似するものであることから、化合物 34はヒトの乾癬に有効である可能性が推 察された。  [0130] As a result, it was found that when mouse auricles were treated with 0.01 and 0.1 w / v% of Compound 34, the auricular swelling induced by TPA was suppressed by 42.0% and 61.9%, respectively. Since this evaluation system is similar to some of the pathologies in human psoriasis, such as epidermal thickening, inflammatory cell infiltration, and production of inflammatory site force in, compound 34 may be effective in human psoriasis Sex was inferred.
試験例 6：ヒト及びマウス肝ミクロソームを用いた in vitro代謝評価系による化合物 (I) のグルクロン酸拘,合代謝の確認 (2) 1 μ mol/Lの化合物 34、肝ミクロソーム（ヒトあるいはマウス）、 25 μ g/mLァラメタシ ン、 3.5 mmol/L塩化マグネシウム及び 100 mmol/Lトリス—塩酸緩衝液（pH 7.4)を含 有する反応液を 37 °Cで 5分間プレインキュペートした。 反応液中のミクロノームの蛋 白濃度は、ヒトについては 0.05 mg/mL、マウスについては 0.025 mg/mLとした。反応 液に最終濃度 2 mmol/Lの UDPGAを添加することにより、反応を開始した。最終的な 反応液の容量は 50 μ Lであった。 37 °Cでインキュベーション後、 1 μ g/mLの I.S.を含 むァセトニトリル溶液 100 μ Lを加え攪拌することにより反応を停止し、反応後の試料 とした。インキュベーション時間はヒトについては 30分、マウスについては 20分とした。 分析試料の前処理、測定及び残存率の算出は試験例 3と同様の方法で実施した。 ヒト肝ミクロソームを用いた in vitro代謝試験において、化合物 34の残存率は 63.5% であった。マウス肝ミクロソームを用いた in vitro代謝試験において、化合物 34の残存 率は 86.4%であった。以上のことから、化合物 34は化合物 1同様、循環血流中に入つ た場合、肝臓でグルクロン酸抱合代謝を受け不活化し、速やかに排泄されることが推 測された。 Test Example 6: Confirmation of glucuronic acid binding and co-metabolism of compound (I) by in vitro metabolic evaluation system using human and mouse liver microsomes (2) Reaction solution containing 1 μmol / L compound 34, liver microsomes (human or mouse), 25 μg / mL alametasin, 3.5 mmol / L magnesium chloride and 100 mmol / L Tris-HCl buffer (pH 7.4) Was preincubated at 37 ° C for 5 minutes. The protein concentration of micronome in the reaction solution was 0.05 mg / mL for humans and 0.025 mg / mL for mice. The reaction was started by adding UDPGA with a final concentration of 2 mmol / L to the reaction solution. The final reaction volume was 50 μL. After incubation at 37 ° C, the reaction was stopped by adding 100 µL of acetonitrile solution containing 1 µg / mL IS and stirring, and used as the sample after the reaction. The incubation time was 30 minutes for humans and 20 minutes for mice. Pretreatment of the analysis sample, measurement, and calculation of the residual ratio were performed in the same manner as in Test Example 3. In an in vitro metabolic test using human liver microsomes, the survival rate of compound 34 was 63.5%. In an in vitro metabolic test using mouse liver microsomes, the residual ratio of Compound 34 was 86.4%. Based on the above, it was estimated that Compound 34, like Compound 1, was inactivated by glucuronidation metabolism in the liver and rapidly excreted when entering the circulating blood stream.
試,験例 7：化合物 (1)の P38M APK阳.害様式の解析 Test, Test Example 7: P38M APK 阳. Harmful Mode Analysis of Compound (1)
ヒト ρ38 αは、 Upstate社 (カタログ番号： Νο.14- 251)より、活性化されたものを購入し た。 ρ38ΜΑΡキナーゼ阻害活性は、 Whitmarsh A. J.及び Davis R. J.の方法 [メソッズ' イン.ェンザィモロジ一（Method. Enzymol.)、 332卷、 .319-336 (2001年）]を参考に、 以下に示す手順により測定した。リン酸ィ匕を受ける基質にはミエリン塩基性タンパク 質 (カタログ番号：133-13493、和光純薬工業） (20 μ g/アツセィ）を用い、反応は、 3- [N-Morpholino]propanesulfonic acid (MOPS) (20 mmol/L, pH 7.2)、 j8 -グリセ口リン 酸 (シグマ社) (25 mmol/L)、 ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) (1 mmol/L)、 NaVO (シグマ一アルドリッチ社）（1 mmol/L)、 dithiothreitol (DTTゝ和  The activated human ρ38 α was purchased from Upstate (Cat. No. Νο.14-251). ρ38ΜΑΡ kinase inhibitory activity was measured by the procedure shown below with reference to the method of Whitmarsh AJ and Davis RJ [Methods Enzymol., 332 卷, .319-336 (2001)]. . Myelin basic protein (catalog number: 133-13493, Wako Pure Chemical Industries, Ltd.) (20 μg / Atsusei) was used as the substrate to receive phosphate, and the reaction was performed using 3- [N-Morpholino] propanesulfonic acid ( MOPS) (20 mmol / L, pH 7.2), j8-Glycetophosphate (Sigma) (25 mmol / L), ethylenebis (oxyethylenenitrilo) tetraacetic acid (EGTA) (1 mmol / L), NaVO (Sigma-Aldrich) (1 mmol / L), dithiothreitol (DTT
4  Four
光純薬工業）（1 mmol/L)、 adenosine 5， -triphosphate (ATPゝシグマ社） (20 μ mol/L )及び MgCl (18.75 mmol/L)を含む溶液中（合計 40 L/アツセィ）で行った。ヒト p38 Kojun Pharmaceutical Co., Ltd. (1 mmol / L), adenosine 5, -triphosphate (ATP ゝ Sigma) (20 μmol / L) and MgCl (18.75 mmol / L) in solution (total 40 L / Atsusei) It was. Human p38
2  2
α及びィ匕合物 34を目的の濃度下において 60分間プレインキュベーションした後、 [ γ -32Ρ]ΑΤΡ(1 μ Ci/アツセィ）を添加することにより反応を開始し、 30 °Cで 15分間イン キュベーシヨンした。 4.5 v/v %リン酸（10 μ L/well)をカ卩えることにより反応を停止させ た後、 45 μ Lの反応液をリン酸セルロース紙（p81 paper, Code No. 3698023、 Whatma n International, Maidstone, UK)に吸着させた。リン酸セルロース紙を 0.75 v/v %リン 酸にて洗浄し、リン酸セルロース紙に残存したリン酸化ミエリン塩基性タンパク質（ [32 P])の放射活性をシンチレーシヨンカウンター（TRI-CARB2700TR、 PerkinElmer、 Bos ton、 MA、 USA)のプログラム（データモード： cpm、測定時間： 1 min、 Background subs tract : none,測定エネルギー域： LL 0.0— UL 2000)またはシンチレーシヨンカウンタ 一（LS6500、 BeckmanCoulter、 Fullerton、 CA、 USA)のプログラム（データモード： cpm 、測定時間： 1 min、 Background substract :none、測定エネノレギー域： high)を用いて 測定した。試験化合物は DMSOに溶解して添加した。得られた放射活性より反応速 度 (mol/unit/min)を算出した後、それらの逆数と ATP濃度の逆数をプロット（ラインゥ ヱ一バーバークプロット） [ェンザィムス（Enzymes)、第 3版、 p.55- 57 (1979年）]するこ とにより、反応速度の半分の速度を与える際の基質濃度 (Km値)及び反応最大速度 (Vmax)を求めた。 Pre-incubation of α and y compound 34 at the desired concentration for 60 minutes, then start the reaction by adding [γ- 32 Ρ] Ci (1 μ Ci / atse), 15 minutes at 30 ° C Incubated. Stop the reaction by adding 4.5 v / v% phosphoric acid (10 μL / well). Thereafter, 45 μL of the reaction solution was adsorbed on cellulose phosphate paper (p81 paper, Code No. 3698023, Whatman International, Maidstone, UK). Cellulose phosphate paper was washed with 0.75 v / v% phosphoric acid, and the radioactivity of phosphorylated myelin basic protein ([32 P]) remaining on the cellulose phosphate paper was measured by a scintillation counter (TRI-CARB2700TR, PerkinElmer, Bos ton, MA, USA) program (Data mode: cpm, Measurement time: 1 min, Background subtract: none, Measurement energy range: LL 0.0—UL 2000) or Scintillation counter (LS6500, BeckmanCoulter, Fullerton, CA) , USA) (data mode: cpm, measurement time: 1 min, Background substract: none, measurement energy range: high). The test compound was dissolved in DMSO and added. After calculating the reaction rate (mol / unit / min) from the radioactivity obtained, plot the reciprocal of these and the reciprocal of the ATP concentration (Rhein-Barberk plot) [Enzymes, 3rd edition, p. .55-57 (1979)] to obtain the substrate concentration (Km value) and maximum reaction rate (Vmax) when giving half the reaction rate.
その結果、表 2に示すように化合物 34の Vmaxは化合物濃度に応じて低下し、一方 m値は化合物濃度に影響されな力つた。従って、化合物 34はァロステリック型阻害形 式である化合物の性質を持つことが判明し、ァロステリック型の阻害形式を持つことが 推定された。 As a result, as shown in Table 2, the Vmax of compound 34 decreased according to the compound concentration, while the m value was not affected by the compound concentration. Therefore, Compound 34 was found to have the properties of a compound that is an allosteric type inhibition form, and it was presumed to have an allosteric form of inhibition.
[表 2] 表 2 [Table 2] Table 2
化合物 34 (nmo l /L) Km ( l /L) Vmax (pmo l / un i t/m i n)  Compound 34 (nmo l / L) Km (l / L) Vmax (pmo l / un i t / m i n)
0 76.75 21 10.89  0 76.75 21 10.89
3 69.22 1877.89  3 69.22 1877.89
10 76.6 1395.15  10 76.6 1395.15
30 82.37 327.95  30 82.37 327.95
100 82.04 213.27  100 82.04 213.27
1000 68.96 188.81 以上、試験例 1〜6の結果を総合すると、循環血流中に入った場合、化合物 1及び 3 4は肝臓でグルクロン酸抱合代謝を受け、不活ィ匕するとともに速やかに循環血中から 消失する。そして、局所に投与した場合、化合物 1は組織内濃度の AUCと血漿中濃 度の AUCの比が 1780000倍、化合物 34は組織内濃度と血漿中濃度の比が 675倍以 上であり、全身的な曝露がないことから、全身曝露による P38MAPK阻害作用に基づ く副作用をほとんど引き起こすことなぐ局所での薬効を実現できることが推定される 。一方グルクロン酸抱合代謝を受けないと推定される BIRB796においては、局所に投 与した場合、局所濃度と血漿中濃度の比が 300倍に過ぎず、血漿中濃度が非常に高 くなる。よって、 BIRB796においては、局所に投与した場合でも全身的な曝露が起こり 、 P38MAPK阻害作用に基づく全身的な副作用の発現が起きる事が推定された。また 、試験例 7の結果より、化合物（I)は p38MAPKに対してァロステリック阻害形式を示す ことが判明した。よって、ァロステリック阻害形式による阻害のため、化合物 (I)は細胞 内での活性が強くなるために in vivoでの活性が強くなること、 p38MAPKからの乖離が 遅いために in vivoで長時間作用することが推定され、局所投与剤に適した性質を持 つことが推定された。 1000 68.96 188.81 Above, combining the results of Test Examples 1-6, when entering the circulating bloodstream, compounds 1 and 3 4 undergo glucuronidation metabolism in the liver, become inactive and rapidly circulate Disappear from inside. And when administered topically, Compound 1 has a tissue concentration of AUC and plasma concentration. The ratio of the AUC of the drug is 1.78 million times, and the ratio of the tissue concentration to the plasma concentration is 675 times or more, and there is no systemic exposure.Therefore, side effects based on the P38MAPK inhibitory effect due to systemic exposure. It is estimated that a local medicinal effect can be realized without causing it. On the other hand, in BIRB796, which is presumed not to undergo glucuronidation metabolism, the ratio of local concentration to plasma concentration is only 300 times when administered locally, and the plasma concentration becomes very high. Therefore, in BIRB796, it was estimated that systemic exposure occurred even when administered locally, and systemic side effects based on P38MAPK inhibitory action occurred. In addition, from the results of Test Example 7, it was found that Compound (I) exhibits an asterosteric inhibition mode with respect to p38MAPK. Therefore, due to inhibition by the allosteric inhibition form, compound (I) has a strong activity in vivo because of its strong intracellular activity, and it works for a long time in vivo because of its slow dissociation from p38MAPK. It was presumed that it had properties suitable for topical administration.
[0134] 本発明に係る局所投与剤は、局所投与された場合、局所濃度が血漿中濃度に対 して 350倍以上、好ましくは 500倍以上、より好ましくは 1000倍以上、さらに好ましくは 2 000倍以上の濃度となる P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩をそのまま単独で投与することも可能であるが、通常各種の医薬製剤と して提供するのが望ましい。また、それら医薬製剤は、動物及び人に使用されるもの である。  [0134] When administered locally, the topical administration agent of the present invention has a local concentration of 350 times or more, preferably 500 times or more, more preferably 1000 times or more, more preferably 2 000 times the plasma concentration. Although it is possible to administer a compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof at a concentration of twice or more as it is, it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
[0135] 本発明に係る医薬製剤は、任意の他の治療上有効である 1つまたは 2つ以上の他 の有効成分との混合物として使用することもできる。またそれら医薬製剤は、活性成 分を薬理学的に許容される一種もしくはそれ以上の担体と一緒に混合し、製剤学の 技術分野にぉ 、てよく知られて 、る任意の方法により製造される。  [0135] The pharmaceutical formulations according to the present invention may also be used as a mixture with any other therapeutically effective one or more other active ingredients. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmacologically acceptable carriers. The
投与経路としては、治療に際し最も効果的なものを使用するのが望ましぐ例えば 吸入、経皮、点鼻、点眼等の局所投与方法が挙げられる。  As the administration route, it is desirable to use the most effective one in the treatment, for example, local administration methods such as inhalation, transdermal, nasal drop, and eye drop.
[0136] 投与形態としては、例えば吸入剤、外用剤、点鼻剤、点眼剤、注射剤等が挙げられ る。  [0136] Examples of the administration form include inhalants, external preparations, nasal drops, eye drops, injections and the like.
吸入剤は活性成分を粉末状、液状または懸濁状にして、吸入噴射剤または担体中 に配合し、適当な吸入容器に充填することにより製造される。また上記活性成分が粉 末の場合は通常の機械的粉末吸入器を、液状または懸濁状の場合はネブライザ一 等の吸入器をそれぞれ使用することもできる。該吸入噴射剤としては公知のものを広 く使用でき、フロン- 11、フロン- 12、フロン- 21、フロン- 22、フロン- 113、フロン- 114、フ ロン- 123、フロン- 142c、フロン- 134a、フロン- 227、フロン- C318、 1,1,1,2-テトラフル ォロェタン（HFC- 134a)、 1,1,1,2,3,3,3-ヘプタフルォロプロパン（HFC- 227)等のフロ ン系化合物、プロパン、イソブタン、 n-ブタン等の炭化水素類、ジェチルエーテル等 のエーテル類、窒素ガス、炭酸ガス等の圧縮ガス等を例示でき、懸濁状の製剤の場 合はソルビタントリオ一レート等の懸濁補助剤を添加してもよい。 Inhalants are produced by formulating the active ingredient in powder, liquid or suspension, blending it into an inhalation propellant or carrier, and filling it into a suitable inhaler. The active ingredient is powder In the case of powder, a normal mechanical powder inhaler can be used, and in the case of liquid or suspension, an inhaler such as a nebulizer can be used. A wide variety of inhalable propellants can be used, such as Freon-11, Freon-12, Freon-21, Freon-22, Freon-113, Freon-114, Freon-123, Freon-142c, Freon- 134a, CFC-227, CFC-C318, 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) For example, in the case of a suspension formulation, a fluorine-based compound such as propane, isobutane, hydrocarbons such as n-butane, ethers such as jetyl ether, compressed gas such as nitrogen gas and carbon dioxide, etc. May be added with a suspension aid such as sorbitan triorate.
[0137] 外用剤に適当な剤形としては、特に限定されるものではないが、例えば軟膏剤、ク リーム剤等が挙げられる。これらは、例えば白色ワセリン等の基剤に活性成分を溶解 または混合分散して製造できる。 [0137] Suitable dosage forms for external preparations are not particularly limited, and examples thereof include ointments and creams. These can be produced, for example, by dissolving or mixing the active ingredient in a base such as white petrolatum.
点鼻剤は、例えば滅菌精製水に活性成分を加え、必要により塩ィ匕ナトリウム等の等 張化剤、 P-ヒドロキシ安息香酸エステル等の防腐剤、リン酸バッファ一等の緩衝剤等 を用いて製造できる。  For nasal drops, for example, an active ingredient is added to sterilized purified water, and if necessary, an isotonic agent such as sodium chloride sodium salt, a preservative such as P-hydroxybenzoic acid ester, a buffering agent such as a phosphate buffer, etc. are used. Can be manufactured.
[0138] 点眼剤は、リン酸バッファー、ホウ酸バッファ一等の緩衝剤、塩化ナトリウム等の等 張化剤、塩ィ匕ベンザルコ-ゥム、 P-ヒドロキシ安息香酸エステル等の防腐剤等を用い て製造できる。  [0138] As eye drops, buffering agents such as phosphate buffer and boric acid buffer, tonicity agents such as sodium chloride, preservatives such as salt benzalcoum, P-hydroxybenzoate, etc. are used. Can be manufactured.
注射剤は、塩溶液、ブドウ糖溶液または塩溶液とブドウ糖溶液の混合液等の希釈 剤または溶剤等を用いて製造できる。  The injection can be produced using a diluent or solvent such as a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
[0139] また、上記各製剤には、乳糖、マンニット等の賦形剤、澱粉等の崩壊剤、ステアリン 酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤、大豆レシチ ン、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤等カゝら選択される 1種もし くはそれ以上の補助成分を添加することもできる。 [0139] Further, in each of the above preparations, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, soybean lecithin, fatty acid ester One or more auxiliary components selected from surfactants such as surfactants and plasticizers such as glycerin can be added.
化合物 (I)またはその薬理学的に許容される塩の投与量及び投与回数は、投与形 態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度等により異なるが、通 常成人一人当り 1 μ g〜1000 mg、好ましくは 0.05〜100 mg、より好ましくは 0.01〜20 mgを一日一回ないし数回投与する。しかしながら、これら投与量及び投与回数に関 しては、前述の種々の条件により変動する。 [0140] 以下に、本発明の態様を実施例及び参考例で説明する。しかし、本発明はこれら に限定されるものではない。 The dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration mode, patient age, body weight, nature or severity of symptoms to be treated, etc. 1 μg to 1000 mg, preferably 0.05 to 100 mg, more preferably 0.01 to 20 mg per person is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above. [0140] Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples. However, the present invention is not limited to these.
参考例 1： 6- (2-クロ口フエ-ル)- 7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリン（ィ匕合 物 1)  Reference Example 1: 6- (2-Black Mole) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 1)
工程 1  Process 1
臭化カリウム（193 g, 1.62 mol)及び臭素（33.0 mL, 649 mmol)を水（1000 mL)に溶 解し、氷冷下、 2-フルォロ- 4-メトキシベンズアルデヒド（50.0 g, 324 mmol)をカ卩えた 後、室温で 3時間攪拌した。反応混合物に水を加え、結晶を濾取し、 5-ブロモ -2-フ ルォ口- 4-メトキシベンズアルデヒド（ィ匕合物 A1) (72.2 g, 95%)を得た。  Dissolve potassium bromide (193 g, 1.62 mol) and bromine (33.0 mL, 649 mmol) in water (1000 mL), and add 2-fluoro-4-methoxybenzaldehyde (50.0 g, 324 mmol) under ice cooling. After raising, the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the crystals were collected by filtration to give 5-bromo-2-fluoro-4-methoxybenzaldehyde (Compound A1) (72.2 g, 95%).
JH NMR (300 MHz, CDC1 ) δ (ppm) 3.98 (s, 3H), 6.78 (d, J = 11.7 Hz, 1H), 8.06 (d,  JH NMR (300 MHz, CDC1) δ (ppm) 3.98 (s, 3H), 6.78 (d, J = 11.7 Hz, 1H), 8.06 (d,
3  Three
J = 7.7 Hz, 1H), 10.17 (s, 1H).  J = 7.7 Hz, 1H), 10.17 (s, 1H).
工程 2  Process 2
化合物 Al (20.0 g, 85.8 mmol)を DMA (300 mL)に溶解し、炭酸グァ-ジン（30.9 g, 172 mmol)をカ卩えた後、 140 °Cで 2時間攪拌した。反応混合物を氷水に加えた後、生 じた結晶を濾取し、 2-ァミノ- 6-ブロモ -7-メトキシキナゾリン (ィ匕合物 A2) (16.4 g, 75%) を得た。  Compound Al (20.0 g, 85.8 mmol) was dissolved in DMA (300 mL), guanidine carbonate (30.9 g, 172 mmol) was added, and the mixture was stirred at 140 ° C. for 2 hours. The reaction mixture was added to ice water, and the resulting crystals were collected by filtration to obtain 2-amino-6-bromo-7-methoxyquinazoline (Compound A2) (16.4 g, 75%).
JH NMR (300 MHz, DMSO— d ) δ (ppm) 4.00 (s, 3H), 5.24 (brs, 2H), 6.92 (s, 1H), 7. J H NMR (300 MHz, DMSO— d) δ (ppm) 4.00 (s, 3H), 5.24 (brs, 2H), 6.92 (s, 1H), 7.
6  6
88 (s, 1H), 8.82 (s, 1H).  88 (s, 1H), 8.82 (s, 1H).
[0141] 工程 3 [0141] Step 3
化合物 A2 (16.0 g, 65.3 mmol)を THF (330 mL)に溶解し、ジョードメタン（53.0 mL, 658 mmol)、亜硝酸イソアミル（26.3 mL, 196 mmol)及びヨウ化銅（3.73 g, 19.6 mmol )を加えた後、 60 °Cで 8時間攪拌した。反応混合物の不溶物を濾別した後、減圧下、 溶媒を留去した。残渣にへキサンを加えた後、生じた結晶を濾取することで 6-ブロモ -2-ョード -7-メトキシキナゾリン (ィ匕合物 A3) (13.7 g, 5了％)を得た。  Compound A2 (16.0 g, 65.3 mmol) was dissolved in THF (330 mL), jodomethane (53.0 mL, 658 mmol), isoamyl nitrite (26.3 mL, 196 mmol) and copper iodide (3.73 g, 19.6 mmol) Then, the mixture was stirred at 60 ° C for 8 hours. The insoluble material in the reaction mixture was filtered off, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting crystals were collected by filtration to obtain 6-bromo-2-iodo-7-methoxyquinazoline (Compound A3) (13.7 g, 5%).
1H NMR (300 MHz, DMSO— d ) δ (ppm) 4.06 (s, 3H), 7.48 (s, 1H), 8.50 (s, 1H), 9.13  1H NMR (300 MHz, DMSO— d) δ (ppm) 4.06 (s, 3H), 7.48 (s, 1H), 8.50 (s, 1H), 9.13
6  6
(s, 1H).  (s, 1H).
工程 4  Process 4
化合物 A3 (6.84 g, 18.8 mmol)を THF (140 mL)に溶解し、トリェチルァミン（7.80 mL , 56.3 mmol)及びイソプロピルアミン（16.9 mL, 188 mmol)をカ卩えた後、室温でー晚 攪拌した。反応混合物に酢酸ェチル、塩酸を加え、生じた結晶を濾取した。濾液を 減圧濃縮し、水を加えた後生じた結晶を濾取した。得られた結晶を合わせ、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 = 1/4)で精製することで 6-ブロモ- 2-イソプロピルァミノ- 7-メトキシキナゾリン (ィ匕合物 A4) (2.23 g, 40%)を得た。 Compound A3 (6.84 g, 18.8 mmol) was dissolved in THF (140 mL) and triethylamine (7.80 mL) was dissolved. , 56.3 mmol) and isopropylamine (16.9 mL, 188 mmol) were added and stirred at room temperature. Ethyl acetate and hydrochloric acid were added to the reaction mixture, and the resulting crystals were collected by filtration. The filtrate was concentrated under reduced pressure, and water was added, and the resulting crystals were collected by filtration. The obtained crystals were combined and purified by silica gel column chromatography (ethyl acetate / hexane = 1/4) to give 6-bromo-2-isopropylamino-7-methoxyquinazoline (Compound A4) ( 2.23 g, 40%).
1H NMR (300 MHz, DMSO— d ) δ (ppm) 1.19 (d, J = 6.6 Hz, 6H), 3.96 (s, 3H), 4.11— 1H NMR (300 MHz, DMSO— d) δ (ppm) 1.19 (d, J = 6.6 Hz, 6H), 3.96 (s, 3H), 4.11—
6  6
4.23 (m, 1H), 6.93 (s, 1H), 7.27 (brs, 1H), 8.05 (s, 1H), 8.90 (s, 1H).  4.23 (m, 1H), 6.93 (s, 1H), 7.27 (brs, 1H), 8.05 (s, 1H), 8.90 (s, 1H).
工程 5 Process 5
化合物 A4 (1.20 g, 4.05 mmol)をジォキサン（20 mL)及び水（20 mL)に溶解し、 2- クロ口フエ-ルホウ酸（0.900 g, 5.76 mmol)、炭酸ナトリウム（1.03 g, 9.72 mmol)及び [ Ι, -ビス (ジフエ-ルホスフイノ)フエ口セン]ジクロロパラジウム（197 mg, 0.241 mmol) を加えた後、加熱還流下、 2時間攪拌した。不溶物をセライトで濾別した後、酢酸ェチ ル、水を加え有機層を分離した。有機層を水で洗浄後、無水硫酸マグネシウムで乾 燥した。減圧下、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（酢酸ェチ ル /へキサン = 1/5)で精製することで、 6-(2-クロ口フエ-ル) -2-イソプロピルァミノ- 7- メトキシキナゾリン（ィ匕合物 A5) (873 mg, 66%)を得た。  Compound A4 (1.20 g, 4.05 mmol) was dissolved in dioxane (20 mL) and water (20 mL), 2-chloro-or-borate (0.900 g, 5.76 mmol), sodium carbonate (1.03 g, 9.72 mmol) And [Ι, -bis (diphenylphosphino) pheucene] dichloropalladium (197 mg, 0.241 mmol) were added, and the mixture was stirred for 2 hours under reflux with heating. Insoluble material was filtered off through celite, and ethyl acetate and water were added to separate the organic layer. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/5). Mino-7-methoxyquinazoline (Compound A5) (873 mg, 66%) was obtained.
JH NMR (270 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.4 Hz, 6H), 3.89 (s, 3H), 4.33 (sep J H NMR (270 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.4 Hz, 6H), 3.89 (s, 3H), 4.33 (sep
3  Three
, J = 6.4 Hz, 1H), 5.25 (brs, 1H), 6.99 (s, 1H), 7.31-7.34 (m, 3H), 7.45-7.49 (m, 2 H), 8.81 (s, 1H).  , J = 6.4 Hz, 1H), 5.25 (brs, 1H), 6.99 (s, 1H), 7.31-7.34 (m, 3H), 7.45-7.49 (m, 2 H), 8.81 (s, 1H).
工程 6 Process 6
化合物 A5 (2.50 g, 7.63 mmol)をジクロ口エタン（140 mL)に溶解し、三臭化ホウ素（ 7.20 mL, 76.3 mmol)を加えた後、ー晚加熱還流下した。反応混合物に、酢酸ェチル 、水を加え有機層を分離した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥し た後、減圧下、溶媒を留去し、化合物 1 (1.27 g, 53%)を得た。  Compound A5 (2.50 g, 7.63 mmol) was dissolved in dichloromouth ethane (140 mL), boron tribromide (7.20 mL, 76.3 mmol) was added, and the mixture was heated to reflux. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 1 (1.27 g, 53%).
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.19 (d, J = 6.4 Hz, 6H), 4.16—4.30 (m, 1H), 5.2  1H NMR (270 MHz, CDC1) δ (ppm) 1.19 (d, J = 6.4 Hz, 6H), 4.16—4.30 (m, 1H), 5.2
3  Three
2 (brs, 1H), 6.65 (brs, 1H), 7.06 (s, 1H), 7.29-7.34 (m, 3H), 7.40 (s, 1H), 7.47-7.5 0 (m, 1H), 8.73 (s, 1H).  2 (brs, 1H), 6.65 (brs, 1H), 7.06 (s, 1H), 7.29-7.34 (m, 3H), 7.40 (s, 1H), 7.47-7.5 0 (m, 1H), 8.73 (s , 1H).
APCI m/z (M+H)+ 314. [0143] 参考例 2： 6-(2-クロ口フエ-ル)- 7-ヒドロキシ -2-イソプロピルァミノ- 8- (プロポキシカル ボニル)キナゾリン (ィ匕合物 2) APCI m / z (M + H) + 314. [0143] Reference Example 2: 6- (2-Black Mole) -7-Hydroxy-2-isopropylamino-8- (propoxycarbonyl) quinazoline (Compound 2)
工程 1  Process 1
化合物 8 (2.11 g, 5.40 mmol)を塩化メチレン (40 mL)に溶解し、 0 °Cに冷却後、トリ ェチノレアミン（2.26 mL, 16.2 mmol)及びメトキシメチノレクロリド（1.23 mL, 16.2 mmol) を加え、室温で 2時間攪拌した。反応混合物に炭酸水素ナトリウム水溶液、塩化メチ レンを加え有機層を分離した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥 し、減圧下、溶媒を留去した。残渣をエーテルでリスラリーし、 8-ブロモ -6- (2-クロロフ ェ-ル )-2-イソプロピルァミノ- 7- (メトキシメチルォキシ)キナゾリン (ィ匕合物 A6) (1.82 g , 78%)を得た。  Compound 8 (2.11 g, 5.40 mmol) is dissolved in methylene chloride (40 mL), cooled to 0 ° C, and then added to triethylenamine (2.26 mL, 16.2 mmol) and methoxymethylol chloride (1.23 mL, 16.2 mmol). And stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution and methyl chloride, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was reslurried with ether to give 8-bromo-6- (2-chlorophenyl) -2-isopropylamino-7- (methoxymethyloxy) quinazoline (Compound A6) (1.82 g, 78% )
JH NMR (270 MHz, CDCl ) δ (ppm) 1.35 (d, J = 6.6 Hz, 6H), 3.02 (s, 3H), 4.32-4.4 J H NMR (270 MHz, CDCl) δ (ppm) 1.35 (d, J = 6.6 Hz, 6H), 3.02 (s, 3H), 4.32-4.4
3  Three
4 (m, IH), 4.92 (s, 2H), 5.35 (s, IH), 7.30-7.42 (m, 3H), 7.48-7.54 (m, 2H), 8.87 (s , IH).  4 (m, IH), 4.92 (s, 2H), 5.35 (s, IH), 7.30-7.42 (m, 3H), 7.48-7.54 (m, 2H), 8.87 (s, IH).
工程 2  Process 2
化合物 A6 (150 mg, 0.357 mmol)、酢酸パラジウム（16.0 mg, 0.0713 mmol) , 1,3—ビ ス (ジフエ-ルホスフイノ)プロパン（29.4 mg, 0.0713 mmol)及び炭酸カリウム（73.9 mg, Compound A6 (150 mg, 0.357 mmol), palladium acetate (16.0 mg, 0.0713 mmol), 1,3-bis (diphenylphosphino) propane (29.4 mg, 0.0713 mmol) and potassium carbonate (73.9 mg,
0.535 mmol)をプロパノール（1.5 mL)及び DMF (1 mL)に溶解し、系内を一酸化炭 素で置換した後、 90 °Cで 4時間攪拌した。反応混合物に飽和食塩水、酢酸ェチルを 加え、有機層を分離し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで 乾燥し、減圧下、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（酢酸ェ チル /へキサン = 1/6)で精製し、化合物 2 (37.2 mg, 26%)を得た。 0.535 mmol) was dissolved in propanol (1.5 mL) and DMF (1 mL), and the system was replaced with carbon monoxide, followed by stirring at 90 ° C for 4 hours. To the reaction mixture were added saturated brine and ethyl acetate, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane = 1/6 to acetic acid E chill /) to give compound 2 (37.2 mg, 26%) .
1H NMR (300 MHz, CDCl ) δ (ppm) 1.09 (t, J = 7.5 Hz, 3H), 1.32 (d, J = 6.4 Hz, 6H  1H NMR (300 MHz, CDCl) δ (ppm) 1.09 (t, J = 7.5 Hz, 3H), 1.32 (d, J = 6.4 Hz, 6H
3  Three
), 1.92 (qt, J = 7.5, 6.6 Hz, 2H), 4.33-4.47 (m, IH), 4.45 (t, J = 6.6 Hz, 2H), 5.20- 5.27 (m, IH), 7.32-7.36 (m, 3H), 7.48-7.52 (m, IH), 7.59 (s, IH), 8.72 (s, IH), 13. 3 (brs, IH).  ), 1.92 (qt, J = 7.5, 6.6 Hz, 2H), 4.33-4.47 (m, IH), 4.45 (t, J = 6.6 Hz, 2H), 5.20-5.27 (m, IH), 7.32-7.36 ( m, 3H), 7.48-7.52 (m, IH), 7.59 (s, IH), 8.72 (s, IH), 13. 3 (brs, IH).
APCI m/z (M+H)+ 400. APCI m / z (M + H) + 400.
[0144] 参考例 3： 8-カルボキシ -6-(2-クロ口フエ-ル)- 7-ヒドロキシ- 2- (イソプロピルァミノ)キ ナゾリン (化合物 3) 工程 1 [0144] Reference Example 3: 8-Carboxy-6- (2-chromophore) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 3) Process 1
化合物 A5 (3.67 g, 11.2 mmol)を酢酸（140 mL)に溶解し、臭素（2.01 mL, 39.2 mm ol)を加えた後、 60 °Cで 2時間攪拌した。反応混合物に、アンモニア水溶液を加え、 生じた結晶を濾取した。結晶を酢酸ェチルに溶解し、水で洗浄後、無水硫酸マグネ シゥムで乾燥した。減圧下、溶媒を留去し、 8-ブロモ - 6-(2-クロ口フエ-ル) -2-イソプ 口ピルアミノ- 7-メトキシキナゾリン (ィ匕合物 A7) (4.21 g, 93%)を得た。  Compound A5 (3.67 g, 11.2 mmol) was dissolved in acetic acid (140 mL), bromine (2.01 mL, 39.2 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. An aqueous ammonia solution was added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off, and 8-bromo-6- (2-chlorophenol) -2-isopropylpyramino-7-methoxyquinazoline (Compound A7) (4.21 g, 93%) was added. Obtained.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.24 (d, J = 6.4 Hz, 6H), 3.48 (s, 3H), 4.20 JH NMR (270 MHz, DMSO— d) δ (ppm) 1.24 (d, J = 6.4 Hz, 6H), 3.48 (s, 3H), 4.20
6  6
-4.32 (m, 1H), 7.43-7.50 (m, 3H), 7.57-7.65 (m, 2H), 7.70 (s, 1H), 9.05 (s, 1H). 工程 2  -4.32 (m, 1H), 7.43-7.50 (m, 3H), 7.57-7.65 (m, 2H), 7.70 (s, 1H), 9.05 (s, 1H).
化合物 A7 (358 mg, 0.88 mmol)、トリブチル (1-エトキシビュル)スズ（357 μし, 1.06 mmol)及びテトラキス (トリフエ-ルホスフィン)パラジウム（51 mg, 0.044 mmol)を DMF ( 4 mL)に溶解し、 120 °Cにて 2時間攪拌した。放冷後、反応混合物に 10%フッ化力リウ ム水溶液を加え、更に 10分間攪拌した。水と酢酸ェチルを加え、有機層を分離し飽 和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、溶媒を留 去した。残渣を THF (8 mL)に溶解し、 1 mol/L塩酸 (2 mL)をカ卩え、室温で 4時間攪拌 した。反応混合物に水と酢酸ェチルを加え、有機層を分離し飽和食塩水で洗浄した 。有機層を無水硫酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /へキサン = 1/3)で精製し、 8-ァセチル- 6- (2-クロ口フエ-ル) -2-イソプロピルァミノ- 7-メトキシキナゾリン（ィ匕合物 A8) (132 mg, 4 1%)を得た。  Compound A7 (358 mg, 0.88 mmol), tributyl (1-ethoxybutyl) tin (357 μl, 1.06 mmol) and tetrakis (triphenylphosphine) palladium (51 mg, 0.044 mmol) dissolved in DMF (4 mL) The mixture was stirred at 120 ° C for 2 hours. After allowing to cool, a 10% aqueous solution of lithium fluoride was added to the reaction mixture, and the mixture was further stirred for 10 minutes. Water and ethyl acetate were added, the organic layer was separated and washed with saturated Japanese salt water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (8 mL), 1 mol / L hydrochloric acid (2 mL) was added, and the mixture was stirred at room temperature for 4 hr. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to give 8-acetyl-6- (2-chlorophenol) -2-isopropylamino-7-methoxyquinazoline (I Compound A8) (132 mg, 4 1%) was obtained.
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.28 (d, J = 6.4 Hz, 6H), 2.74 (s, 3H), 3.51 (s, 3  1H NMR (270 MHz, CDC1) δ (ppm) 1.28 (d, J = 6.4 Hz, 6H), 2.74 (s, 3H), 3.51 (s, 3
3  Three
H), 4.15-4.27 (m, 1H), 5.21 (d, J = 6.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.49-7.52 (m, 1H), 7.54 (s, 1H), 8.86 (s, 1H).  H), 4.15-4.27 (m, 1H), 5.21 (d, J = 6.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.49-7.52 (m, 1H), 7.54 (s, 1H), 8.86 (s, 1H).
APCI m/z (M+H)+370. APCI m / z (M + H) + 370.
工程 3 Process 3
20%水酸化カリウム水溶液（8 mL)に、氷冷化、臭素（0.352 mL, 6.09 mmol)、及び 化合物 A8 (751 mg, 2.03 mmol)を含むジォキサン溶液（16 mL)を加え、室温で 1時間 攪拌後、 100 °Cに昇温し、 2時間攪拌した。反応混合物に水を加え、 1 mol/L塩酸で p Hを 4に調整した。析出した結晶をろ過し、 8-カルボキシ -6-(2-クロ口フエ-ル) -2-イソ プロピルァミノ- 7-メトキシキナゾリン（ィ匕合物 A9) (555 mg, 74%)を得た。 To 20% aqueous potassium hydroxide solution (8 mL) was added ice-cooled, dioxane solution (16 mL) containing bromine (0.352 mL, 6.09 mmol) and compound A8 (751 mg, 2.03 mmol), and the mixture was stirred at room temperature for 1 hour. After stirring, the temperature was raised to 100 ° C. and stirred for 2 hours. Add water to the reaction mixture and p with 1 mol / L hydrochloric acid. H was adjusted to 4. The precipitated crystals were filtered to obtain 8-carboxy-6- (2-chlorophenol) -2-isopropylamino-7-methoxyquinazoline (Compound A9) (555 mg, 74%).
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.39 (d, J = 6.4 Hz, 6H), 3.79 (s, 3H), 4.13 (b  1H NMR (270 MHz, CDC1) δ (ppm) 1.39 (d, J = 6.4 Hz, 6H), 3.79 (s, 3H), 4.13 (b
3  Three
rs, 1H), 5.67 (brs, 1H), 7.33-7.40 (m, 3H), 7.50-7.53 (m, 1H), 7.74 (s, 1H), 8.96 (s , 1H). rs, 1H), 5.67 (brs, 1H), 7.33-7.40 (m, 3H), 7.50-7.53 (m, 1H), 7.74 (s, 1H), 8.96 (s, 1H).
APCI m/z (M+H)+ 372. APCI m / z (M + H) + 372.
工程 4 Process 4
化合物 A9を用 、、参考例 1の工程 6と同様の方法でィ匕合物 3を得た。  Compound 3 was obtained in the same manner as in Step 6 of Reference Example 1 using Compound A9.
JH NMR (300 MHz, DMSO— d ) δ (ppm) 1.30 (d, J = 6.4 Hz, 6H), 4.17-4.21 (m, 1H), JH NMR (300 MHz, DMSO— d) δ (ppm) 1.30 (d, J = 6.4 Hz, 6H), 4.17-4.21 (m, 1H),
6  6
7.35-7.41 (m, 3H), 7.49-7.52 (m, 1H), 7.79 (s, 1H), 9.01 (s, 1H).  7.35-7.41 (m, 3H), 7.49-7.52 (m, 1H), 7.79 (s, 1H), 9.01 (s, 1H).
APCI m/z (M+H)+ 358. APCI m / z (M + H) + 358.
参考例 4： 6- (2-クロ口フエ-ル)- 7-ヒドロキシ- 2-イソプロピルァミノ- 8- (N-メトキシ- N- メチルァミノカルボ-ル)キナゾリン（化合物 4) Reference Example 4: 6- (2-Black mouth) -7-hydroxy-2-isopropylamino-8- (N-methoxy-N-methylaminocarbol) quinazoline (compound 4)
工程 1 Process 1
化合物 A9 (93 mg, 0.25 mmol)を DMF(2 mL)に溶解し、 N-メトキシ- N-メチルァミン 塩酸塩（37 mg, 0.38 mmol) , 1-ェチル -3- (3-ジメチルァミノプロピル)カルボジイミド 塩酸塩（96 mg, 0.50 mmol) , 1-ヒドロキシベンゾトリアゾール 1水和物（68 mg, 0.50 m mol)、トリエチルァミン（0.070 mL, 0.50 mmol)を加えた後、室温で 3時間攪拌した。反 応混合物に水、炭酸水素ナトリウム水溶液を加え、有機層を分離し、飽和食塩水で 洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /へキサン = 1/1)で精製し、 6_(2-ク ロロフエ-ル) -2-イソプロピルァミノ- 7-メトキシ- 8-(N-メトキシ- N-メチルァミノカルボ- ル)キナゾリン (ィ匕合物 A10) (91 mg, 88%)を得た。  Compound A9 (93 mg, 0.25 mmol) was dissolved in DMF (2 mL) and N-methoxy-N-methylamine hydrochloride (37 mg, 0.38 mmol), 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (96 mg, 0.50 mmol), 1-hydroxybenzotriazole monohydrate (68 mg, 0.50 mmol) and triethylamine (0.070 mL, 0.50 mmol) were added, followed by stirring at room temperature for 3 hours. . Water and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 6_ (2-chlorophenol) -2-isopropylamino-7-methoxy-8- (N-methoxy-N- Methylaminocarbo) quinazoline (Compound A10) (91 mg, 88%) was obtained.
1H NMR (270 MHz, DMSO— d ) δ (ppm) 1.22 (d, J = 6.4 Hz, 6H), 3.24 (brs, 3H), 3.5  1H NMR (270 MHz, DMSO— d) δ (ppm) 1.22 (d, J = 6.4 Hz, 6H), 3.24 (brs, 3H), 3.5
6  6
3 (s, 3H), 3.59 (brs, 3H), 4.03—4.16 (m, 1H), 7.06 (brs, 1H), 7.40-7.44 (m, 3H), 7.5 2-7.57 (m, 1H), 7.64 (s, 1H), 9.00 (s, 1H).  3 (s, 3H), 3.59 (brs, 3H), 4.03—4.16 (m, 1H), 7.06 (brs, 1H), 7.40-7.44 (m, 3H), 7.5 2-7.57 (m, 1H), 7.64 (s, 1H), 9.00 (s, 1H).
工程 2 Process 2
化合物 Al 0を用 、、参考例 1の工程 6と同様の方法でィ匕合物 4を得た。 H NMR (300 MHz, DMSO— d ) δ (ppm) 1.22 (d, J = 6.4 Hz, 6H), 3.21 (s, 3H), 3.62 ( Compound 4 was obtained in the same manner as in Step 6 of Reference Example 1 using Compound Al0. H NMR (300 MHz, DMSO— d) δ (ppm) 1.22 (d, J = 6.4 Hz, 6H), 3.21 (s, 3H), 3.62 (
6  6
s, 3H), 4.03-4.14 (m, IH), 6.68 (brs, IH), 7.36-7.40 (m, 3H), 7.47-7.52 (m, IH), 7. 50 (s, IH), 8.84 (s, IH).  s, 3H), 4.03-4.14 (m, IH), 6.68 (brs, IH), 7.36-7.40 (m, 3H), 7.47-7.52 (m, IH), 7.50 (s, IH), 8.84 ( s, IH).
APCI m/z (M+H)+401. APCI m / z (M + H) + 401.
[0147] 参考例 5： 8-ァセチル- 6- (2-クロ口フエ-ル)- 7-ヒドロキシ- 2- (イソプロピルァミノ)キナ ゾリン (化合物 5)  [0147] Reference Example 5: 8-Acetyl-6- (2-chlorophenol) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 5)
化合物 A8を用 、、参考例 1の工程 6と同様の方法でィ匕合物 5を得た。  Compound 5 was obtained in the same manner as in Step 6 of Reference Example 1 using Compound A8.
JH NMR (300 MHz, CDCl ) δ (ppm) 1.41 (d, J = 6.6 Hz, 6H), 3.10 (s, 3H), 4.25—4.3  JH NMR (300 MHz, CDCl) δ (ppm) 1.41 (d, J = 6.6 Hz, 6H), 3.10 (s, 3H), 4.25—4.3
3  Three
5 (m, IH), 7.31-7.45 (m, 3H), 7.51-7.54 (m, IH), 7.78 (s, IH), 8.22 (d, J = 6.6 Hz, IH), 8.86 (s, IH).  5 (m, IH), 7.31-7.45 (m, 3H), 7.51-7.54 (m, IH), 7.78 (s, IH), 8.22 (d, J = 6.6 Hz, IH), 8.86 (s, IH) .
APCI m/z (M+H)+ 356. APCI m / z (M + H) + 356.
[0148] 参考例 6： 6- (2,4-ジフルオロフェ-ル )-8- (4-フルオロフェ-ル )-2-イソプロピルァミノ- 7-ヒドロキシキナゾリン (ィ匕合物 6)  [0148] Reference Example 6: 6- (2,4-Difluorophenol) -8- (4-Fluorophenol) -2-isopropylamino-7-hydroxyquinazoline (Compound 6)
工程 1  Process 1
化合物 A4及び 2 ,4-ジフルオロフヱニルホウ酸を用 、、参考例 1の工程 5と同様の方 法で化合物 6-(2,4-ジフルオロフェ-ル )-2-イソプロピルァミノ- 7-メトキシキナゾリン（ 化合物 All)を得た。  Compound 6- (2,4-difluorophenyl) -2-isopropylamino-7 in the same manner as in Step 5 of Reference Example 1 using Compound A4 and 2,4-difluorophenylboronic acid -Methoxyquinazoline (compound All) was obtained.
JH NMR (300 MHz, CDCl ) δ (ppm) 1.30 (d, J = 6.4 Hz, 6H), 3.90 (s, 3H), 4.28—4.3 J H NMR (300 MHz, CDCl) δ (ppm) 1.30 (d, J = 6.4 Hz, 6H), 3.90 (s, 3H), 4.28-4.3
3  Three
5 (m, IH), 5.09 (d, J = 6.4 Hz, IH), 6.86—6.97 (m, 2H), 6.98 (s, IH), 7.29-7.35 (m, IH), 7.58 (s, IH), 8.80 (s, IH).  5 (m, IH), 5.09 (d, J = 6.4 Hz, IH), 6.86—6.97 (m, 2H), 6.98 (s, IH), 7.29-7.35 (m, IH), 7.58 (s, IH) , 8.80 (s, IH).
APCI m/z (M+H)+ 330. APCI m / z (M + H) + 330.
工程 2  Process 2
化合物 Allを用い、参考例 3の工程 1と同様の方法で 8-ブロモ -6-(2,4-ジフルオロフ ェ-ル )-2-イソプロピルァミノ- 7-メトキシキナゾリン (ィ匕合物 A12)を得た。  8-Bromo-6- (2,4-difluorophenol) -2-isopropylamino-7-methoxyquinazoline (Compound A12) using Compound All in the same manner as in Step 1 of Reference Example 3. Got.
1H NMR (300 MHz, CDCl ) δ (ppm) 1.35 (d, J = 6.6 Hz, 6H), 3.62 (s, 3H), 4.33—4.4  1H NMR (300 MHz, CDCl) δ (ppm) 1.35 (d, J = 6.6 Hz, 6H), 3.62 (s, 3H), 4.33—4.4
3  Three
4 (m, IH), 5.37 (brs, IH), 6.91-7.01 (m, 2H), 7.38-7.46 (m, IH), 7.55 (s, IH), 8.86 (s, IH).  4 (m, IH), 5.37 (brs, IH), 6.91-7.01 (m, 2H), 7.38-7.46 (m, IH), 7.55 (s, IH), 8.86 (s, IH).
APCI m/z (M+H)+ 408, 410. [0149] 工程 3 APCI m / z (M + H) + 408, 410. [0149] Step 3
ィ匕合物 A12 (122 mg, 0.30 mmol)、 4-フルオロフェ-ルホウ酸（50 mg, 0.36 mmol)、 炭酸ナトリウム（64 mg, 0.60 mmol)及びテトラキス (トリフエ-ルホスフィン)パラジウム（1 7 mg, 0.015 mmol)に対し、アルゴン雰囲気下、ジォキサン（2 mL)及び水（1 mL)を 加えた後、 2時間加熱還流を行った。不溶物をセライトで濾別した後、希塩酸を加え、 反応混合物を中性にし、酢酸ェチルで抽出した。有機層を水で洗浄後、無水硫酸マ グネシゥムで乾燥し、減圧下、溶媒を留去した。残渣をエタノールでリスラリーすること で 6- (2,4-ジフルオロフェ-ル )-8- (4-フルオロフェ-ル )-2-イソプロピルアミノ- 7-メト キシキナゾリン (ィ匕合物 A13) (114 mg, 90%)を得た。  Compound A12 (122 mg, 0.30 mmol), 4-fluorophenylboric acid (50 mg, 0.36 mmol), sodium carbonate (64 mg, 0.60 mmol) and tetrakis (triphenylphosphine) palladium (17 mg, 0.015 mmol) was added with dioxane (2 mL) and water (1 mL) in an argon atmosphere, and then heated under reflux for 2 hours. Insoluble material was filtered off through celite, diluted hydrochloric acid was added to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was reslurried with ethanol to give 6- (2,4-difluorophenol) -8- (4-fluorophenol) -2-isopropylamino-7-methoxyquinazoline (Compound A13) (114 mg, 90%).
工程 4  Process 4
化合物 A13を用 、、参考例 1の工程 6と同様の方法でィ匕合物 6を得た。  Compound 6 was obtained in the same manner as in Step 6 of Reference Example 1 using Compound A13.
JH NMR (300 MHz, CDC1 ) δ (ppm) 1.16 (d, J = 6.4 Hz, 6H), 3.93 (brs, IH), 5.09 (b  JH NMR (300 MHz, CDC1) δ (ppm) 1.16 (d, J = 6.4 Hz, 6H), 3.93 (brs, IH), 5.09 (b
3  Three
rs, IH), 6.90-7.01 (m, 2H), 7.19-7.25 (m, 2H), 7.39-7.54 (m, 3H), 7.55 (s, IH), 8.8 0 (s, IH).  rs, IH), 6.90-7.01 (m, 2H), 7.19-7.25 (m, 2H), 7.39-7.54 (m, 3H), 7.55 (s, IH), 8.8 0 (s, IH).
APCI m/z (M+H)+ 410. APCI m / z (M + H) + 410.
[0150] 参考例 7： 6- (2-クロ口フエ-ル)- 7-ヒドロキシ- 8-ョード -2- (イソプロピルァミノ)キナゾリ ン (化合物 7)  [0150] Reference Example 7: 6- (2-Black-Fuel) -7-Hydroxy-8-odo-2- (isopropylamino) quinazoline (Compound 7)
化合物 1 (52 mg, 0.17 mmol)、ヨウ化ナトリウム（28 mg, 0.18 mmol)、水酸化ナトリウ ム（8 mg, 0.18 mmol)及び亜塩素酸ナトリウム（275 μ L, 0.18 mmol)をメタノール（0.6 mL)に溶解し、系内をアルゴンで置換した後、 0 °Cで 50分間攪拌した。反応混合物に 水、 20%チォ硫酸ナトリウム水溶液、 1 mol/L塩酸を順次加え、析出した結晶を濾別し 、化合物 7 (72 mg, 98%)を得た。  Compound 1 (52 mg, 0.17 mmol), sodium iodide (28 mg, 0.18 mmol), sodium hydroxide (8 mg, 0.18 mmol) and sodium chlorite (275 μL, 0.18 mmol) in methanol (0.6 mL) ) And the system was replaced with argon, followed by stirring at 0 ° C. for 50 minutes. Water, a 20% aqueous sodium thiosulfate solution, and 1 mol / L hydrochloric acid were sequentially added to the reaction mixture, and the precipitated crystals were separated by filtration to obtain Compound 7 (72 mg, 98%).
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.36 (d, J = 6.4 Hz, 6H), 4.34—4.41 (m, IH), 5.2  1H NMR (270 MHz, CDC1) δ (ppm) 1.36 (d, J = 6.4 Hz, 6H), 4.34—4.41 (m, IH), 5.2
3  Three
5 (brs, IH), 7.26-7.38 (m, 3H), 7.45 (s, IH), 7.50-7.60 (m, IH), 8.71 (s, IH).  5 (brs, IH), 7.26-7.38 (m, 3H), 7.45 (s, IH), 7.50-7.60 (m, IH), 8.71 (s, IH).
[0151] 参考例 8： 8-ブロモ -6- (2-クロ口フエ-ル)- 7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリ ン (化合物 8) [0151] Reference Example 8: 8-Bromo-6- (2-chlorophenol) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 8)
化合物 A7 (4.21 g, 10.4 mmol)をジクロ口エタン（90 mL)に溶解し、三臭化ホウ素（9. 80 mL, 104 mmol)をカ卩えた後、 5時間加熱還流した。反応混合物に、 28%アンモニア 水を加え、生じた結晶を濾取した。反応混合物を氷水に加えた後、炭酸水素ナトリウ ム水溶液、クロ口ホルムをカ卩ぇ有機層を分離した。有機層を無水硫酸マグネシウムで 乾燥し、減圧下、溶媒を留去し、化合物 8 (2.12 g, 52%)を得た。 Compound A7 (4.21 g, 10.4 mmol) was dissolved in diclonal ethane (90 mL), boron tribromide (9.80 mL, 104 mmol) was added, and the mixture was heated to reflux for 5 hours. 28% ammonia in the reaction mixture Water was added and the resulting crystals were collected by filtration. After adding the reaction mixture to ice water, the organic layer was separated from the aqueous sodium hydrogen carbonate solution and black mouth form. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 8 (2.12 g, 52%).
1H NMR (270 MHz, DMSO— d ) δ (ppm) 1.24 (d, J = 6.4 Hz, 6H), 4.20-4.32 (m, 1H),  1H NMR (270 MHz, DMSO— d) δ (ppm) 1.24 (d, J = 6.4 Hz, 6H), 4.20-4.32 (m, 1H),
6  6
7.36-7.48 (m, 4H), 7.53-7.60 (m, 2H), 8.91 (s, 1H), 9.87 (s, 1H).  7.36-7.48 (m, 4H), 7.53-7.60 (m, 2H), 8.91 (s, 1H), 9.87 (s, 1H).
ESI m/z (M+H)+ 392. ESI m / z (M + H) + 392.
参考例 9： 8- (4-カルボキシフエ-ル)- 6- (2-クロ口フエ-ル)- 7-ヒドロキシ- 2- (イソプロ ピルァミノ)キナゾリン (化合物 9) Reference Example 9: 8- (4-Carboxyphenol) -6- (2-Chlorophenyl) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 9)
工程 1 Process 1
化合物 A6 (100 mg, 0.230 mmol)、 4-カルボキシフエ-ルホウ酸（46 mg, 0.28 mmol )、炭酸ナトリウム（49 mg, 0.46 mmol)及びテトラキス (トリフエ-ルホスフィン)パラジゥ ム（13 mg, 0.012 mmol)に対し、アルゴン雰囲気下、ジォキサン（1.5 mL)及び水（1.5 mL)を加えた後、 3時間加熱還流を行った。不溶物をセライトで濾別した後、希塩酸を 加え、反応混合物を中性にし、酢酸ェチルで抽出した。有機層を水で洗浄後、無水 硫酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /へキサン =2/1)で精製し、 8-(4-カルボキシフエ-ル)- 6-(2 -クロ口フエ-ル) -2-イソプロピルァミノ- 7- (メトキシメチルォキシ)キナゾリン（ィ匕合物 A1 4) (75.1 mg, 69%)を得た。  Compound A6 (100 mg, 0.230 mmol), 4-carboxyphenylboronic acid (46 mg, 0.28 mmol), sodium carbonate (49 mg, 0.46 mmol) and tetrakis (triphenylphosphine) palladium (13 mg, 0.012 mmol) ) Was added with dioxane (1.5 mL) and water (1.5 mL) in an argon atmosphere, and then heated under reflux for 3 hours. Insoluble material was filtered off through celite, diluted hydrochloric acid was added to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) to give 8- (4-carboxyphenyl) -6- (2-chlorophenol) -2-isopropylamino. -7- (Methoxymethyloxy) quinazoline (Compound A1 4) (75.1 mg, 69%) was obtained.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.08 (d, J = 5.0 Hz, 6H), 3.32 (s, 3H), 3.65— J H NMR (270 MHz, DMSO— d) δ (ppm) 1.08 (d, J = 5.0 Hz, 6H), 3.32 (s, 3H), 3.65—
6  6
3.85 (m, 1H), 4.27 (s, 2H), 7.30-7.66 (m, 7H), 7.75 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H ), 9.09 (s, 1H).  3.85 (m, 1H), 4.27 (s, 2H), 7.30-7.66 (m, 7H), 7.75 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 9.09 (s, 1H).
ESI m/z (M+H)+ 478. ESI m / z (M + H) + 478.
工程 2 Process 2
化合物 A14 (45.0 mg, 0.0945 mmol)をジォキサン（1 mL)に溶解し、 6 mol/L塩酸（0 .010 mL)を加えた後、室温で 2時間攪拌した。反応混合物に水を加え、酢酸ェチル で抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下、溶媒を 留去した。残渣をエーテルでリスラリーすることでィ匕合物 9 (34.0 mg, 83%)を得た。 JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.08 (d, J = 6.4 Hz, 6H), 3.60—3.85 (m, 1H), •(HI 's -iq) ζζ'ΖΙ '(Ηΐ 's) 26"8 '(Η2 'ω) 8 Compound A14 (45.0 mg, 0.0945 mmol) was dissolved in dioxane (1 mL), 6 mol / L hydrochloric acid (0.010 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was reslurried with ether to give Compound 9 (34.0 mg, 83%). J H NMR (270 MHz, DMSO— d) δ (ppm) 1.08 (d, J = 6.4 Hz, 6H), 3.60—3.85 (m, 1H), • (HI 's -iq) ζζ'ΖΙ' (Ηΐ 's) 26 "8' (Η2 'ω) 8
S"Z-2S"Z '(HS 'ω) 9^"Z-9S"Z '(Η2 '^Η ΐ·8 = f 'Ρ) Ζ '(Ηΐ Ί S6'9 '(Ηΐ 'ω) 06Τ S "Z-2S" Z '(HS' ω) 9 ^ "Z-9S" Z '(Η2' ^ Η ΐ8 = f 'Ρ) Ζ' (Ηΐ Ί S6'9 '(Ηΐ' ω) 06Τ
-S9T '(Η2 's) ΐ9·ε '(Η9 'ΖΗ S'9 = f 'Ρ) 60· ΐ ( d) g ( OS 'z 00S) 醒 Ητ -S9T '(Η2' s) ΐ9 · ε '(Η9' Ζ Η S'9 = f 'Ρ) 60 ΐ (d) g (OS' z 00S) Awakening Η τ
、 翁^; 1¾ェ0)6[^ 拳、、 ¾f¾邈 ^ / ェ ( ^ /^^ ^ / - , 翁 ^; 1¾e0) 6 [^ fist, ¾f¾ 邈 ^ / e (^ / ^^^ /-
)-Ζ-^ ^-ΐ-( /—^Δ ^-Ζ)-9-[ /—^Δ( /^^^ /^)- -8： Up}% [ ΐ0]
Figure imgf000060_0001
) -Ζ- ^ ^ -ΐ- (/ — ^ Δ ^ -Ζ) -9- [/ — ^ Δ (/ ^^^ / ^)--8: Up}% [ΐ0]
Figure imgf000060_0001
•(HI 's) S6'8 '(Ηΐ 's) Ζ0·8 '(Ηΐ '^Η Ζ·Ζ = f 'Ρ) 16 •Ζ '(Ηΐ 'ΖΗ Ζ·Ζ = f 'Ρ) 69"Z '(HS 'ω) 8S"Z-TS"Z '(HS 'ω) 6 · - 0 ·Ζ '(Ηΐ Ί 00·  • (HI 's) S6'8' (Ηΐ 's) Ζ0 · 8' (Ηΐ '^ Η Ζ · Ζ = f' Ρ) 16 • Ζ '(Ηΐ' ΖΗ Ζ · Ζ = f 'Ρ) 69 " Z '(HS' ω) 8S "Z-TS" Z '(HS' ω) 6 ·-0 · Ζ '(Ηΐ Ί 00
'(Ηΐ 'ω) 06·ε- 09·ε '(Η9 'ΖΗ V9 = f 'Ρ) 90· ΐ ( d) g ( OSWd 'z LZ) 醒 HT '(Ηΐ' ω) 06 · ε- 09 · ε '(Η9' Ζ Η V9 = f 'Ρ) 90 · ΐ (d) g (OSWd' z LZ) Awakening H T
。 01 ^^^ u ^ zw a>e ^ \ \ ¾r ¾s i v呦
Figure imgf000060_0002
. 01 ^^^ u ^ zw a> e ^ \ \ ¾r ¾s iv 呦
Figure imgf000060_0002
•(H ΐ Ί 06 ΐ '(Ηΐ 's) 60·6 '(Ηΐ 's) 5Γ8 '(Ηΐ '^Η 9"Ζ = f 'Ρ) 26"Ζ '(Η2 'ω) 08· ^' Ζ '(HS 'ω) 09"Z-2S"Z ΗΖ 'ω) Ζ ' - ΐ ·Ζ '(Ηΐ Ί ££'L ΗΖ 's) SZ'f '(Ηΐ 'ω) S8T • (H ΐ Ί 06 ΐ '(Ηΐ' s) 60 · 6 '(Ηΐ' s) 5Γ8 '(Ηΐ' ^ Η 9 "Ζ = f 'Ρ) 26"Ζ' (Η2 'ω) 08 · ^' Ζ '(HS' ω) 09 "Z-2S" Z ΗΖ 'ω) Ζ'-ΐ · Ζ '(Ηΐ Ί ££' L ΗΖ ' s ) SZ'f' (Ηΐ 'ω) S8T
-S9T '(HS 's) Ζ£'£ '(Η9 'ΖΗ 9·， = f 'Ρ) Ζ0·ΐ ( d) 9 ( OS 'z LZ) 醒 Ητ -S9T '(HS' s) Ζ £ '£' (Η9 ' Ζ Η 9 ·, = f' Ρ) Ζ0 · ΐ (d) 9 (OS 'z LZ) Awakening Η τ
。 (STVi¾J^»ベ ίί 、  . (STVi¾J ^ »Be ίί,
^(/^^ ^ /^^： 4 ) - ci l - ( / ェ crn^- S)- 9- ( / ェ 、^ ^ (/ ^^ ^ / ^^: 4)-ci l-(/ é crn ^-S) -9-(/ é, ^
^ / - S)- 8 翁^; 1¾ェ0)6[^ 拳ヽ ¾¾邈 ^ / ェ ^：^ - ε ^ /-S)-8 翁 ^; 1¾e0) 6 [^ Fist ¾¾ 邈 ^ / é ^ ： ^-ε
ΐ¾Χ  ΐ¾Χ
(/ (/
Figure imgf000060_0003
： 0Tp}% [SSTO]
Figure imgf000060_0003
: 0Tp}% [SSTO]
' +(H+ ) z/ui IS3 •(HI 's-iq) 02"6 '(Ηΐ 's) ε' + (H +) z / ui IS3 • (HI' s-iq) 02 "6 '(Ηΐ' s) ε
·8 '(Η2 'ΖΗ Z'S = f 'Ρ) 66"Ζ '(Η 'ω) ΐ9·Ζ— SS'Z '(HS 'ω) Ζ ' — '(Ηΐ Ί S0'  · 8 '(Η2' ΖΗ Z'S = f 'Ρ) 66 "Ζ' (Η 'ω) ΐ9 · Ζ— SS'Z' (HS 'ω) Ζ' — '(Ηΐ Ί S0'
6ξ 6ξ
8L£Zl£/900Zdr/13d ΐひ I/900Z OAV APCI m/z (M+H)+ 448. 8L £ Zl £ / 900Zdr / 13d ΐ ひ I / 900Z OAV APCI m / z (M + H) + 448.
参考例 12： 8-[3- (カルボキシメチル)フエ-ル] -6-(2-クロ口フエ-ル)- 7-ヒドロキシ -2-( イソプロピルァミノ)キナゾリン (化合物 12) Reference Example 12: 8- [3- (Carboxymethyl) phenol] -6- (2-Chlorophenyl) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 12)
3- (カルボキシメチル)フエ-ルホウ酸を用い、参考例 9の工程 1と同様の方法でカツ プリング反応を行った後、参考例 9の工程 2と同様の方法で脱メトキシメチルイ匕を行う ことでィ匕合物 12を得た。  After performing the coupling reaction in the same manner as in Step 1 of Reference Example 9, using 3- (carboxymethyl) phenolic boric acid, demethoxymethylation is performed in the same manner as in Step 2 of Reference Example 9. So I got Compound 12.
JH NMR (300 MHz, DMSO— d ) δ (ppm) 1.08 (d, J = 6.6 Hz, 6H), 3.59 (s, 2H), 3.70— J H NMR (300 MHz, DMSO— d) δ (ppm) 1.08 (d, J = 6.6 Hz, 6H), 3.59 (s, 2H), 3.70—
6  6
3.95 (m, 1H), 6.98 (brs, 1H), 7.22-7.47 (m, 7H), 7.52-7.58 (m, 2H), 8.91 (s, 1H). APCI m/z (M+H)+ 448. 3.95 (m, 1H), 6.98 (brs, 1H), 7.22-7.47 (m, 7H), 7.52-7.58 (m, 2H), 8.91 (s, 1H). APCI m / z (M + H) + 448 .
参考例 13： 6,8-ジ (2-クロ口フエ-ル)- 7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリン（ 化合物 13) Reference Example 13: 6,8-di (2-black mouth phenol) -7-hydroxy-2- (isopropylamino) quinazoline (compound 13)
工程 1 Process 1
ィ匕合物 A6 (70.0 mg, 0.161 mmol)、 2—クロ口フエ-ルホウ酸（50.0 mg, 0.322 mmol) 、リン酸三カリウム（103 mg, 0.483 mmol)、トリス (ジベンジリデンアセトン)ジパラジウム (15.0 mg, 0.0161 mmol)及び 2- (ジシクロへキシルフエ-ルホスフイノ)ビフエ-ル（23. 0 mg, 0.0644 mmol)に対し、アルゴン雰囲気下、ジォキサン（1 mL)及び水（1 mL)を 加えた後、 1.5時間加熱還流を行った。反応混合物に水、酢酸ェチルを加え有機層 を分離し、水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /へキサン = 1/9)で 精製し、 6,8-ジ (2-クロ口フエ-ル) -2-イソプロピルァミノ- 7- (メトキシメチルォキシ)キナ ゾリン（ィ匕合物 A16) (60.0 mg, 80%)を得た。  Compound A6 (70.0 mg, 0.161 mmol), 2-Fe-borate (50.0 mg, 0.322 mmol), tripotassium phosphate (103 mg, 0.483 mmol), tris (dibenzylideneacetone) dipalladium ( After adding dioxane (1 mL) and water (1 mL) to 15.0 mg, 0.0161 mmol) and 2- (dicyclohexylphenolphosphino) biphenol (23.0 mg, 0.0644 mmol) under an argon atmosphere The mixture was refluxed for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9) to give 6,8-di (2-chlorophenol) -2-isopropylamino-7- (methoxymethyloxy) Quinazoline (Compound A16) (60.0 mg, 80%) was obtained.
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.02—1.20 (m, 6H), 2.66 (s, 3H), 3.70—4.00 (m,  1H NMR (270 MHz, CDC1) δ (ppm) 1.02—1.20 (m, 6H), 2.66 (s, 3H), 3.70—4.00 (m,
3  Three
1H), 4.40-4.48 (m, 2H), 5.17 (s, 1H), 7.28-7.36 (m, 4H), 7.40-7.62 (m, 4H), 7.68 ( s, 1H), 8.92 (s, 1H).  1H), 4.40-4.48 (m, 2H), 5.17 (s, 1H), 7.28-7.36 (m, 4H), 7.40-7.62 (m, 4H), 7.68 (s, 1H), 8.92 (s, 1H) .
APCI m/z (M+H)+ 468. APCI m / z (M + H) + 468.
工程 2 Process 2
化合物 Al 6を用 、、参考例 9の工程 2と同様の方法で化合物 13を得た。  Compound 13 was obtained in the same manner as in Step 2 of Reference Example 9 using Compound Al6.
JH NMR (270 MHz, CDC1 ) δ (ppm) 1.10 - 1.18 (m, 6H), 3.78—3.98 (m, 1H), 5.20 (brs , 1H), 7.32-7.64 (m, 10H), 8.80 (s, 1H). JH NMR (270 MHz, CDC1) δ (ppm) 1.10-1.18 (m, 6H), 3.78—3.98 (m, 1H), 5.20 (brs , 1H), 7.32-7.64 (m, 10H), 8.80 (s, 1H).
APCI m/z (M+H)+ 424. APCI m / z (M + H) + 424.
[0156] 参考例 14： 6- (2-クロ口フエ-ル)- 8- (2-フルオロフェ-ル )-7-ヒドロキシ- 2- (イソプロピ ルァミノ)キナゾリン (化合物 14)  [0156] Reference Example 14: 6- (2-Black-Fuel) -8- (2-Fluorophenol) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 14)
工程 1  Process 1
化合物 A6 (100 m g, 0.230 mmol)、 2-フルオロフェ-ルホウ酸（64.0 mg, 0.457 mmo 1)、リン酸三カリウム（146 mg, 0.688 mmol)、トリス (ジベンジリデンアセトン)ジパラジゥ ム（21.0 mg, 0.0229 mmol)及び 2- (ジシクロへキシルフヱ-ルホスフイノ)ビフエ-ル（3 2.0 mg, 0.0913 mmol)に対し、アルゴン雰囲気下、ジォキサン（1.5 mL)及び水（1.5 mL)を加えた後、 1.5時間加熱還流を行った。反応混合物に水、酢酸ェチルを加え有 機層を分離し、水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /トルエン = 1/9 )で精製し、 6- (2-クロ口フエ-ル)- 8- (2-フルオロフェ-ル )-2-イソプロピルァミノ- 7- (メ トキシメチルォキシ)キナゾリン（ィ匕合物 A17) (88.0 mg, 85%)を得た。  Compound A6 (100 mg, 0.230 mmol), 2-fluorophenylboric acid (64.0 mg, 0.457 mmo 1), tripotassium phosphate (146 mg, 0.688 mmol), tris (dibenzylideneacetone) dipalladium (21.0 mg, 0.0229 mmol) and 2- (dicyclohexyl-l-phosphosino) biphenyl (3 2.0 mg, 0.0913 mmol) under argon atmosphere, dioxane (1.5 mL) and water (1.5 mL) were added, and then heated under reflux for 1.5 hours. Went. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / toluene = 1/9) to give 6- (2-chlorophenol) -8- (2-fluorophenol) -2-isopropylamino-7- (Methoxymethyloxy) quinazoline (Compound A17) (88.0 mg, 85%) was obtained.
JH NMR (270 MHz, CDC1 ) δ (ppm) 1.08—1.20 (m, 6H), 2.66 (s, 3H), 3.80—4.00 (m,  JH NMR (270 MHz, CDC1) δ (ppm) 1.08—1.20 (m, 6H), 2.66 (s, 3H), 3.80—4.00 (m,
3  Three
1H), 4.44 (s, 2H), 5.23 (brs, 1H), 7.13-7.25 (m, 2H), 7.30-7.41 (m, 3H), 7.45-7.53 (m, 3H), 7.62 (s, 1H), 8.92 (s, 1H).  1H), 4.44 (s, 2H), 5.23 (brs, 1H), 7.13-7.25 (m, 2H), 7.30-7.41 (m, 3H), 7.45-7.53 (m, 3H), 7.62 (s, 1H) , 8.92 (s, 1H).
APCI m/z (M+H)+ 452. APCI m / z (M + H) + 452.
工程 2  Process 2
化合物 Al 7を用い、参考例 9の工程 2と同様の方法で化合物 14を得た。  Compound 14 was obtained in the same manner as in Step 2 of Reference Example 9 using Compound Al7.
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.12-1.22 (m, 6H), 3.80—4.20 (m, 1H), 7.22-7.5  1H NMR (270 MHz, CDC1) δ (ppm) 1.12-1.22 (m, 6H), 3.80—4.20 (m, 1H), 7.22-7.5
3  Three
7 (m, 10H), 8.80 (s, 1H).  7 (m, 10H), 8.80 (s, 1H).
ESI m/z (M+H)+ 408. ESI m / z (M + H) + 408.
[0157] 参考例 15： 6- (2-クロ口フエ-ル)- 8- (2,6-ジフルオロフェ-ル )-7-ヒドロキシ- 2- (イソプ 口ピルァミノ)キナゾリン (ィ匕合物 15)  [0157] Reference Example 15: 6- (2-Black-Fouling) -8- (2,6-Difluorophenol) -7-Hydroxy-2- (Isopropylpyramino) quinazoline (Compound 15) )
工程 1  Process 1
2,6-ジフルオロフヱ-ルホウ酸及び配位子として 2_ (ジシクロへキシルホスフイノ) -2， -ジメチルアミノビフエ-ルを用い、実施例 13の工程 1と同様の方法で 6-(2-クロ口フエ -ル) -8- (2,6-ジフルオロフェ-ル )-2-イソプロピルァミノ- 7- (メトキシメチルォキシ)キ ナゾリン (ィ匕合物 A18)を得た。 Using 2-6-difluorophenylboric acid and 2_ (dicyclohexylphosphino) -2, -dimethylaminobiphenyl as the ligand, the same procedure as in Step 1 of Example 13 was performed. Hue -L) -8- (2,6-difluorophenol) -2-isopropylamino-7- (methoxymethyloxy) quinazoline (Compound A18) was obtained.
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.16 (d, J = 6.4 Hz, 6H), 2.72 (s, 3H), 3.80—4.0  1H NMR (270 MHz, CDC1) δ (ppm) 1.16 (d, J = 6.4 Hz, 6H), 2.72 (s, 3H), 3.80—4.0
3  Three
0 (m, IH), 4.49 (s, 2H), 5.12 (d, J = 7.6 Hz, IH), 7.01 (t, J = 7.8 Hz, 2H), 7.31-7.4 2 (m, 3H), 7.45-7.53 (m, 2H), 7.67 (s, IH), 8.92 (s, IH).  0 (m, IH), 4.49 (s, 2H), 5.12 (d, J = 7.6 Hz, IH), 7.01 (t, J = 7.8 Hz, 2H), 7.31-7.4 2 (m, 3H), 7.45- 7.53 (m, 2H), 7.67 (s, IH), 8.92 (s, IH).
工程 2 Process 2
化合物 Al 8を用 、、参考例 9の工程 2と同様の方法で化合物 15を得た。  Compound 15 was obtained in the same manner as in Step 2 of Reference Example 9 using Compound Al8.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.02—1.08 (m, 6H), 3.54—3.66 (m, IH), 7.08 JH NMR (270 MHz, DMSO— d) δ (ppm) 1.02—1.08 (m, 6H), 3.54—3.66 (m, IH), 7.08
6  6
(brs, IH), 7.13 (t, J = 8.1 Hz, 2H), 7.40-7.51 (m, 4H), 7.52-7.60 (m, IH), 7.63 (s, IH), 8.93 (s, IH), 9.45 (s, IH).  (brs, IH), 7.13 (t, J = 8.1 Hz, 2H), 7.40-7.51 (m, 4H), 7.52-7.60 (m, IH), 7.63 (s, IH), 8.93 (s, IH), 9.45 (s, IH).
APCI m/z (M+H)+ 426. APCI m / z (M + H) + 426.
参考例 16： 6-ベンゾィル -7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリン（化合物 16) 工程 1 Reference Example 16: 6-Benzyl-7-hydroxy-2- (isopropylamino) quinazoline (Compound 16) Step 1
5-ブロモ -2-フルォロ- 4-メトキシベンズアルデヒド（1 g, 4.3 mmol)、トシル酸一水和 物（163 mg, 0.86 mmol)及びオルトギ酸トリメチル（2.4 mL, 21 mmol)をメタノール（20 mL)に溶解し、加熱還流下 1時間攪拌した。反応混合物を放冷後、トリェチルアミン（ 2 mL)を加え、更に 10分間攪拌した。これに飽和食塩水、酢酸ェチルを加え、有機層 を分離し飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下 、溶媒を留去し、 5-ブロモ -2-フルォ口- 4-メトキシベンズアルデヒドジメチルァセター ル (ィ匕合物 A19) (1.19 g, 100%)を得た。  5-Bromo-2-fluoro-4-methoxybenzaldehyde (1 g, 4.3 mmol), tosylic acid monohydrate (163 mg, 0.86 mmol) and trimethyl orthoformate (2.4 mL, 21 mmol) in methanol (20 mL) And stirred for 1 hour under reflux. The reaction mixture was allowed to cool, triethylamine (2 mL) was added, and the mixture was further stirred for 10 min. To this were added saturated brine and ethyl acetate, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 5-bromo-2-fluoro-4-4-methoxybenzaldehyde dimethylacetate (Compound A19) (1.19 g, 100%) Got.
1H NMR (300 MHz, CDC1 ) δ (ppm) 3.37 (s, 6H), 3.77 (s, 3H), 5.61 (s, IH), 6.69 (d,  1H NMR (300 MHz, CDC1) δ (ppm) 3.37 (s, 6H), 3.77 (s, 3H), 5.61 (s, IH), 6.69 (d,
3  Three
J = 11.7 Hz, IH), 7.37 (d, J = 8.4 Hz, IH).  J = 11.7 Hz, IH), 7.37 (d, J = 8.4 Hz, IH).
工程 2 Process 2
化合物 A19 (5 g, 18 mmol)を THF (70 mL)に溶解し、 -70 °Cにて 20分間攪拌した。 これに- 70 °Cで、 n-ブチルリチウム（1.53 mol/Lへキサン溶液， 15 mL, 23 mmol)を 加え、更に 10分間攪拌した。 -70 °Cにて、反応混合物に Ν,Ν-ジメチルベンズアミド (8 g, 53 mmol)の THF溶液 (20 mL)を滴下し、更に 20分間攪拌した。反応混合物に水 、酢酸ェチルを加え、有機層を分離し飽和食塩水で洗浄した。有機層を無水硫酸マ グネシゥムで乾燥し、次いで減圧下、溶媒を留去し、シロップ状の残渣を得た。残渣 をアセトン（20 mL)に溶解し、これにトシル酸一水和物（1.7 g, 8.9 mmol)をカ卩え、室 温にて 30分間攪拌した。これに飽和重層水、酢酸ェチルを加え、有機層を分離し飽 和重層水、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧 下、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（酢酸ェチル /へキサ ン = 1/4)で精製し、 5-ベンゾィル -2-フルォ口- 4-メトキシベンズアルデヒド（化合物 A 20) (1.6 g, 35%)を得た。 Compound A19 (5 g, 18 mmol) was dissolved in THF (70 mL) and stirred at -70 ° C for 20 minutes. To this was added n-butyllithium (1.53 mol / L hexane solution, 15 mL, 23 mmol) at -70 ° C, and the mixture was further stirred for 10 minutes. A THF solution (20 mL) of Ν, Ν-dimethylbenzamide (8 g, 53 mmol) was added dropwise to the reaction mixture at −70 ° C., and the mixture was further stirred for 20 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. The organic layer is anhydrous Then, the residue was dried with glycine, and then the solvent was distilled off under reduced pressure to obtain a syrupy residue. The residue was dissolved in acetone (20 mL), tosylic acid monohydrate (1.7 g, 8.9 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Saturated multistory water and ethyl acetate were added thereto, and the organic layer was separated and washed with saturated multistory water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4) to give 5-benzoyl-2-fluorine-4-methoxybenzaldehyde (compound A 20) (1.6 g, 35%). .
JH NMR (270 MHz, CDC1 ) δ (ppm) 3.84 (s, 3H), 6.76 (d, J = 12.2 Hz, IH), 7.43-7. J H NMR (270 MHz, CDC1) δ (ppm) 3.84 (s, 3H), 6.76 (d, J = 12.2 Hz, IH), 7.43-7.
3  Three
48 (m, 2H), 7.56-7.62 (m, IH), 7.75-7.78 (m, 2H), 7.91 (d, J = 8.1 Hz, IH), 10.2 (s , IH).  48 (m, 2H), 7.56-7.62 (m, IH), 7.75-7.78 (m, 2H), 7.91 (d, J = 8.1 Hz, IH), 10.2 (s, IH).
工程 3 Process 3
炭酸グァ-ジン（1.6 g, 8.6 mmol)を DMA (35 mL)に溶解し、 160 °Cにて 20分間攪 拌した。これに化合物 A20 (1.6 g, 6.2 mmol)を加え、更に 50分間攪拌した。反応混合 物を放冷後、水、酢酸ェチルを加え、有機層を分離し水で洗浄した。有機層を無水 硫酸マグネシウムで乾燥し、減圧下、溶媒を留去した。得られた固体をへキサン/ジ ェチルエーテル（1/1)でリスラリーした。固体を濾取し、 2-ァミノ- 6-ベンゾィル -7-メト キシキナゾリン (ィ匕合物 A21) (965 mg, 56%)を得た。  Guazine carbonate (1.6 g, 8.6 mmol) was dissolved in DMA (35 mL) and stirred at 160 ° C. for 20 minutes. Compound A20 (1.6 g, 6.2 mmol) was added thereto, and the mixture was further stirred for 50 minutes. The reaction mixture was allowed to cool, water and ethyl acetate were added, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was reslurried with hexane / diethyl ether (1/1). The solid was collected by filtration to give 2-amino-6-benzoyl-7-methoxyquinazoline (Compound A21) (965 mg, 56%).
JH NMR (300 MHz, CDC1 ) δ (ppm) 3.84 (s, 3H), 5.27 (brs, 2H), 6.97 (s, IH), 7.43- J H NMR (300 MHz, CDC1) δ (ppm) 3.84 (s, 3H), 5.27 (brs, 2H), 6.97 (s, IH), 7.43-
3 Three
7.48 (m, 2H), 7.56-7.61 (m, IH), 7.73 (s, IH), 7.81-7.83 (m, 2H), 8.90 (s, IH). 工程 4  7.48 (m, 2H), 7.56-7.61 (m, IH), 7.73 (s, IH), 7.81-7.83 (m, 2H), 8.90 (s, IH). Step 4
化合物 A21 (965 mg, 3.4 mmol)、ヨウ化銅（394 mg, 2.1 mmol)、ジョードメタン（2.8 mL, 34 mmol)及び亜硝酸イソアミル（1.4 mL, 10 mmol)を THF (20 mL)に溶解し、 70 °Cにて 4時間攪拌した。反応混合物を放冷後、へキサン（100 mL)を加え、沈殿物を 濾取した。得られた沈殿物を DMF (10 mL)に溶解し、これにイソプロピルアミン（0.88 mL, 10 mmol)、トリエチルァミン（0.96 mL, 6.9 mmol)をカ卩え、室温にて 30分間攪拌し た。これに水、酢酸ェチルを加え、有機層を分離し水で洗浄した。有機層を無水硫 酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /へキサン = 1/1)で精製し、 6-ベンゾィル -2-イソプロピルアミ ノ -7-メトキシキナゾリン（ィ匕合物 A22) (394 mg, 35%)を得た。 Compound A21 (965 mg, 3.4 mmol), copper iodide (394 mg, 2.1 mmol), jodomethane (2.8 mL, 34 mmol) and isoamyl nitrite (1.4 mL, 10 mmol) were dissolved in THF (20 mL). The mixture was stirred at 70 ° C for 4 hours. The reaction mixture was allowed to cool, hexane (100 mL) was added, and the precipitate was collected by filtration. The obtained precipitate was dissolved in DMF (10 mL), and isopropylamine (0.88 mL, 10 mmol) and triethylamine (0.96 mL, 6.9 mmol) were added thereto and stirred at room temperature for 30 minutes. . Water and ethyl acetate were added thereto, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 6-benzoyl-2-isopropylamino No-7-methoxyquinazoline (Compound A22) (394 mg, 35%) was obtained.
1H NMR (300 MHz, CDCl ) δ (ppm) 1.32 (d, J = 6.4 Hz, 6H), 3.83 (s, 3H), 4.28—4.3  1H NMR (300 MHz, CDCl) δ (ppm) 1.32 (d, J = 6.4 Hz, 6H), 3.83 (s, 3H), 4.28-4.3
3  Three
6 (m, IH), 5.34 (brs, IH), 6.96 (s, IH), 7.41-7.47 (m, 2H), 7.54-7.60 (m, IH), 7.68 (s, IH), 7.79-7.83 (m, 2H), 8.81 (s, IH).  6 (m, IH), 5.34 (brs, IH), 6.96 (s, IH), 7.41-7.47 (m, 2H), 7.54-7.60 (m, IH), 7.68 (s, IH), 7.79-7.83 ( m, 2H), 8.81 (s, IH).
APCI m/z (M+H)+322. APCI m / z (M + H) + 322.
工程 5 Process 5
化合物 A22 (114 mg, 0.35 mmol)及び三臭化ホウ素（1 mol/L塩化メチレン溶液， 1.8 mL,1.7 mmol)を塩化メチレン (2 mL)に溶解し、室温にて 1時間攪拌した。反応混合 物を 0 °Cに冷却後、飽和重層水をカ卩えた。これにクロ口ホルムをカ卩え、有機層を分離 し飽和重層水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、溶媒 を留去した。得られた固体をへキサン/ジェチルエーテル（1/1)でリスラリーした。固 体を濾取し、化合物 16 (65 mg, 60%)を得た。  Compound A22 (114 mg, 0.35 mmol) and boron tribromide (1 mol / L methylene chloride solution, 1.8 mL, 1.7 mmol) were dissolved in methylene chloride (2 mL) and stirred at room temperature for 1 hour. After cooling the reaction mixture to 0 ° C., saturated multistory water was added. To this, black mouth form was added, and the organic layer was separated and washed with saturated multistory water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting solid was reslurried with hexane / jetyl ether (1/1). The solid was collected by filtration to obtain Compound 16 (65 mg, 60%).
JH NMR (270 MHz, CDCl ) δ (ppm) 1.30 (d, J = 6.4 Hz, 6H), 4.29-4.40 (m, IH), 5.3 J H NMR (270 MHz, CDCl) δ (ppm) 1.30 (d, J = 6.4 Hz, 6H), 4.29-4.40 (m, IH), 5.3
3  Three
4 (brs, IH), 7.00 (s, IH), 7.52-7.58 (m, 2H), 7.61-7.72 (m, 3H), 7.95 (s, IH), 8.74 (s, IH), 12.0 (brs, IH).  4 (brs, IH), 7.00 (s, IH), 7.52-7.58 (m, 2H), 7.61-7.72 (m, 3H), 7.95 (s, IH), 8.74 (s, IH), 12.0 (brs, IH).
ESI m/z (M+H)+ 308. ESI m / z (M + H) + 308.
参考例 17 : 7-ヒドロキシ -2-イソプロピルァミノ- 6-フエノキシキナゾリン（ィ匕合物 17) 工程 1 Reference Example 17: 7-Hydroxy-2-isopropylamino-6-phenoxyquinazoline (Compound 17) Step 1
化合物 A4 (480 mg, 1.62 mmol)、ヨウ化銅（77.0 mg, 0.405 mmol)、炭酸カリウム（45 0 mg, 3.24 mmol)及びフエノール（610 mg, 6.48 mmol)を DMF (5 mL)に溶解し、 140 °Cにて 16時間攪拌した。放冷後、反応混合物に飽和食塩水、酢酸ェチルを加えた 後、有機層を分離し水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した。減 圧下、溶媒を留去し、 2-イソプロピルァミノ- 7-メトキシ -6-フエノキシキナゾリン (ィ匕合 物 A23) (366 mg, 67%)を得た。  Compound A4 (480 mg, 1.62 mmol), copper iodide (77.0 mg, 0.405 mmol), potassium carbonate (45 0 mg, 3.24 mmol) and phenol (610 mg, 6.48 mmol) were dissolved in DMF (5 mL). The mixture was stirred at 140 ° C for 16 hours. After allowing to cool, saturated brine and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-isopropylamino-7-methoxy-6-phenoxyquinazoline (Compound A23) (366 mg, 67%).
ESI m/z (M+H)+ 310. ESI m / z (M + H) + 310.
工程 2 Process 2
化合物 A23 (360 mg, 1.16 mmol)をジクロ口エタン（4 mL)に溶解し、三臭化ホウ素（ 5.81 mL, 5.81 mmol)を加え、 80 °Cにて 16時間攪拌した。放冷後、反応混合物を氷
Figure imgf000066_0001
OOUIUI εο·ο ' 6· ）マ ^^ ^^\_ ^ ^ { y .^—^ ^) .?,- \\ (louiui 8S '§ω IS)濯 Compound A23 (360 mg, 1.16 mmol) was dissolved in dichroic ethane (4 mL), boron tribromide (5.81 mL, 5.81 mmol) was added, and the mixture was stirred at 80 ° C. for 16 hours. After cooling, the reaction mixture is iced
Figure imgf000066_0001
OOUIUI εο · ο '6 ·) Ma ^^ ^^ \ _ ^ ^ {y ^^ ^), -..? \\ (louiui 8S' § ω IS)濯
^ /—^Δ /^-Ζ、つ 缀 /— -^¾0ou"ii WO '§ω T0T)Wi¾J^ ^ / — ^ Δ / ^-Ζ 、 tsu 缀 / —-^ ¾0 ou "ii WO ' § ω T0T) Wi¾J ^
ΐ¾Χ  ΐ¾Χ
(6ΐ呦^
Figure imgf000066_0002
[29 TO] •(Ηΐ 'ω) ε8·6- 08·6 '(Ηΐ 's) 68·8 '(Ηΐ 'ω) 09·8- S'8 '(Ηΐ 'ω) 0Γ8- WT8 '(Ηΐ 's) 29" '(Ηΐ 'ω) S'Z— IS'Z '(Η 'ω) W L-^ L '(Ηΐ '^Η 9·9 = f 'Ρ) 80"Z (6ΐ 呦 ^
Figure imgf000066_0002
[29 TO] • (Ηΐ 'ω) ε8 · 6- 08 · 6' (Ηΐ 's) 68 · 8' (Ηΐ 'ω) 09 · 8- S'8' (Ηΐ 'ω) 0Γ8- WT8' ( Ηΐ 's) 29 "' (Ηΐ 'ω) S'Z— IS'Z' (Η 'ω) W L- ^ L' (Ηΐ '^ Η 9 · 9 = f' Ρ) 80" Z
'(Ηΐ 'ω) 6 — 8ΐ· '(Η9 'ΖΗ 9·9 = f 'Ρ) OS"! ( d) g ( OS 'z 00S) 醒 HT '(Ηΐ' ω) 6 — 8ΐ · '(Η9' Ζ Η 9 · 9 = f 'Ρ) OS "! (D) g (OS' z 00S) Awakening H T
Figure imgf000066_0003
Figure imgf000066_0003
•(HI 's) 6 • (HI 's) 6
8·8 '(Ηΐ 'ω) SL'S-LL'S '(Ηΐ 'ω) ZS'L~9L'L '(Ηΐ 's) 09"Ζ '(Ηΐ 'ω) 8S'Z— SS'Z '(Ηΐ 'ω  8 · 8 '(Ηΐ' ω) SL'S-LL'S '(Ηΐ' ω) ZS'L ~ 9L'L '(Ηΐ' s) 09 "Ζ '(Ηΐ' ω) 8S'Z— SS'Z '(Ηΐ 'ω
) IS'Z— '(Ηΐ 'ω) WL-OVL '(HS 'ω) SS' - 9 '(Ηΐ '^Η ·9 = f 'Ρ) 80"S '(Ηΐ 's jq) Ζ8·ε '(Ηε sz'£ '(Η9 'ΖΗ V9 = f 'ρ) fvi ( a) g (ειつ αつ 'ζ οοε) Η醒 ΗΤ ) IS'Z— '(Ηΐ' ω) WL-OVL '(HS' ω) SS '-9' (Ηΐ '^ Η 9 = f' Ρ) 80 "S '(Ηΐ' s jq) Ζ8 · ε '(Ηε sz' £ '(Η9' Ζ Η V9 = f 'ρ) fvi (a) g ( ε ια α ′ ζ οοε) Awakening Η Τ
。 ( ν呦  . (ν 呦
^^ べ ίί 、 ^( f — S)— 8— — ,^ ci l/ — S—( / -ェ crn^— S)— 9 ΐ¾Χ  ^^ Be ίί, ^ (f — S) — 8— —, ^ ci l / — S— (/-é crn ^ — S) — 9 ΐ¾Χ
^( fi — S)— 8—^^ 、 — Z— — S—( / ェ cm^— S)— 9： 8Tp}% [Ϊ9Ϊ0]
Figure imgf000066_0004
^ (fi — S) — 8 — ^^, — Z— — S— (/ écm ^ — S) — 9: 8Tp}% [Ϊ9Ϊ0]
Figure imgf000066_0004
•(HI 's) 29"8 '(HI 'ZH Γ8 = f TF '(HI 's) 0  • (HI 's) 29 "8' (HI 'ZH Γ8 = f TF' (HI 's) 0
VI '(Ηΐ 'ω) Ϊ2- -8Γ '(HS '^H Γ8 = f erZ-60"Z '(HI 's) 96·9 '(Ηΐ Ί SO'S  VI '(Ηΐ' ω) Ϊ2- -8Γ '(HS' ^ H Γ8 = f erZ-60 "Z '(HI' s) 96 ・ 9 '(Ηΐ Ί SO'S
'(Ηΐ 'ω) ΖΖ' -^Ζ' '(Η9 'ΖΗ ·9 = f 'Ρ) SZ'l ( d) g (^-\DQD 'ζ OLZ) 醒 Ητ '(Ηΐ' ω) ΖΖ '-^ Ζ''(Η9' Ζ Η 9 = f 'Ρ) SZ'l (d) g (^-\ DQD' ζ OLZ) Awakening Η τ
。 (%SS 'S ω ο·38) ΐί¾?^ ^ ^m 、止 s教 ^ ^ ^^^m'B'^ ^ m  . (% SS 'S ω ο · 38) ΐί¾? ^ ^ ^ M, stop suk ^ ^ ^^^ m'B' ^ ^ m
S9 S9
8L£ZU/900Zdr/13d ΐひ I/900Z OAV 42 mg, 1.03 mmol)を加えた後、一酸化炭素雰囲気下、 80 °Cで一晩攪拌した。反応 混合物に水を加え、酢酸ェチルで抽出した後、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。減圧下、溶媒を留去し、残渣を分取薄層クロマトグラフ ィー（酢酸ェチル /へキサン =3/7)で精製することで、 2-イソプロピルァミノ- 7-メトキシ - 6-(2-メチルベンゾィル)キナゾリン（ィ匕合物 A25) (34 mg, 29%)を得た。 8L £ ZU / 900Zdr / 13d ΐ ひ I / 900Z OAV 42 mg, 1.03 mmol) was added, and the mixture was stirred overnight at 80 ° C. in a carbon monoxide atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate / hexane = 3/7) to give 2-isopropylamino-7-methoxy-6- (2 -Methylbenzoyl) quinazoline (Compound A25) (34 mg, 29%) was obtained.
1H NMR (300 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 2.47 (s, 3H), 3.81 (s, 3  1H NMR (300 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 2.47 (s, 3H), 3.81 (s, 3
3  Three
H), 4.25-4.38 (m, 1H), 5.17-5.27 (m, 1H), 6.91 (s, 1H), 7.15-7.23 (m, 1H), 7.25-7. 41 (m, 3H), 7.74 (s, 1H), 8.80 (s, 1H).  H), 4.25-4.38 (m, 1H), 5.17-5.27 (m, 1H), 6.91 (s, 1H), 7.15-7.23 (m, 1H), 7.25-7.41 (m, 3H), 7.74 ( s, 1H), 8.80 (s, 1H).
工程 2  Process 2
化合物 A25を用 、、参考例 16の工程 5と同様の方法で化合物 19を得た。  Compound 19 was obtained in the same manner as in Step 5 of Reference Example 16 using Compound A25.
JH NMR (300 MHz, CDC1 ) δ (ppm) 1.30 (d, J = 6.6 Hz, 6H), 2.33 (s, 3H), 4.27-4.4  JH NMR (300 MHz, CDC1) δ (ppm) 1.30 (d, J = 6.6 Hz, 6H), 2.33 (s, 3H), 4.27-4.4
3  Three
1 (m, 1H), 5.35 (br s, 1H), 6.99 (s, 1H), 7.28-7.38 (m, 3H), 7.41-7.50 (m, 1H), 7.6 7 (s, 1H), 8.67 (s, 1H), 12.24 (s, 1H).  1 (m, 1H), 5.35 (br s, 1H), 6.99 (s, 1H), 7.28-7.38 (m, 3H), 7.41-7.50 (m, 1H), 7.6 7 (s, 1H), 8.67 ( s, 1H), 12.24 (s, 1H).
[0163] 参考例 20： 6-(3-クロ口ベンゾィル )-7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリン（ィ匕 合物 20) [0163] Reference Example 20: 6- (3-Chlorobenzoyl) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 20)
工程 1  Process 1
3-クロロフヱ-ルホウ酸を用い、参考例 19の工程 1と同様の方法で 6-(3-クロ口ベン ゾィル )-2-イソプロピルァミノ- 7-メトキシキナゾリン (ィ匕合物 A26)を得た。  Using 3-chlorophenol-boric acid in the same manner as in Step 1 of Reference Example 19, 6- (3-chlorobenzoyl) -2-isopropylamino-7-methoxyquinazoline (Compound A26) was obtained. It was.
JH NMR (300 MHz, CDC1 ) δ (ppm) 1.32 (d, J = 6.6 Hz, 6H), 3.83 (s, 3H), 4.26-4.4  JH NMR (300 MHz, CDC1) δ (ppm) 1.32 (d, J = 6.6 Hz, 6H), 3.83 (s, 3H), 4.26-4.4
3  Three
0 (m, 1H), 5.26 (br s, 1H), 6.97 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.51-7.57 (m, 1H) , 7.65 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.71 (s, 1H), 7.77 (t, J = 1.8 Hz, 1H), 8.84 (s , 1H).  0 (m, 1H), 5.26 (br s, 1H), 6.97 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.51-7.57 (m, 1H), 7.65 (ddd, J = 7.8 , 1.8, 1.2 Hz, 1H), 7.71 (s, 1H), 7.77 (t, J = 1.8 Hz, 1H), 8.84 (s, 1H).
工程 2  Process 2
化合物 A26を用 、、参考例 16の工程 5と同様の方法でィ匕合物 20を得た。  Compound 20 was obtained in the same manner as in Step 5 of Reference Example 16 using Compound A26.
1H NMR (300 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 4.28-4.42 (m, 1H), 5.3  1H NMR (300 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 4.28-4.42 (m, 1H), 5.3
3  Three
0-5.45 (m, 1H), 7.01 (s, 1H), 7.45-7.65 (m, 3H), 7.68-7.71 (m, 1H), 7.90 (s, 1H), 8 .75 (s, 1H), 11.85 (s, 1H).  0-5.45 (m, 1H), 7.01 (s, 1H), 7.45-7.65 (m, 3H), 7.68-7.71 (m, 1H), 7.90 (s, 1H), 8.75 (s, 1H), 11.85 (s, 1H).
[0164] 参考例 21： 7-ヒドロキシ -2-イソプロピルァミノ- 6-(3-メトキシベンゾィル)キナゾリン（ィ匕 合物 21) [0164] Reference Example 21: 7-Hydroxy-2-isopropylamino-6- (3-methoxybenzoyl) quinazoline Compound 21)
3-メトキシフエ二ルホウ酸を用い、参考例 19の工程 1及び参考例 16の工程 5と同様の 方法で化合物 21を得た。なお本参考例において、キナゾリン 6位の 3-メトキシベンゾィ ルが 3-ヒドロキシベンゾィルに変換されたィ匕合物 22も得られた。  Compound 21 was obtained in the same manner as in Step 1 of Reference Example 19 and Step 5 of Reference Example 16 using 3-methoxyphenylboric acid. In this reference example, Compound 22 in which 3-methoxybenzoyl at the 6-position of quinazoline was converted to 3-hydroxybenzoyl was also obtained.
1H NMR (300 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 3.89 (s, 3H), 4.29-4.4  1H NMR (300 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 3.89 (s, 3H), 4.29-4.4
3  Three
2 (m, 1H), 5.35 (br s, 1H), 7.01 (s, 1H), 7.14-7.25 (m, 3H), 7.46 (t, J = 7.8 Hz, 1H) , 7.99 (s, 1H), 8.75 (s, 1H), 12.01 (s, 1H).  2 (m, 1H), 5.35 (br s, 1H), 7.01 (s, 1H), 7.14-7.25 (m, 3H), 7.46 (t, J = 7.8 Hz, 1H), 7.99 (s, 1H), 8.75 (s, 1H), 12.01 (s, 1H).
[0165] 参考例 22： 7-ヒドロキシ -6-(3-ヒドロキシベンゾィル )-2- (イソプロピルァミノ)キナゾリン [0165] Reference Example 22: 7-Hydroxy-6- (3-hydroxybenzoyl) -2- (isopropylamino) quinazoline
(化合物 22)  (Compound 22)
化合物 22は、参考例 21において化合物 21とともに得られた。  Compound 22 was obtained together with compound 21 in Reference Example 21.
JH NMR (270 MHz, CDC1 ) δ (ppm) 1.30 (d, J = 6.8 Hz, 6H), 4.28-4.43 (m, 1H), 7.0  JH NMR (270 MHz, CDC1) δ (ppm) 1.30 (d, J = 6.8 Hz, 6H), 4.28-4.43 (m, 1H), 7.0
3  Three
0 (s, 1H), 7.09-7.17 (m, 2H), 7.20-7.30 (m, 1H), 7.37-7.47 (m, 1H), 7.97 (s, 1H), 8 .74 (s, 1H), 11.99 (br s, 1H).  0 (s, 1H), 7.09-7.17 (m, 2H), 7.20-7.30 (m, 1H), 7.37-7.47 (m, 1H), 7.97 (s, 1H), 8.74 (s, 1H), 11.99 (br s, 1H).
[0166] 参考例 23： 6- (3-クロ口- 4-フルォロベンゾィル )-7-ヒドロキシ- 2- (イソプロピルァミノ)キ ナゾリン (化合物 23) [0166] Reference Example 23: 6- (3-Chloro-4-fluorobenzoyl) -7-hydroxy-2- (isopropylamino) quinazoline (Compound 23)
3-クロ口- 4-フルオロフヱ-ルホウ酸を用い、参考例 19の工程 1及び参考例 16のェ 程 5と同様の方法でィ匕合物 23を得た。  Compound 23 was obtained in the same manner as in Step 1 of Reference Example 19 and Step 5 of Reference Example 16 by using 3-chloro-4-fluorophenylboric acid.
JH NMR (300 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 4.28-4.42 (m, 1H), 5.3 J H NMR (300 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 4.28-4.42 (m, 1H), 5.3
3  Three
8 (br s, 1H), 7.02 (s, 1H), 7.29-7.37 (m, 1H), 7.57-7.67 (m, 1H), 7.77-7.84 (m, 1H) , 7.89 (s, 1H), 8.76 (s, 1H), 11.73 (s, 1H).  8 (br s, 1H), 7.02 (s, 1H), 7.29-7.37 (m, 1H), 7.57-7.67 (m, 1H), 7.77-7.84 (m, 1H), 7.89 (s, 1H), 8.76 (s, 1H), 11.73 (s, 1H).
[0167] 参考例 24： 6-(3,5-ジメチルベンゾィル )-7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリン [0167] Reference Example 24: 6- (3,5-Dimethylbenzoyl) -7-hydroxy-2- (isopropylamino) quinazoline
(化合物 24)  (Compound 24)
3,5-ジメチルフエ-ルホウ酸を用い、参考例 19の工程 1及び参考例 16の工程 5と同 様の方法で化合物 24を得た。  Compound 24 was obtained in the same manner as in Step 1 of Reference Example 19 and Step 5 of Reference Example 16 using 3,5-dimethylphenolboric acid.
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.30 (d, J = 6.5 Hz, 6H), 2.42 (s, 6H), 4.28—4.4  1H NMR (270 MHz, CDC1) δ (ppm) 1.30 (d, J = 6.5 Hz, 6H), 2.42 (s, 6H), 4.28—4.4
3  Three
2 (m, 1H), 5.28-5.40 (m, 1H), 6.99 (s, 1H), 7.24-7.31 (m, 3H), 7.96 (s, 1H), 8.75 (s , 1H), 12.07 (s, 1H).  2 (m, 1H), 5.28-5.40 (m, 1H), 6.99 (s, 1H), 7.24-7.31 (m, 3H), 7.96 (s, 1H), 8.75 (s, 1H), 12.07 (s, 1H).
[0168] 参考例 25： 6-ベンゾィル -7-ヒドロキシ- 2- [1- (メチルスルホ -ル)ピぺリジン- 4-ィルァ ミノ]キナゾリン (ィ匕合物 25) [0168] Reference Example 25: 6-Benzyl-7-hydroxy-2- [1- (methylsulfol) piperidine-4-ylua Mino] quinazoline (25)
工程 1 Process 1
5-ブロモ -2-フルォロ- 4-メトキシベンズアルデヒド（1 g, 4.3 mmol)、トシル酸一水和 物（163 mg, 0.86 mmol)及びオルトギ酸トリメチル（2.4 mL, 21 mmol)をメタノール（20 mL)に溶解し、加熱還流下 1時間攪拌した。反応混合物を放冷後、トリェチルアミン（ 2 mL)を加え、更に 10分間攪拌した。これに飽和食塩水、酢酸ェチルを加え、有機層 を分離し飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下 、溶媒を留去し、 5-ブロモ -2-フルォ口- 4-メトキシベンズアルデヒドジメチルァセター ル（1.19 g, 100%)を得た。  5-Bromo-2-fluoro-4-methoxybenzaldehyde (1 g, 4.3 mmol), tosylic acid monohydrate (163 mg, 0.86 mmol) and trimethyl orthoformate (2.4 mL, 21 mmol) in methanol (20 mL) And stirred for 1 hour under reflux. The reaction mixture was allowed to cool, triethylamine (2 mL) was added, and the mixture was further stirred for 10 min. To this were added saturated brine and ethyl acetate, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 5-bromo-2-fluorine-4-methoxybenzaldehyde dimethylacetate (1.19 g, 100%).
JH NMR (300 MHz, CDC1 ) δ (ppm) 3.37 (s, 6H), 3.77 (s, 3H), 5.61 (s, IH), 6.69 (d, J H NMR (300 MHz, CDC1) δ (ppm) 3.37 (s, 6H), 3.77 (s, 3H), 5.61 (s, IH), 6.69 (d,
3  Three
J = 11.7 Hz, IH), 7.37 (d, J = 8.4 Hz, IH).  J = 11.7 Hz, IH), 7.37 (d, J = 8.4 Hz, IH).
工程 2 Process 2
5-ブロモ -2-フルォ口- 4-メトキシベンズアルデヒドジメチルァセタール（5 g, 18 mmo 1)を THF (70 mL)に溶解し、 -70 °Cにて 20分間攪拌した。これに- 70 °Cで、 n-ブチル リチウム（1.53 mol/Lへキサン溶液， 15 mL, 23 mmol)をカ卩え、更に 10分間攪拌した。 -70 °Cにて、反応混合物に Ν,Ν-ジメチルベンズアミド（8 g, 53 mmol)の THF溶液（20 mL)を滴下し、更に 20分間攪拌した。反応混合物に水、酢酸ェチルを加え、有機層 を分離し飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、次いで 減圧下、溶媒を留去し、シロップ状の残渣を得た。残渣をアセトン (20 mL)に溶解し、 これにトシル酸一水和物（1.7 g, 8.9 mmol)、をカ卩え、室温にて 30分間攪拌した。これ に飽和重層水、酢酸ェチルを加え、有機層を分離し飽和重層水、飽和食塩水で洗 浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、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（酢酸ェチル /へキサン = 1/4)で精製し、 5-ベンゾ ィル- 2-フルォ口- 4-メトキシベンズアルデヒド（1.6 g, 35%)を得た。  5-Bromo-2-fluorinated 4-methoxybenzaldehyde dimethyl acetal (5 g, 18 mmo 1) was dissolved in THF (70 mL) and stirred at -70 ° C for 20 minutes. To this was added n-butyl lithium (1.53 mol / L hexane solution, 15 mL, 23 mmol) at -70 ° C, and the mixture was further stirred for 10 minutes. A THF solution (20 mL) of Ν, Ν-dimethylbenzamide (8 g, 53 mmol) was added dropwise to the reaction mixture at −70 ° C., and the mixture was further stirred for 20 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a syrupy residue. The residue was dissolved in acetone (20 mL). Tosylic acid monohydrate (1.7 g, 8.9 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Saturated multistory water and ethyl acetate were added thereto, and the organic layer was separated and washed with saturated multistory water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4) to obtain 5-benzoyl-2-fluoro-4-methoxybenzaldehyde (1.6 g, 35%).
1H NMR (270 MHz, CDC1 ) δ (ppm) 3.84 (s, 3H), 6.76 (d, J = 12.2 Hz, IH), 7.43-7. 1H NMR (270 MHz, CDC1) δ (ppm) 3.84 (s, 3H), 6.76 (d, J = 12.2 Hz, IH), 7.43-7.
3  Three
48 (m, 2H), 7.56-7.62 (m, IH), 7.75-7.78 (m, 2H), 7.91 (d, J = 8.1 Hz, IH), 10.2 (s , IH).  48 (m, 2H), 7.56-7.62 (m, IH), 7.75-7.78 (m, 2H), 7.91 (d, J = 8.1 Hz, IH), 10.2 (s, IH).
工程 3 炭酸グァ-ジン（1.6 g, 8.6 mmol) ^DMA(35 mL)に溶解し、 160 °Cにて 20分間攪 拌した。これに 5-ベンゾィル -2-フルォ口- 4-メトキシベンズアルデヒド（1.6 g, 6.2 mmo 1)を加え、更に 50分間攪拌した。反応混合物を放冷後、水、酢酸ェチルを加え、有機 層を分離し水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、溶媒 を留去した。得られた固体をへキサン/ジェチルエーテル（1/1)でリスラリーした。固 体を濾取し、 2-ァミノ- 6-ベンゾィル -7-メトキシキナゾリン（ィ匕合物 A27) (965 mg, 56%) を得た。 Process 3 Dissolved in guanidine carbonate (1.6 g, 8.6 mmol) ^ DMA (35 mL) and stirred at 160 ° C for 20 minutes. To this was added 5-benzoyl-2-fluorine-4-methoxybenzaldehyde (1.6 g, 6.2 mmo 1), and the mixture was further stirred for 50 minutes. The reaction mixture was allowed to cool, water and ethyl acetate were added, and the organic layer was separated and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting solid was reslurried with hexane / jetyl ether (1/1). The solid was collected by filtration to obtain 2-amino-6-benzoyl-7-methoxyquinazoline (Compound A27) (965 mg, 56%).
JH NMR (300 MHz, CDCl ) δ (ppm) 3.84 (s, 3H), 5.27 (br s, 2H), 6.97 (s, IH), 7.43 J H NMR (300 MHz, CDCl) δ (ppm) 3.84 (s, 3H), 5.27 (br s, 2H), 6.97 (s, IH), 7.43
3  Three
-7.48 (m, 2H), 7.56-7.61 (m, IH), 7.73 (s, IH), 7.81-7.83 (m, 2H), 8.90 (s, IH). 工程 4  -7.48 (m, 2H), 7.56-7.61 (m, IH), 7.73 (s, IH), 7.81-7.83 (m, 2H), 8.90 (s, IH). Step 4
化合物 A27及び 1- (メチルスルホ -ル)ピぺリジン- 4-ィルァミンを用い、参考例 1のェ 程 3、 4及び参考例 16の工程 5と同様の方法でィ匕合物 25を得た。  Compound 25 was obtained in the same manner as in Steps 3 and 4 of Reference Example 1 and Step 5 of Reference Example 16 using Compound A27 and 1- (methylsulfol) piperidin-4-ylamine.
JH NMR (300 MHz, CDCl ) δ (ppm) 1.60—1.79 (m, 2H), 2.18—2.33 (m, 2H), 2.84 (s,  JH NMR (300 MHz, CDCl) δ (ppm) 1.60—1.79 (m, 2H), 2.18—2.33 (m, 2H), 2.84 (s,
3  Three
3H), 2.92-3.05 (m, 2H), 3.74—3.83 (m, 2H), 4.13—4.29 (m, IH), 5.42 (br s, IH), 7.0 2 (s, IH), 7.52-7.79 (m, 5H), 8.00 (s, IH), 8.80 (s, IH), 12.06 (s, IH).  3H), 2.92-3.05 (m, 2H), 3.74—3.83 (m, 2H), 4.13—4.29 (m, IH), 5.42 (br s, IH), 7.0 2 (s, IH), 7.52-7.79 ( m, 5H), 8.00 (s, IH), 8.80 (s, IH), 12.06 (s, IH).
[0170] 参考例 26： 6-ベンゾィル -7-ヒドロキシ- 2-(4-テトラヒドロビラ-ルァミノ)キナゾリン（ィ匕 合物 26) [0170] Reference Example 26: 6-Benzyl-7-hydroxy-2- (4-tetrahydrovillaramino) quinazoline (Compound 26)
化合物 A27及び 4-アミノテトラヒドロピランを用い、参考例 1の工程 3、 4及び参考例 1 6の工程 5と同様の方法でィ匕合物 26を得た。  Compound 26 was obtained in the same manner as in Steps 3 and 4 of Reference Example 1 and Step 5 of Reference Example 16 using Compound A27 and 4-aminotetrahydropyran.
1H NMR (300 MHz, CDCl ) δ (ppm) 1.60—1.70 (m, 2H), 2.01—2.21 (m, 2H), 3.52—3.6  1H NMR (300 MHz, CDCl) δ (ppm) 1.60—1.70 (m, 2H), 2.01—2.21 (m, 2H), 3.52—3.6
3  Three
9 (m, 2H), 3.97-4.10 (m, 2H), 4.18-4.37 (m, IH), 5.41 (br s, IH), 7.02 (s, IH), 7.5 1-7.76 (m, 5H), 7.98 (s, IH), 8.76 (s, IH), 12.05 (s, IH).  9 (m, 2H), 3.97-4.10 (m, 2H), 4.18-4.37 (m, IH), 5.41 (br s, IH), 7.02 (s, IH), 7.5 1-7.76 (m, 5H), 7.98 (s, IH), 8.76 (s, IH), 12.05 (s, IH).
[0171] 参考例 27： 2-(trans-4-アミノシクロへキシルァミノ) -6-ベンゾィル - 7-ヒドロキシキナゾ リン (化合物 2ァ） [0171] Reference Example 27: 2- (trans-4-aminocyclohexylamino) -6-benzoyl-7-hydroxyquinazoline (compound 2a)
化合物 A27及び trans-1,4-ジアミノシクロへキサンを用い、参考例 1の工程 3、 4及び 参考例 16の工程 5と同様の方法でィ匕合物 27を得た。  Compound 27 was obtained in the same manner as in Steps 3 and 4 of Reference Example 1 and Step 5 of Reference Example 16 using Compound A27 and trans-1,4-diaminocyclohexane.
JH NMR (300 MHz, DMSO— d ) δ (ppm) 1.29—1.51 (m, 4H), 1.90—2.07 (m, 4H), 2.88 J H NMR (300 MHz, DMSO— d) δ (ppm) 1.29—1.51 (m, 4H), 1.90—2.07 (m, 4H), 2.88
6  6
-3.00 (m, IH), 3.75-3.90 (m, IH), 6.78 (s, IH), 7.50-7.60 (m, 2H), 7.60-7.70 (m, 1 H), 7.71-7.78 (m, 2H), 7.89 (s, 1H), 8.96 (s, 1H). -3.00 (m, IH), 3.75-3.90 (m, IH), 6.78 (s, IH), 7.50-7.60 (m, 2H), 7.60-7.70 (m, 1 H), 7.71-7.78 (m, 2H), 7.89 (s, 1H), 8.96 (s, 1H).
[0172] 参考例 28： 6-ベンゾィル -2-(2,6-ジメチルァ-リノ) -7-ヒドロキシキナゾリン（ィ匕合物 28 ) [0172] Reference Example 28: 6-Benzyl-2- (2,6-dimethylalino) -7-hydroxyquinazoline (Compound 28)
化合物 A27 (201 mg, 0.72 mmol)をジォキサン（7.2 mL)に溶解し、 2,6-ジメチルョー ドベンゼン（110 μし, 0.79 mmol) ,トリス (ジベンジリデンアセトン)ジパラジウム（32.9 m g, 0.036 mmol)、 9,9-ジメチル- 4,5-ビス (ジフエ-ルホスフイノ)キサンテン（46 mg, 0.0 79 mmol)及び炭酸セシウム（328 mg, 1.01 mmol)をカ卩えた後、 100 °Cで 22時間攪拌 した。反応混合物に水を加え、酢酸ェチルで抽出した後、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。減圧下、溶媒を留去し、残渣を分取薄層ク 口マトグラフィー（酢酸ェチル /へキサン =4/6)で精製することで 6-ベンゾィル - 2-(2,6 -ジメチルァ-リノ) -7-メトキシキナゾリン（161 mg, 59%)を得た。得られた 6-ベンゾィル - 2-(2,6-ジメチルァ-リノ) -7-メトキシキナゾリンを用い、参考例 16の工程 5と同様の方 法で化合物 28を得た。  Compound A27 (201 mg, 0.72 mmol) was dissolved in dioxane (7.2 mL), 2,6-dimethyldobenzene (110 μ, 0.79 mmol), tris (dibenzylideneacetone) dipalladium (32.9 mg, 0.036 mmol), After 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (46 mg, 0.0 79 mmol) and cesium carbonate (328 mg, 1.01 mmol) were collected, the mixture was stirred at 100 ° C. for 22 hours. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate / hexane = 4/6) to give 6-benzoyl-2- (2,6-dimethylarino) -7-methoxyquinazoline (161 mg, 59%) was obtained. Using the obtained 6-benzoyl-2- (2,6-dimethylamino) -7-methoxyquinazoline, compound 28 was obtained in the same manner as in Step 5 of Reference Example 16.
JH NMR (300 MHz, CDC1 ) δ (ppm) 2.28 (s, 6H), 6.88 (br s, 1H), 7.02 (s, 1H), 7.16 J H NMR (300 MHz, CDC1) δ (ppm) 2.28 (s, 6H), 6.88 (br s, 1H), 7.02 (s, 1H), 7.16
3  Three
-7.20 (m, 3H), 7.52-7.76 (m, 5H), 8.02 (s, 1H), 8.84 (s, 1H), 11.97 (s, 1H).  -7.20 (m, 3H), 7.52-7.76 (m, 5H), 8.02 (s, 1H), 8.84 (s, 1H), 11.97 (s, 1H).
[0173] 参考例 29： 2-ァ-リノ- 7-ヒドロキシ- 6-(2-メチルフエ-ル)キナゾリン（化合物 29) [0173] Reference Example 29: 2-Alino-7-hydroxy-6- (2-methylphenol) quinazoline (Compound 29)
工程 1  Process 1
化合物 A2及び 2-メチルフエ-ルホウ酸を用 、、参考例 1の工程 5と同様の方法で 2- ァミノ- 7-メトキシ- 6- (2-メチルフエ-ル)キナゾリン (ィ匕合物 A28)を得た。  Using compound A2 and 2-methylphenol boric acid, 2-amino-7-methoxy-6- (2-methylphenol) quinazoline (Compound A28) was prepared in the same manner as in Step 5 of Reference Example 1. Obtained.
工程 2  Process 2
化合物 A28 (150 mg, 0.565 mmol)をジォキサン（5.7 mL)に溶解し、ョードベンゼン（ 70 μ L, 0.622 mmol)、トリス (ジベンジリデンアセトン)ジパラジウム（25.9 mg, 0.028 m mol)、 9,9-ジメチル- 4,5-ビス (ジフエ-ルホスフイノ)キサンテン（36 mg, 0.062 mmol) 及び炭酸セシウム（258 mg, 0.791 mmol)を加えた後、 100 °Cで 20時間攪拌した。反 応混合物に水を加え、酢酸ェチルで抽出した後、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。減圧下、溶媒を留去し、残渣を分取薄層クロマトグ ラフィー（酢酸ェチル /へキサン =3/7)で精製することで 2-ァ-リノ- 7-メトキシ -6-(2- メチルフエ-ル)キナゾリン（ィ匕合物 A29) (164 mg, 85%)を得た。得られた化合物 A29 •Ζ '(Ηΐ 'ω) Z'L-6VL '(Ηΐ '^Η 6"Ζ = f ΟΖΊ '{ΗΖ 'ω) 20"Z-S6"9 '(Ηΐ ε8·9 '(Η ΐ 'ω) 9Γ9— 0 9 '(Ηΐ 'ω) 80^-26"S '(Η2 'ω) 09·ε— 8 ·ε '(Η2 'ω) 66 —98 '(HS 's) 68 '(Η2 'ω) 90 — S6'I ΗΖ 'ω) 89·ΐ— IS'I ( d) g ( OS 'z 00S) 醒 HT Compound A28 (150 mg, 0.565 mmol) was dissolved in dioxane (5.7 mL), and ododobenzene (70 μL, 0.622 mmol), tris (dibenzylideneacetone) dipalladium (25.9 mg, 0.028 mmol), 9,9- Dimethyl-4,5-bis (diphenylphosphino) xanthene (36 mg, 0.062 mmol) and cesium carbonate (258 mg, 0.791 mmol) were added, followed by stirring at 100 ° C. for 20 hours. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate / hexane = 3/7) to give 2-amino-7-methoxy-6- (2-methylphenol). (1) Quinazoline (Compound A29) (164 mg, 85%) was obtained. The obtained compound A29 • Ζ '(Ηΐ' ω) Z'L-6VL '(Ηΐ' ^ Η 6 "Ζ = f ΟΖΊ '{ΗΖ' ω) 20" Z-S6 "9 '(Ηΐ ε8 · 9' (Η ΐ 'ω ) 9Γ9— 0 9 '(Ηΐ' ω) 80 ^ -26 "S '(Η2' ω) 09 · ε— 8 · ε '(Η2' ω) 66 —98 '(HS' s) 68 '(Η2' ω) 90 — S6'I ΗΖ 'ω) 89 · ΐ— IS'I (d) g (OS' z 00S) Awakening H T
。 οε呦^ 翁^; 9 ェ Q) \ \ \ ^zzv ^  . οε 呦 ^ 翁 ^; 9 d Q) \ \ \ ^ zzv ^
•(HI 's) W6 '(Ηΐ 's) Ζ6·8 '(Ηΐ ' s) 99"Z '(Ηΐ 'ω) 2^ -ΐε· '(Ηΐ 'ΖΗ ΐ·8 = f Ϊ2" '(HS 'ω) S6'9— 88·9 '(Ηΐ 'ω) 8Ζ- 9- ΪΓ9 '(Ηΐ 's -iq) 90·， '(HS 's) 68·ε '(Η2 'ω) S9'S- OS'S '(Η2 'ω) 00·ε- 06 '(HS 's) 68 '(Η2 'ω) ΐΐ - 96·ΐ ΗΖ 'ω) 0Z"T-2S"T ( d) ρ ( OS 'z 00S) 醒 Ητ • (HI 's) W6' (Ηΐ 's) Ζ6 · 8' (Ηΐ ' s ) 99 "Z' (Ηΐ 'ω) 2 ^ -ΐε ·' (Ηΐ 'ΖΗ ΐ · 8 = f Ϊ2"' ( HS 'ω) S6'9— 88 · 9' (Ηΐ 'ω) 8Ζ- 9- ΪΓ9' (Ηΐ 's -iq) 90 ·,' (HS 's) 68 · ε' (Η2 'ω) S9'S- OS'S '(Η2' ω) 00 · ε- 06 '(HS' s) 68 '(Η2' ω) ΐΐ-96 · ΐ ΗΖ 'ω) 0Z "T-2S" T (d) ρ (OS' z 00S Awakening Η τ
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Figure imgf000072_0004
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( / ^ )- ΐ、つ 缀コ）（TU O'DdViQ^ (louiui 6ε·ΐ '§ω 60S) SVi¾J^ (/ ^)-ΐ 、 つ 缀 コ） （TU O'DdViQ ^ (louiui 6ε · ΐ ' § ω 60S) SVi¾J ^
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Figure imgf000072_0005
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Be ίί, ^ ^-Be; ^ ri (-^)-ΐ]-s-(é ^^,-ε)-9-^^,-ζ: osp}% [^ ΪΟ]
"(Ηΐ 's) ΗΖ 'ω) 98"Ζ-8Ζ"Ζ '(Ηΐ 's) IS'Z '(Η9 'ω)„·Ζ- Ζ '(Ηΐ 's) Ζ '(Ηΐ 'ω) Ir -20" '(HS 's) OS ( d) g (¾χΐつ 'ζ LZ) 醒 Ητ "(Ηΐ 's) ΗΖ' ω) 98" Ζ-8Ζ "Ζ '(Ηΐ' s) IS'Z '(Η9' ω)„ · Ζ- Ζ '(Ηΐ' s) Ζ '(Ηΐ' ω) Ir -20 "'(HS' s) OS (d) g (¾χΐ つ ' ζ LZ) Awakening Η τ
U U
8L£ZU/900Zdr/13d ΐひ I/900Z OAV 64 (s, 1H), 8.90 (s, 1H). 8L £ ZU / 900Zdr / 13d ΐ ひ I / 900Z OAV 64 (s, 1H), 8.90 (s, 1H).
[0176] 参考例 31： 7-ヒドロキシ -2-イソプロピルァミノ- 6-(3--トロフエ-ル)キナゾリン（化合物 31) [0176] Reference Example 31: 7-hydroxy-2-isopropylamino-6- (3-trophenyl) quinazoline (Compound 31)
工程 1  Process 1
化合物 A1 (35.0 g, 150.4 mmol)を DMF(250 mL)に溶解し、塩化リチウム（19.1 g, 4 51 mmol)を加えた後、 140 °Cで 3時間攪拌した。反応混合物に水を加え、酢酸ェチ ルで抽出し、得られた水層に 2 mol/L塩酸を加え、 pH4程度に調節した。水層を酢酸 ェチルで抽出し、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧 下、溶媒を留去し、 5-ブロモ -2-フルォロ- 4-ヒドロキシベンズアルデヒド（ィ匕合物 A33) (27.1 g, 82%)を得た。  Compound A1 (35.0 g, 150.4 mmol) was dissolved in DMF (250 mL), lithium chloride (19.1 g, 4 51 mmol) was added, and the mixture was stirred at 140 ° C. for 3 hr. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and 2 mol / L hydrochloric acid was added to the resulting aqueous layer to adjust the pH to about 4. The aqueous layer was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-bromo-2-fluoro-4-hydroxybenzaldehyde (Compound A33) (27.1 g, 82%).
JH NMR (300 MHz, CDC1 ) δ (ppm) 6.85 (d, J = 11.4 Hz, 1H), 7.42 (br s, 1H), 8.03 J H NMR (300 MHz, CDC1) δ (ppm) 6.85 (d, J = 11.4 Hz, 1H), 7.42 (br s, 1H), 8.03
3  Three
(d, J = 6.9 Hz, 1H), 10.15 (s, 1H).  (d, J = 6.9 Hz, 1H), 10.15 (s, 1H).
工程 2  Process 2
化合物 A33 (13.5 g, 62 mmol)を DMF (123 mL)に溶解し、炭酸カリウム（17.1 g, 124 mmol)及びベンジルブロミド（11 mL, 93 mmol)をカ卩えた後、室温で 2時間攪拌した。 反応混合物に水を加え、酢酸ェチルで抽出した後、有機層を水、飽和食塩水で洗 浄し、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、残渣をへキサンで リスラリーすることで 4-ベンジルォキシ- 5-ブロモ -2-フルォロベンズアルデヒド（ィ匕合 物 A34) (14.8 g, 78%)を得た。  Compound A33 (13.5 g, 62 mmol) was dissolved in DMF (123 mL), potassium carbonate (17.1 g, 124 mmol) and benzyl bromide (11 mL, 93 mmol) were added, and the mixture was stirred at room temperature for 2 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was reslurried with hexane to obtain 4-benzyloxy-5-bromo-2-fluorobenzaldehyde (Compound A34) (14.8 g, 78%).
1H NMR (270 MHz, CDC1 ) δ (ppm) 5.22 (s, 2H), 6.72 (d, J = 11.9 Hz, 1H), 7.32-7.  1H NMR (270 MHz, CDC1) δ (ppm) 5.22 (s, 2H), 6.72 (d, J = 11.9 Hz, 1H), 7.32-7.
3  Three
50 (m, 5H), 8.08 (d, J = 7.6 Hz, 1H), 10.15 (s, 1H).  50 (m, 5H), 8.08 (d, J = 7.6 Hz, 1H), 10.15 (s, 1H).
[0177] 工程 3 [0177] Step 3
化合物 A34を用い、参考例 1の工程 2と同様の方法で 7-ベンジルォキシ -6-ブロモ- 2-アミノキナゾリン (ィ匕合物 A35)を得た。  Using Compound A34, 7-benzyloxy-6-bromo-2-aminoquinazoline (Compound A35) was obtained in the same manner as in Step 2 of Reference Example 1.
1H NMR (270 MHz, CDC1 ) δ (ppm) 5.13 (br s, 2H), 5.26 (s, 2H), 6.98 (s, 1H), 7.27  1H NMR (270 MHz, CDC1) δ (ppm) 5.13 (br s, 2H), 5.26 (s, 2H), 6.98 (s, 1H), 7.27
3  Three
-7.53 (m, 5H), 7.92 (s, 1H), 8.82 (s, 1H).  -7.53 (m, 5H), 7.92 (s, 1H), 8.82 (s, 1H).
工程 4  Process 4
化合物 A35 (5.0 g, 15.1 mmol)を DMF(150 mL)に溶解し、 5 °Cに冷却後、水素化 (szv ^)ベ ίί、 ^ (,^ )- 、^： べ:^- z -( ェ , ^ - ε) - 9、 ¾^ a> fM^ e¾x Q) ΐ P}% \ \ ¾f ¾邈 -ェ , ^ - ε、 ¾ ν呦 Compound A35 (5.0 g, 15.1 mmol) was dissolved in DMF (150 mL), cooled to 5 ° C, and then hydrogenated. (szv ^) Be ίί 、 ^ (, ^)-、 ^ ： Be: ^-z-(ee, ^-ε)-9, ¾ ^ a> fM ^ e¾x Q) ΐ P}% \ \ ¾f ¾ 邈-, ^-Ε, ¾ ν 呦
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9¾Χ  9¾Χ
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'(Ηΐ 'ΖΗ ΐ·8 = f 9S"Z '(HS 'ω) VL-9Z'L '(Ηΐ 's) ΐΓΖ '(Η2 Z' '(Ηΐ 's -iq) 8 re '(HI 'ω) 6ε·— 9 '(Η9 'ΖΗ ε·9 = f 'ρ) ΖΖΊ ( a) g (ειつ αつ 'ζ οοε) Η醒 ΗΤ '(Ηΐ' ΖΗ ΐ · 8 = f 9S "Z '(HS' ω) VL-9Z'L '(Ηΐ' s) ΐΓΖ '(Η2 Z''(Ηΐ' s -iq) 8 re '(HI' ω) 6ε · — 9 '(Η9' Ζ ε ε9 = f 'ρ) ΖΖΊ (a) g ( ε ια α ′ ζ οοε) Awakening Η Τ
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O'S '(Ηΐ 'ω) εε·— 8ΐ· '(Η9 'ΖΗ S'9 = f 'Ρ) 62"ΐ ( d) g ( 3Q0 'z O S) 醒 HT O'S '(Ηΐ' ω) εε · — 8ΐ · '(Η9' Ζ Η S'9 = f 'Ρ) 62 "ΐ (d) g (3Q0' z OS) Awakening H T
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= f 'Ρ) fV9 '(HZ <s) S '(Ηΐ 'ZH 8·9 = f 'Ρ) S8' '(Ηΐ '^Η ·9 '8·9 = f ' ρ = f 'Ρ) fV9' (HZ <s ) S '(Ηΐ' ZH 8 · 9 = f 'Ρ) S8''(Ηΐ' ^ Η 9 '8 · 9 = f' ρ
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•(HI 's) f6'S '(HI 's) Z9'L '(Η9 'ω) qVLSZ'L '(HI '^H S'Z = Γ?) Z  • (HI 's) f6'S' (HI 's) Z9'L' (Η9 'ω) qVLSZ'L' (HI '^ H S'Z = Γ?) Z
VL '(HI 'ZH S'Z 'Ζ·Ζ = f 'PP) S0"Z '(HI 's) 86·9 '(Ηΐ 'ω) 6 ·9- ·9 '(Ηΐ '^Η Ζ' L = f 'Ρ) 0Γ9 '(Ηΐ 'ω) SS'9— ¾·9 '(Η2 SZ' '(Ηΐ '^Η Ζ·9 = f 'Ρ) ZO'S '(Ηΐ '^Η 9·9 'Ζ •9 = f ' deqp) 8ΐ· '(Η9 'ΖΗ 9·9 = ΓΡ) 6ΐ·ΐ ( d) g ( 〇S 'z 00S) 醒 Ητ L VL '(HI' ZH S'Z 'Ζ · Ζ = f' PP) S0 "Z '(HI' s) 86 · 9 '(Ηΐ' ω) 6 9- 9 '(Ηΐ' ^ Η Ζ ' L = f 'Ρ) 0Γ9' (Ηΐ 'ω) SS'9— ¾ · 9' (Η2 SZ '' (Ηΐ '^ Η Ζ · 9 = f' Ρ) ZO'S '(Ηΐ' ^ Η 9 · 9 ' Ζ • 9 = f 'deqp) 8ΐ ·' (Η9 'Ζ Η 9 · 9 = ΓΡ) 6ΐ · ΐ (d) g ( 〇_S' z 00S) Awakening: Η τ L
8L£ZU/900Zdr/13d ΐひ I/900Z OAV 化合物 A39 (200 mg, 0.502 mmol)及び無水酢酸（237 μ L, 2.51 mmol)を塩化メチ レン（2 mL)に溶解し、トリェチルァミン（70.0 μ L, 0.502 mmol)をカロえ、室温にて 1時 間攪拌した。反応混合物に飽和食塩水、クロ口ホルムを加え、有機層を分離し飽和 食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下、溶媒を 留去した。残渣を分取薄層クロマトグラフィー（クロ口ホルム/メタノール =9/1)で精製 し、 6-(5-ァセチルァミノ- 2-メチルフエ-ル)- 7-ベンジルォキシ- 2- (イソプロピルアミノ )キナゾリン（ィ匕合物 A40) (82 mg, 0.186 mmol)を得た。 8L £ ZU / 900Zdr / 13d ΐ ひ I / 900Z OAV Compound A39 (200 mg, 0.502 mmol) and acetic anhydride (237 μL, 2.51 mmol) are dissolved in methylene chloride (2 mL), and triethylamine (70.0 μL, 0.502 mmol) is added to the mixture. Stir for a while. To the reaction mixture were added saturated brine and chloroform, and the organic layer was separated and washed with saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (black form / methanol = 9/1) to give 6- (5-acetylamino-2-methylphenol) -7-benzyloxy-2- (isopropylamino) quinazoline (I Compound A40) (82 mg, 0.186 mmol) was obtained.
工程 3 Process 3
化合物 A40を用い、参考例 32の工程 2と同様の方法でィ匕合物 33を得た。  Compound 33 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A40.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.19 (d, J = 6.6 Hz, 6H), 2.02 (s, 3H), 2.05 ( JH NMR (270 MHz, DMSO— d) δ (ppm) 1.19 (d, J = 6.6 Hz, 6H), 2.02 (s, 3H), 2.05 (
6  6
s, 3H), 4.16 (dhept, J = 8.3, 6.6 Hz, IH), 6.83 (s, IH), 7.00 (d, J = 8.3 Hz, IH), 7.1 5 (d, J = 8.1 Hz, IH), 7.39-7.47 (m, 3H), 8.85 (s, IH), 9.87 (s, IH), 10.41 (s, IH). 参考例 34： 7-ヒドロキシ -2-イソプロピルァミノ- 6-{3-[(2-モルホリノピリジン- 4-ィル)力 ルポ-ルァミノ]フエ-ル}キナゾリン (ィ匕合物 34) s, 3H), 4.16 (dhept, J = 8.3, 6.6 Hz, IH), 6.83 (s, IH), 7.00 (d, J = 8.3 Hz, IH), 7.1 5 (d, J = 8.1 Hz, IH) , 7.39-7.47 (m, 3H), 8.85 (s, IH), 9.87 (s, IH), 10.41 (s, IH). Reference Example 34: 7-hydroxy-2-isopropylamino-6- {3- [(2-Morpholinopyridine-4-yl) force Lololamino] Ferl} quinazoline (Compound 34)
工程 1 Process 1
2-クロ口イソニコチン酸（300 mg, 1.91 mmol)、炭酸カリウム（790 mg, 5.72 mmol)及 びヨウ化メチル（360 μ L, 5.72 mmol)を DMF (4.5 mL)に溶解し、室温にて 4時間攪拌 した。反応混合物に飽和食塩水、酢酸ェチルを加え、有機層を分離し、飽和食塩水 で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下、溶媒を留去し、 2-ク ロロイソニコチン酸メチルエステル（320 mg, 98%)を得た。  2-Black mouth isonicotinic acid (300 mg, 1.91 mmol), potassium carbonate (790 mg, 5.72 mmol) and methyl iodide (360 μL, 5.72 mmol) were dissolved in DMF (4.5 mL) at room temperature. Stir for 4 hours. Saturated brine and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-chloroisonicotinic acid methyl ester (320 mg, 98%).
1H NMR (300 MHz, CDCl ) δ (ppm) 3.98 (s, 3H), 7.77 (d, J = 4.8 Hz, IH), 7.89 (s, 1  1H NMR (300 MHz, CDCl) δ (ppm) 3.98 (s, 3H), 7.77 (d, J = 4.8 Hz, IH), 7.89 (s, 1
3  Three
H), 8.55 (d, J = 6.4 Hz, IH).  H), 8.55 (d, J = 6.4 Hz, IH).
工程 2 Process 2
2-クロ口イソニコチン酸メチルエステル（320 mg, 1.89 mmol)をモルホリン（5 mL)に 溶解し、 90 °Cにて 4時間攪拌した。反応混合物に飽和食塩水、酢酸ェチルを加え、 有機層を分離し飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、 減圧下、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（酢酸ェチル /へ キサン = 1/4)にて精製し、 2-モルホリノイソニコチン酸メチルエステル（50 mg, 98%)を 99"Ζ '(Η9 'ω) ΖΥΙ- τΐ '(Ηΐ '^Η I 'Ο'ΐε = f 'ΡΡ) 66·9 '(Ηΐ Ζ8·9 '(Ηΐ 'ω) IZ'f 2-Black-mouthed isonicotinic acid methyl ester (320 mg, 1.89 mmol) was dissolved in morpholine (5 mL) and stirred at 90 ° C for 4 hours. To the reaction mixture were added saturated brine and ethyl acetate, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4) and 2-morpholinoisonicotinic acid methyl ester (50 mg, 98%) was purified. 99''Ζ '(Η9' ω) ΖΥΙ- τΐ '(Ηΐ' ^ Η I 'Ο'ΐε = f' ΡΡ) 66 · 9 '(Ηΐ Ζ8 · 9' (Ηΐ 'ω) IZ'f
-fVf '(Η9 's) Ζ6 '(Η9 'ΖΗ ·9 = ΓΡ) 6ΐ·ΐ ( d) g ( OS 'z LZ) 醒 Ητ -fVf '(Η9' s) Ζ6 '(Η9' Ζ Η9 = ΓΡ) 6ΐ · ΐ (d) g (OS 'z LZ) Awakening Η τ
。 呦^ 翁^^ ェ(^
Figure imgf000077_0001
： esp}% [mo] .呦 ^ 翁 ^^
Figure imgf000077_0001
: Esp}% [mo]
•(HI 's) 63 ΐ '(Ηΐ 's) 8ε·0ΐ '(Ηΐ 06·8 '(Ηΐ '^Η 0 •S = f 'Ρ) 6Z'S '(Ηΐ 's) 96"Ζ '(Ηΐ '^Η 8"Ζ = f 'Ρ) 9ΓΖ '(Ηΐ 99· '(Ηΐ '^Η 8"Ζ '6"Ζ  • (HI 's) 63 ΐ' (Ηΐ 's) 8ε · 0ΐ' (Ηΐ 06 ・ 8 '(Ηΐ' ^ Η 0 • S = f 'Ρ) 6Z'S' (Ηΐ 's) 96 "Ζ' (Ηΐ '^ Η 8 "Ζ = f' Ρ) 9ΓΖ '(Ηΐ 99 ·' (Ηΐ '^ Η 8" Ζ' 6 "Ζ
= f 'ΡΡ) 2^" '(Ηΐ 'ΖΗ 6"Ζ = f 'Ρ) SS- '(Ηΐ L 'L '(Ηΐ '^Η O'S = f 'Ρ) fVL '(Ηΐ  = f 'ΡΡ) 2 ^ "' (Ηΐ 'ΖΗ 6" Ζ = f' Ρ) SS- '(Ηΐ L' L '(Ηΐ' ^ Η O'S = f 'Ρ) fVL' (Ηΐ
'ΖΗ 6"Ζ = f 'Ρ) 30"Ζ '(Ηΐ 's) 98·9 '(Ηΐ 'ω) ZZ' -W '(Hf '^Η 6· = f ' ) '(Η ' Ζ Η 6 "Ζ = f' Ρ) 30" Ζ '(Ηΐ' s) 98 · 9 '(Ηΐ' ω) ZZ '-W' (Hf '^ Η 6 · = f') '(Η
'ΖΗ 9· = f ·ε '(Η9 'ΖΗ 9·9 = ΓΡ) 6ΐ·ΐ ( d) g (9ρ―。 SW。 'z 00S) 醒 HT 'ΖΗ 9 · = f · ε' (Η9 ' Ζ Η 9 · 9 = ΓΡ) 6ΐ · ΐ (d) g ( 9 ρ―. SW.' Z 00S) Awakening H T
。 ε呦^ 翁^; s :r )^i^ 拳 w^zw ^  . ε 呦 ^ 翁 ^; s: r) ^ i ^ fist w ^ zw ^
e¾x  e¾x
°-Μ (sw呦^ べ fi 、 { -ェ ^  ° -Μ (sw 呦 ^ be fi, {-
/ ( / - べ , ίί s)]- ε}- 9- ci i - 、^： べ:^- ζ  / (/-Be, ίί s)]-ε}-9- ci i-, ^: be: ^-ζ
•(HI 'ZH V9 = f 'P) 62"8 '(HI 's) 5ΓΖ '(HI '^H 8· = f• (HI 'ZH V9 = f' P) 62 "8 '(HI' s) 5ΓΖ '(HI' ^ H 8 · = f
'ρ) 06·9 'ω) ε6·ε- 88·ε '(H 'ω) ε9·ε— ss's ( a) g (ειつ αつ 'ζ οοε) Η醒 ΗΤ 'ρ) 06 · 9' ω) ε6 · ε- 88 · ε '(H' ω) ε9 · ε— ss's (a) g ( ε ια α ′ ζ οοε) Awakening Η Τ
。
Figure imgf000077_0002
、つ辛爵¾瀚缀、止 m ^ ^^^^^mw ^ ^。 氺っ鑭 ¾»斜萆 ui 9) /— ^ （IOUIUI go '§ω ） エ ^ 濯べ , fi S .
Figure imgf000077_0002
, Spicy ¾ 瀚 缀, stop m ^ ^^^^ mm ^ ^. ¾ 鑭 »» 9) / — ^ (IOUIUI go '§ω) d ^ Rinse, fi S
2¾ェ [S8I0] 2¾ [S8I0]
•(HI 'ZH V9 = f 'Ρ) 0ε·8 '(Ηΐ 's) 8ΓΖ '(Ηΐ '^Η 8· = f 'Ρ) 9ΓΖ '(HS • (HI 'ZH V9 = f' Ρ) 0ε · 8 '(Ηΐ' s) 8ΓΖ '(Ηΐ' ^ Η 8 · = f 'Ρ) 9ΓΖ' (HS
's) ε6·ε 'ω) ssx-ssx 'ω) sex-eex ( a) g (ειつ αつ 'ζ οοε) Η醒 ΗΤ 's) ε6 · ε' ω) ssx-ssx 'ω) sex-eex (a) g ( ε ια α ′ ζ οοε) Awakening Η Τ
9L 9L
8ί£ΖΙ£/900Ζάΐ/13ά \Z LZ\l9mi OAV kつ辛爵 瀚缀止 s教
Figure imgf000078_0001
06·τ ' 8 )呦 n^Z'^^ 、つ鼸疆^ m Οΐ) — ^¾OOUIUI SIS'O '§ω fZ) SWi¾J^^ 8ί £ ΖΙ £ / 900Ζάΐ / 13ά \ Z LZ \ l9mi OAV k
Figure imgf000078_0001
06 · τ '8) 呦 n ^ Z' ^^, 鼸 疆 鼸 疆 ^ m Οΐ) — ^ ¾OOUIUI SIS'O ' § ω fZ) SWi¾J ^^
2¾ェ [9810] 2¾ [9810]
•(HI 's) 96·8 '(Ηΐ 'ω) IS'8 '(Ηΐ 'ω) 02"8 '(Ηΐ 'ω) 06"Ζ '(Η ΐ 's) 89· '(Ηΐ 'ΖΗ 6"Ζ 'ΐ·8 = f 'ΡΡ) 9S"Z '(HS 'ω) ZS"Z-0S"Z '(HS 'ω) 6ΓΖ '(Ηΐ 'ω) • (HI 's) 96 · 8' (Ηΐ 'ω) IS'8' (Ηΐ 'ω) 02 "8' (Ηΐ 'ω) 06" Ζ' (Η ΐ 's) 89 ·' (Ηΐ 'ΖΗ 6 "Ζ 'ΐ · 8 = f' ΡΡ) 9S" Z '(HS' ω) ZS "Z-0S" Z '(HS' ω) 6ΓΖ '(Ηΐ' ω)
60"Ζ '(Ηΐ 's -iq) SS'S '(Η2 9Γ3 '(Η 9 's) \Ζ'Ζ ( d) g (¾χΐつ 'ζ LZ) 醒 Ητ 60 "Ζ '(Ηΐ' s -iq) SS'S '(Η2 9Γ3' (Η 9 ' s ) \ Ζ'Ζ (d) g (¾χΐ つ' ζ LZ) Awakening Η τ
。 (SW呦^ . (SW 呦 ^
] ベ fi、 ^ ( -ェ cH - ε)- 9- (,fi- ^ - 9 - 、^： べ:^- ¾
Figure imgf000078_0002
] Be fi, ^ (-e cH-ε)-9- (, fi- ^-9-, ^: Be: ^-¾
Figure imgf000078_0002
ZW  ZW
•(HI 's) 6·8 '(Ηΐ 'ω) ¾·8 '(Η ΐ 'ω) IZS '(Ηΐ 'ω) WL '(Ηΐ 's) 69"Ζ '(Ηΐ '^Η 6"Ζ '6"Ζ = f 'ΡΡ) 8S"Z '(HS 'ω) LZ' L- ZZ'L '(Ηΐ 's) ΟΓΖ '(Η2 S HZ 's OS'S ( d) g ( 3Q0 'z O S) 醒 HT • (HI 's) 6 · 8' (Ηΐ 'ω) ¾ · 8' (Η ΐ 'ω) IZS' (Ηΐ 'ω) WL' (Ηΐ 's) 69 "Ζ' (Ηΐ '^ Η 6" Ζ '6 "Ζ = f' ΡΡ) 8S" Z '(HS' ω) LZ 'L- ZZ'L' (Ηΐ 's) ΟΓΖ' (Η2 S HZ ' s OS'S (d) g (3Q0' z OS Awakening H T
(fW(^^)ベ fi、 ^( / -ェ cH-- ε)- 9- 、^： べ:^- ,^ ΐ¾Χ  (fW (^^) be fi, ^ (/ -e cH-- ε)-9-, ^: be: ^-, ^ ΐ¾Χ
(ζε呦^ べ ίί、 ^：{ ェ [ ^ - / （  (ζε 呦 ^ be ίί, ^: {ew [^-/ (
•(HI 's) ΖΖ·6 '(Ηΐ 's) 88·8 '(Ηΐ S6"Z • (HI 's) ΖΖ · 6' (Ηΐ 's) 88 · 8' (Ηΐ S6 "Z
'(Ηΐ 's) 08· ΗΖ 'ω) 29"Z-8S"Z '(Ηΐ '^Η S'Z 'Ζ·Ζ = f 'ΡΡ) Ζ '(Ηΐ '^Η Ζ·Ζ = f 'Ρ) 7 L '(Ηΐ 'ΖΗ S'Z = f 'Ρ) WL '(Ηΐ 8·9 '(Ηΐ 'ω) ZZ^-OV '(Η 'ω) — 60 '(Ηΐ' s) 08 · ΗΖ 'ω) 29 "Z-8S" Z' (Ηΐ '^ Η S'Z' Ζ · Ζ = f 'ΡΡ) Ζ' (Ηΐ '^ Η Ζ · Ζ = f' L) 7 L '(Ηΐ' ΖΗ S'Z = f 'Ρ) WL' (Ηΐ 8 · 9 '(Ηΐ' ω) ZZ ^ -OV '(Η' ω) — 60
'(HS 'ω) 66·ΐ- 6Γΐ '(Η9 'ΖΗ 9·9 = ΓΡ) 6ΐ·ΐ ( d) g ( OS 'z 00S) 醒 Ητ '(HS' ω) 66 · ΐ-6Γΐ '(Η9' Ζ Η 9 · 9 = ΓΡ) 6ΐ · ΐ (d) g (OS 'z 00S) Awakening Η τ
(9ε呦^ べ fi、 ^( ^(9ε 呦 ^ be fi, ^ (^
Figure imgf000078_0003
810]
Figure imgf000078_0003
810]
'(Ηΐ ' s) WOl '(Ηΐ 's) Ζΐ ΐ '(Ηΐ 's) 06·8 '(Ηΐ 's) 86"Ζ '(Ηΐ '^Η S- = f 'Ρ) 9ΓΖ '(Ηΐ 's) '(Ηΐ' s ) WOl '(Ηΐ' s) Ζΐ ΐ '(Ηΐ' s) 06/8 '(Ηΐ' s) 86 "Ζ '(Ηΐ' ^ Η S- = f 'Ρ) 9ΓΖ' (Ηΐ 's)
LL LL
8L£Zl£/900Zdr/13d °-Μ (sw ^)ベ ίί 、 (,ίί- " ^ - 9¾ - { -ェ [ ^ - ^ / ( ェ , ^ ^ - ε)]- ε}- 9- ^： べ:^- ΐ¾Χ - 9¾- { -ェ [ ^ - ^ / ( ェ , ^ ^ ;^- ε)]- ε}- 9： 8Sp}% [Ζ8Ϊ0]8L £ Zl £ / 900Zdr / 13d ° -Μ (sw ^) Be ίί, (, ίί- "^-9¾-{-e [^-^ / (ェ, ^ ^-ε)]-ε}-9- ^: Be: ^-ΐ¾Χ- 9¾- {--[^-^ / (, ^ ^; ^-ε)]-ε}-9: 8Sp}% [Ζ8Ϊ0]
•(HI 's) sroi '(Ηΐ 's) C6• (HI 's) sroi' (Ηΐ 's) C6
•8 '(Ηΐ 's) 0 ·8 '(Ηΐ 'ΖΗ Γ3 = f 'Ρ) LZ'S '(Ηΐ 'ω) 86"Z-26"Z '(Ηΐ 'ω) ΖΖ·Ζ- ΟΓΖ '(Η ΐ 's) 89· '(Η2
Figure imgf000079_0001
'ω • 8 '(Ηΐ' s) 0 · 8 '(Ηΐ' ΖΗ Γ3 = f 'Ρ) LZ'S' (Ηΐ 'ω) 86 "Z-26"Z' (Ηΐ 'ω) ΖΖ · Ζ- ΟΓΖ' (Η ΐ 's) 89
Figure imgf000079_0001
'ω
) zrs- 69·ε SST-TST '(Η9 's) srs ( a) g (9p-os^a 'z LZ) 醒 HT ) zrs- 69 · ε SST-TST '(Η9' s ) srs (a) g ( 9 p-os ^ a 'z LZ) Awakening H T
。
Figure imgf000079_0002
.
Figure imgf000079_0002
e¾x  e¾x
"(Ηΐ 's) S6'8 '(Ηΐ ' s -iq) S8"Z '(Ηΐ 's -iq) 8Z"Z '(Ηΐ 'ω) L'L-Z9'L '(Ηΐ 's) 89· '(HZ 'ω) Z 'Z- SS'Z '(HS  "(Ηΐ 's) S6'8' (Ηΐ 's -iq) S8" Z' (Ηΐ 's -iq) 8Z "Z' (Ηΐ 'ω) L'L-Z9'L' (Ηΐ 's) 89 · '(HZ' ω) Z 'Z- SS'Z' (HS
<s) ΖΓΖ '(HI 's) 2Γ '(HI 's) 60"Z '(Ηΐ 'ω) 06·9— 98·9 '(Η2 's) 6Γ3 '(Η '^Η O'S = f 8·ε '(H 'ΖΗ O'S = f 09·ε '(Η9 's) 0£'Ζ ( d) g ( 3Q0 'z OOS) 醒 HT < s ) ΖΓΖ '(HI' s) 2Γ '(HI' s) 60 "Z '(Ηΐ' ω) 06 · 9— 98 · 9 '(Η2' s) 6Γ3 '(Η' ^ Η O'S = f 8 Ε '(H' ΖΗ O'S = f 09 · ε '(Η9' s ) 0 £ 'Ζ (d) g (3Q0' z OOS) Awakening H T
°-M  ° -M
¾
Figure imgf000079_0003
べ -ェ ^ -^ - べ ^ 士 )]¾
Figure imgf000079_0003
Be-e ^-^-Bee ^)
- ε}- 9- (,fi- ^ - 9 - 4 べ:^- 翁^; ^¾ι ^εί^ 拳 -ε}-9- (, fi- ^-9-4: ^-翁 ^; ^ ¾ι ^ εί ^ fist
ヽ
Figure imgf000079_0004
ヽ
Figure imgf000079_0004
•(HI 's) 06·8 '(Ηΐ 's) 29"• (HI 's) 06 · 8' (Ηΐ 's) 29 "
Ζ '(HS 'ω) 9£'L-LZ'L Hf 'ω) ZZ'L-LVL HZ 'ω) 66·9- 6·9 '(Ηΐ 'ω) ΐ6·9 '(Ηΐ 'ω) Ζ '(HS' ω) 9 £ 'L-LZ'L Hf' ω) ZZ'L-LVL HZ 'ω) 66 · 9- 6 · 9' (Ηΐ 'ω) ΐ6 · 9' (Ηΐ 'ω)
69·9 HZ 's) I'S '(Η2 's -iq) 9Τ '(Η 9 's) 0£'Z ( d) g ( 3Q0 'z OOS) 醒 HT 69 9 HZ 's) I'S' (Η2 's -iq) 9Τ' (Η 9 ' s ) 0 £' Z (d) g (3Q0 'z OOS) Awakening H T
。 (%96 '§ω OZZ)
Figure imgf000079_0005
. (% 96 ' § ω OZZ)
Figure imgf000079_0005
] ベ fi、 ^P(,fi- ^ - 9 - ^： べ:^- ( / ェ , ^ - ε)- 9、つ
Figure imgf000079_0006
、氺 ] Be fi, ^ P (, fi- ^-9-^: Be: ^-(/, ^-ε)-9,
Figure imgf000079_0006
, 氺
8L£ZU/900Zdr/13d ΐひ I/900Z OAV H NMR (300 MHz, CDC1 ) δ (ppm) 2.31 (s, 6H), 3.02 (s, 6H), 5.15 (s, 2H), 6.88 (d 8L £ ZU / 900Zdr / 13d ΐ ひ I / 900Z OAV H NMR (300 MHz, CDC1) δ (ppm) 2.31 (s, 6H), 3.02 (s, 6H), 5.15 (s, 2H), 6.88 (d
3  Three
d, J = 8.4, 2.4 Hz, IH), 7.03 (s, IH), 7.01-7.07 (m, IH), 7.17 (s, 3H), 7.26-7.45 (m , 8H), 7.65-7.71 (m, IH), 7.69 (s, IH), 7.81 (br s, IH), 7.84-7.88 (m, IH), 8.92 (s, IH).  d, J = 8.4, 2.4 Hz, IH), 7.03 (s, IH), 7.01-7.07 (m, IH), 7.17 (s, 3H), 7.26-7.45 (m, 8H), 7.65-7.71 (m, IH), 7.69 (s, IH), 7.81 (br s, IH), 7.84-7.88 (m, IH), 8.92 (s, IH).
工程 2  Process 2
化合物 A48を用い、参考例 32の工程 2と同様の方法でィ匕合物 38を得た。  Compound 38 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A48.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 2.18 (s, 6H), 2.97 (s, 6H), 6.81 (s, IH), 6.86  JH NMR (270 MHz, DMSO— d) δ (ppm) 2.18 (s, 6H), 2.97 (s, 6H), 6.81 (s, IH), 6.86
6  6
-6.95 (m, IH), 7.09 (s, 3H), 7.21-7.42 (m, 6H), 7.68 (s, IH), 7.71-7.77 (m, IH), 7. 96 (s, IH), 8.37 (s, IH), 8.92 (s, IH), 9.95 (s, IH).  -6.95 (m, IH), 7.09 (s, 3H), 7.21-7.42 (m, 6H), 7.68 (s, IH), 7.71-7.77 (m, IH), 7. 96 (s, IH), 8.37 (s, IH), 8.92 (s, IH), 9.95 (s, IH).
[0188] 参考例 39： 7-ヒドロキシ -2-イソプロピルァミノ- 6- (ナフタレン- 1-ィル)キナゾリン（ィ匕合 物 39) [0188] Reference Example 39: 7-Hydroxy-2-isopropylamino-6- (naphthalene-1-yl) quinazoline (Compound 39)
化合物 A36及び 1-ナフタレンボロン酸を用い、参考例 1の工程 5及び参考例 32のェ 程 2と同様の方法でィ匕合物 39を得た。  Compound 39 was obtained in the same manner as in Step 5 of Reference Example 1 and Step 2 of Reference Example 32 using Compound A36 and 1-naphthaleneboronic acid.
JH NMR (300 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.3 Hz, 6H), 4.27-4.41 (m, IH), 5.0 J H NMR (300 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.3 Hz, 6H), 4.27-4.41 (m, IH), 5.0
3  Three
3-5.16 (m, IH), 7.13 (s, IH), 7.43-7.68 (m, 6H), 7.92-8.02 (m, 2H), 8.82 (s, IH).  3-5.16 (m, IH), 7.13 (s, IH), 7.43-7.68 (m, 6H), 7.92-8.02 (m, 2H), 8.82 (s, IH).
[0189] 参考例 40： 7-ヒドロキシ- 2-イソプロピルアミノ- 6- {3- [(3-モルホリノフエ-ル)カルバモ ィル]フエ-ル}キナゾリン（化合物 40) [0189] Reference Example 40: 7-hydroxy-2-isopropylamino-6- {3- [(3-morpholinophenol) carbamoyl] phenol} quinazoline (Compound 40)
工程 1  Process 1
3-モルホリノァ-リン及び3-(4,4,5,5,-テトラメチル-1,3,2-ジォキサボロラン-2-ィル） 安息香酸を用い、参考例 34の工程 4と同様の方法でアミド化を行い、 N-(3-モルホリノ フエ二ル)- 3-(4,4,5, 5-テトラメチル -1,3,2-ジォキサボロラン- 2-ィル)ベンズアミドを得 た。  Using 3-morpholinoa-line and 3- (4,4,5,5, -tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid in the same manner as in Step 4 of Reference Example 34 Amidation was carried out to obtain N- (3-morpholinophenyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) benzamide.
1H NMR (300 MHz, CDC1 ) δ (ppm) 1.38 (s, 12H), 3.22 (t, J = 4.8 Hz, 4H), 3.87 (t,  1H NMR (300 MHz, CDC1) δ (ppm) 1.38 (s, 12H), 3.22 (t, J = 4.8 Hz, 4H), 3.87 (t,
3  Three
J = 4.8 Hz, 4H), 6.68-6.74 (m, IH), 6.95—7.02 (m, IH), 7.21-7.30 (m, IH), 7.48-7. 57 (m, 2H), 7.84 (br s, IH), 7.95—8.02 (m, IH), 8.04—8.10 (m, IH), 8.20 (br s, IH). 工程 2  J = 4.8 Hz, 4H), 6.68-6.74 (m, IH), 6.95—7.02 (m, IH), 7.21-7.30 (m, IH), 7.48-7. 57 (m, 2H), 7.84 (br s , IH), 7.95—8.02 (m, IH), 8.04—8.10 (m, IH), 8.20 (br s, IH).
化合物 A36及び N-(3-モルホリノフエ-ル)- 3-(4,4,5,5-テトラメチル -1,3,2-ジォキサ ボロラン- 2-ィル)ベンズアミドを用い、参考例 1の工程 5と同様の方法で 7-ベンジルォ キシ- 2-イソプロピルアミノ- 6- {3- [(3-モルホリノフエ-ル)力ルバモイル]フエ-ル}キナ ゾリン (ィ匕合物 A49)を得た。 Using Compound A36 and N- (3-morpholinophenol) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide, In the same way as in step 5, Xyl-2-isopropylamino-6- {3-[(3-morpholinophenol) strength rubermoyl] phenol} quinazoline (Compound A49) was obtained.
1H NMR (270 MHz, CDCl ) δ (ppm) 1.31 (d, J = 6.4 Hz, 6H), 3.17—3.20 (m, 4H), 3.8  1H NMR (270 MHz, CDCl) δ (ppm) 1.31 (d, J = 6.4 Hz, 6H), 3.17—3.20 (m, 4H), 3.8
3  Three
4-3.87 (m, 4H), 4.25-4.37 (m, IH), 5.11-5.14 (m, IH), 5.23 (s, 2H), 6.70 (dd, J = 8 .2, 2.1 Hz, IH), 6.79-6.82 (m, IH), 7.10 (s, IH), 7.19-7.37 (m, 6H), 7.47 (dd, J = 2 .0, 2.0 Hz, IH), 7.53 (dd, J = 7.7, 7.7 Hz, IH), 7.60—7.61 (m, IH), 7.75-7.79 (m, 2 H), 7.86 (ddd, J = 7.9, 1.3, 1.2 Hz, IH), 8.06—8.07 (m, IH), 8.84 (s, IH).  4-3.87 (m, 4H), 4.25-4.37 (m, IH), 5.11-5.14 (m, IH), 5.23 (s, 2H), 6.70 (dd, J = 8.2, 2.1 Hz, IH), 6.79-6.82 (m, IH), 7.10 (s, IH), 7.19-7.37 (m, 6H), 7.47 (dd, J = 2.0, 2.0 Hz, IH), 7.53 (dd, J = 7.7, 7.7 Hz, IH), 7.60—7.61 (m, IH), 7.75-7.79 (m, 2 H), 7.86 (ddd, J = 7.9, 1.3, 1.2 Hz, IH), 8.06—8.07 (m, IH), 8.84 (s, IH).
工程 3 Process 3
化合物 A49を用い、参考例 32の工程 2と同様の方法でィ匕合物 40を得た。  Compound 40 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A49.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.18 (d, J = 6.4 Hz, 6H), 3.07—3.10 (m, 4H), JH NMR (270 MHz, DMSO— d) δ (ppm) 1.18 (d, J = 6.4 Hz, 6H), 3.07—3.10 (m, 4H),
6  6
3.72-3.76 (m, 4H), 4.12-4.20 (m, IH), 6.70 (dd, J = 8.3, 1.5 Hz, IH), 6.87 (s, IH), 7.06 (d, J = 7.9 Hz, IH), 7.18 (dd, J = 8.3, 7.9 Hz, IH), 7.30 (br s, IH), 7.42 (s, 1 3.72-3.76 (m, 4H), 4.12-4.20 (m, IH), 6.70 (dd, J = 8.3, 1.5 Hz, IH), 6.87 (s, IH), 7.06 (d, J = 7.9 Hz, IH) , 7.18 (dd, J = 8.3, 7.9 Hz, IH), 7.30 (br s, IH), 7.42 (s, 1
H), 7.56 (dd, J = 7.8, 7.8 Hz, IH), 7.76-7.80 (m, 2H), 7.89 (d, J = 7.8 Hz, IH), 8.1H), 7.56 (dd, J = 7.8, 7.8 Hz, IH), 7.76-7.80 (m, 2H), 7.89 (d, J = 7.8 Hz, IH), 8.1
3 (s, IH), 8.90 (s, IH), 10.13 (s, IH), 10.63 (br s, IH). 3 (s, IH), 8.90 (s, IH), 10.13 (s, IH), 10.63 (br s, IH).
参考例 41： 7-ヒドロキシ -2-イソプロピルァミノ- 6-{3-[(2-モルホリノピリジン- 4-ィル)力 ルバモイル]フエ-ル}キナゾリン（化合物 41) Reference Example 41: 7-Hydroxy-2-isopropylamino-6- {3-[(2-morpholinopyridine-4-yl) force Rubamoyl] phenol} quinazoline (Compound 41)
工程 1 Process 1
化合物 A36を用い、参考例 43の工程 2と同様の方法で 7-ベンジルォキシ -2-イソプ 口ピルァミノ- 6-(4,4,5,5-テトラメチル -1,3,2-ジォキサボロラン- 2-ィル)キナゾリン（ィ匕 合物 A50)を得た。  7-Benzyloxy-2-isopyramino-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- in the same manner as in Step 2 of Reference Example 43, using Compound A36 Yl) quinazoline (I compound A50) was obtained.
1H NMR (270 MHz, CDCl ) δ (ppm) 1.21—1.39 (m, 18H), 4.23—4.38 (m, IH), 5.23 (s,  1H NMR (270 MHz, CDCl) δ (ppm) 1.21—1.39 (m, 18H), 4.23—4.38 (m, IH), 5.23 (s,
3  Three
2H), 6.92 (s, IH), 7.30-7.34 (m, IH), 7.34-7.41 (m, 2H), 7.62-7.68 (m, 2H), 8.04 ( s, IH), 8.81 (s, IH).  2H), 6.92 (s, IH), 7.30-7.34 (m, IH), 7.34-7.41 (m, 2H), 7.62-7.68 (m, 2H), 8.04 (s, IH), 8.81 (s, IH) .
工程 2 Process 2
化合物 A50及び 3-ョード -N- (2-モルホリノピリジン- 4-ィル)ベンズアミド [2-モルホリ ノビリジン- 4-ィルァミン (WO05/023761)及び 3-ョード安息香酸力 得ることができる ]を用い、参考例 1の工程 5と同様の方法で 7-ベンジルォキシ -2-イソプロピルァミノ- 6 -{3-[(2-モルホリノピリジン- 4-ィル)力ルバモイル]フエ-ル}キナゾリン（ィ匕合物 A51)を 2¾ Compound A50 and 3-iodo-N- (2-morpholinopyridine-4-yl) benzamide [2-morpholinoviridine-4-ylamine (WO05 / 023761) and 3-iodobenzoic acid can be obtained] 7-Benzyloxy-2-isopropylamino-6- {3-[(2-morpholinopyridine-4-yl) power rubermoyl] phenol} quinazoline (compound) in the same manner as in Step 5 of Reference Example 1. A51) 2¾
•(Ηΐ 'ZH 6·0 ' • (Ηΐ 'ZH 6 · 0'
O'S = f 'ΡΡ) 28"8 '(Ηΐ 'ZH 6 'S'l = f 'PP) '(HZ 'ω) 80·8- S0'8 '(Ηΐ '^Η S'l '0· e = f 'ρρ) LL'L '(HI 'ω) ΐζ- -er '(HS 66·ε ( a) g (ειつ αつ 'ζ οοε) Η醒 ΗΤ O'S = f 'ΡΡ) 28 "8' (Ηΐ 'ZH 6'S'l = f 'PP)' (HZ 'ω) 80 ・ 8- S0'8' (Ηΐ '^ Η S'l' 0 · e = f 'ρρ) LL'L' (HI 'ω) ΐζ- -er' (HS 66 · ε (a) g ( ε ια α ′ ζ οοε) Awakening Η Τ
- (%0Ζ 8S) エ ^ 濯べ / -ェ ΰ / - - S ^ -(% 0Ζ 8S) D ^ Rinse /-ΰ ΰ /--S ^
（06/θΐ
Figure imgf000082_0001
(06 / θΐ
Figure imgf000082_0001
°^^ m、止 ϊί教 ^nm^ m^^ ^ ^。 ·ΠΦ ^ 翻 つ。  ° ^^ m, ϊ 教 ί 教 ^ nm ^ m ^^ ^ ^. · ΠΦ ^
001止^蹈 べ
Figure imgf000082_0002
001 stop
Figure imgf000082_0002
-f L^(\omm WZ '§ω 86Z) ^^ ^ (\omm 88Ζ0 '§ω ΐ·6 ） ^ -
Figure imgf000082_0003
、つ ¾缀 コ） (ΐω S'S)ベエ i¾0ou"n SZ'I OOS) エ ^ 濯べ crn^- s -f L ^ (\ omm WZ ' § ω 86Z) ^^ ^ (\ omm 88Ζ0' § ω ΐ · 6) ^-
Figure imgf000082_0003
(缀 ω S'S) Bei i¾0 ou "n SZ'I OOS) d ^ Rinse crn ^-s
ΐ¾Χ  ΐ¾Χ
- ェ [ ^ ^ / / - べ;^ fi ( -ェ ΰ / - - - ε}- 9： Zf ^ [Ϊ6Ϊ0] -[[^ ^ / /-Be; ^ fi (-ΰ ΰ /---ε}-9: Zf ^ [Ϊ6Ϊ0]
"(Ηΐ 's -iq) 59 ΐ '(Ηΐ 's) Ο^ ΐ '(Ηΐ 's) ΐ6·8 '(Ηΐ 's) 5Γ8  "(Ηΐ 's -iq) 59 ΐ' (Ηΐ 's) Ο ^ ΐ' (Ηΐ 's) ΐ6 · 8' (Ηΐ 's) 5Γ8
'(Ηΐ 'ZH S"S = f 'Ρ) 90·8 '(Ηΐ '9"Ζ = f 'Ρ) Ϊ6"Ζ '(Ηΐ '^Η 6"Ζ = f 'Ρ) S8"Z '(Ηΐ LL' L '(Ηΐ 'ΖΗ 9"Ζ '6"Ζ = f 'ΡΡ) 09· '(Ηΐ '^Η 2"ΐ = f 'Ρ) ZZ'L '(Ηΐ '^Η 2"ΐ 'S'S = f 'ΡΡ) 8ΓΖ '(Ηΐ 'ΖΗ ΐ·8 = f 'Ρ) 90"Ζ '(Ηΐ 88·9 '(Ηΐ 'ω) ΐ - εΐ· '(Η 'ω) S T-O T '(Ηΐ' ZH S "S = f 'Ρ) 90 · 8' (Ηΐ '9" Ζ = f' Ρ) Ϊ6 "Ζ '(Ηΐ' ^ Η 6" Ζ = f 'Ρ) S8 "Z' ( Ηΐ LL 'L' (Ηΐ 'ΖΗ 9 "Ζ' 6" Ζ = f 'ΡΡ) 09 ·' (Ηΐ '^ Η 2 "ΐ = f' Ρ) ZZ'L '(Ηΐ' ^ Η 2" ΐ ' S'S = f 'ΡΡ) 8ΓΖ' (Ηΐ 'ΖΗ ΐ · 8 = f' Ρ) 90 "Ζ '(Ηΐ 88 · 9' (Ηΐ 'ω) ΐ-εΐ ·' (Η 'ω) S TO T
'(Η 'ω) ·ε— 8ε·ε '(Η9 'ΖΗ 9·9 = f 'Ρ) ΟΖΊ ( g ( OS 'z LZ) 醒 ΗΤ '(Η' ω) · ε— 8ε · ε '(Η9' Ζ Η 9 · 9 = f 'Ρ) ΟΖΊ (g (OS' z LZ) awakening Η Τ
Figure imgf000082_0004
SV呦
Figure imgf000082_0004
SV 呦
ε¾χ ε¾χ
•(Ηΐ 's) 8·8 '(Ηΐ • (Ηΐ 's) 8 · 8' (Ηΐ
'ZH Z'S = f 'Ρ) 60·8 '(Ηΐ 'ω) 90·8- SO'8 ΗΖ 'ω) Ζ8"Ζ-8Ζ"Ζ '(Ηΐ 8ΓΖ '(Ηΐ ΐ  'ZH Z'S = f' Ρ) 60 ・ 8 '(Ηΐ' ω) 90 ・ 8- SO'8 ΗΖ 'ω) Ζ8 "Ζ-8Ζ" Ζ' (Ηΐ 8ΓΖ '(Ηΐ ΐ
9"Ζ '(Ηΐ 'ΖΗ Ζ·Ζ '6"Ζ = f 'ΡΡ) 93"Ζ '(Η9 'ω) 8S"Z-S2"Z '(Ηΐ 0ΓΖ '(Ηΐ '^Η Ζ·ΐ 'Ζ· e = f 'ρρ) 9 ·9 '{ΗΖ <s) s '(HI sre-ore '(HI 'ω) 9ε· ss' '(Η wz-o 9 "Ζ '(Ηΐ' ΖΗ Ζ · Ζ '6" Ζ = f' ΡΡ) 93 "Ζ '(Η9' ω) 8S" Z-S2 "Z '(Ηΐ 0ΓΖ' (Ηΐ '^ Η Ζ · ΐ' E e = f 'ρρ) 9 9' {ΗΖ <s ) s' (HI sre-ore '(HI' ω) 9ε ss''(Η wz-o
8·ε 'ω) wz-wz 'ΖΗ V9 = f 'ρ) ιε·ΐ ( a) g (ε ιつ 'ζ οοε) Η醒 ΗΤ 8 · ε 'ω) wz-wz' Ζ Η V9 = f 'ρ) ιε · ΐ (a) g ( ε ι one' ζ οοε) Awakening Η Τ
18 18
8ί£ΖΙ£/900Ζάΐ/13ά ΐひ I/900Z OAV 2-(4-フルオロフェ -ル)イソニコチン酸メチルエステル（278 mg, 1.20 mmol)をメタノ ール（2 mL)に溶解し、 2 mol/L水酸化ナトリウム水溶液（2 mL, 4.0 mmol)をカ卩えた後 、室温で一晩攪拌した。減圧下、溶媒を留去して得られた反応混合物を水に溶解し た。酢酸ェチルで洗净した後、 1 mol/L塩酸を加えた後生じた結晶を濾取し、 2-(4-フ ルォロフエ-ル)イソニコチン酸（134 mg, 51%)を得た。 8ί £ ΖΙ £ / 900Ζάΐ / 13ά ΐ ひ I / 900Z OAV 2- (4-Fluorophenol) isonicotinic acid methyl ester (278 mg, 1.20 mmol) was dissolved in methanol (2 mL), and 2 mol / L aqueous sodium hydroxide solution (2 mL, 4.0 mmol) was added to the solution. After stirring, the mixture was stirred overnight at room temperature. The reaction mixture obtained by distilling off the solvent under reduced pressure was dissolved in water. After washing with ethyl acetate, 1 mol / L hydrochloric acid was added and the resulting crystals were collected by filtration to give 2- (4-fluorophenyl) isonicotinic acid (134 mg, 51%).
得られた 2- (4-フルオロフェ -ル)イソニコチン酸（126 mg, 0.582 mmol)を DMF (2 mL )に溶解し、 1-ェチル -3-(3-ジメチルァミノプロピル)カルボジイミド塩酸塩（134 mg, 0. 698 mmol) , 1-ヒドロキシベンゾトリアゾール（89.0 mg, 0.582 mmol)、及び 3- (4,4,5,5- テトラメチル- 1,3,2-ジォキサボロラン- 2-ィル)ァ-リン（153 mg, 0.698 mmol)をカ卩えた 後、室温で 1.5時間、 50 °Cで 3時間攪拌した。反応混合物に水を加え、酢酸ェチルで 抽出した後、有機層を飽和重曹水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下 、溶媒を留去することで 2-(4-フルオロフェ-ル)- N-[3-(4,4,5,5-テトラメチル -1,3,2- ジォキサボロラン- 2-ィル)フエ-ル]イソニコチンアミド（202 mg, 83%)を得た。  The obtained 2- (4-fluorophenyl) isonicotinic acid (126 mg, 0.582 mmol) was dissolved in DMF (2 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 134 mg, 0. 698 mmol), 1-hydroxybenzotriazole (89.0 mg, 0.582 mmol), and 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) After adding a phosphorus (153 mg, 0.698 mmol), the mixture was stirred at room temperature for 1.5 hours and at 50 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 2- (4-fluorophenol) -N- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) [Fuel] isonicotinamide (202 mg, 83%) was obtained.
JH NMR (300 MHz, CDC1 ) δ (ppm) 1.36 (s, 12H), 7.17-7.23 (m, 2H), 7.44 (dd, J = JH NMR (300 MHz, CDC1) δ (ppm) 1.36 (s, 12H), 7.17-7.23 (m, 2H), 7.44 (dd, J =
3  Three
7.9, 7.4 Hz, IH), 7.57 (dd, J = 5.0, 1.7 Hz, IH), 7.63—7.66 (m, IH), 7.79 (d, J = 1.7 Hz, IH), 7.89 (br s, IH), 8.04-8.12 (m, 4H), 8.84 (d, J = 5.0 Hz, IH).  7.9, 7.4 Hz, IH), 7.57 (dd, J = 5.0, 1.7 Hz, IH), 7.63—7.66 (m, IH), 7.79 (d, J = 1.7 Hz, IH), 7.89 (br s, IH) , 8.04-8.12 (m, 4H), 8.84 (d, J = 5.0 Hz, IH).
工程 3 Process 3
化合物 A36及び 2-(4-フルオロフェ-ル)- N-[3-(4,4,5,5-テトラメチル -1,3,2-ジォキ サボロラン- 2-ィル)フエ-ル]イソニコチンアミドを用い、参考例 1の工程 5と同様の方 法で 7-ベンジルォキシ -6-{3-[2- (4-フルオロフェ -ル)ピリジン- 4-ィルカルボ-ルアミ ノ]フエ-ル}-2- (イソプロピルァミノ)キナゾリン (ィ匕合物 A52)を得た。  Compound A36 and 2- (4-fluorophenol) -N- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) phenol] isonicotine 7-Benzyloxy-6- {3- [2- (4-fluorophenyl) pyridine-4-ylcarbolamino] phenol} -2 in the same manner as in Step 5 of Reference Example 1 using amide -(Isopropylamino) quinazoline (Compound A52) was obtained.
1H NMR (270 MHz, CDC1 ) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 4.26—4.38 (m, IH), 5.0 1H NMR (270 MHz, CDC1) δ (ppm) 1.31 (d, J = 6.6 Hz, 6H), 4.26—4.38 (m, IH), 5.0
3  Three
7-5.10 (m, IH), 5.25 (s, 2H), 7.08 (s, IH), 7.16-7.22 (m, 2H), 7.27-7.33 (m, 2H),7. 35-7.40 (m, 2H), 7.45-7.46 (m, 2H), 7.55-7.57 (m, IH), 7.64 (s, IH), 7.83-7.85 (m , 2H), 8.04-8.09 (m, 2H), 8.11 (s, 2H), 8.84 (s, IH), 8.85 (s, IH).  7-5.10 (m, IH), 5.25 (s, 2H), 7.08 (s, IH), 7.16-7.22 (m, 2H), 7.27-7.33 (m, 2H), 7. 35-7.40 (m, 2H ), 7.45-7.46 (m, 2H), 7.55-7.57 (m, IH), 7.64 (s, IH), 7.83-7.85 (m, 2H), 8.04-8.09 (m, 2H), 8.11 (s, 2H ), 8.84 (s, IH), 8.85 (s, IH).
工程 4 Process 4
化合物 A52を用い、参考例 32の工程 2と同様の方法でィ匕合物 42を得た。  Compound 42 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A52.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.18 (d, J = 6.4 Hz, 6H), 4.12-4.20 (m, IH), 6.86 (s, IH), 7.02-7.05 (m, IH), 7.34-7.47 (m, 4H), 7.67 (s, IH), 7.78-7.82 (m, 2 H), 7.99-8.00 (m, IH), 8.22-8.27 (m, 2H), 8.41 (s, IH), 8.84—8.86 (m, IH), 8.90 (s,JH NMR (270 MHz, DMSO— d) δ (ppm) 1.18 (d, J = 6.4 Hz, 6H), 4.12-4.20 (m, IH), 6.86 (s, IH), 7.02-7.05 (m, IH), 7.34-7.47 (m, 4H), 7.67 (s, IH), 7.78-7.82 (m, 2 H), 7.99-8.00 (m, IH) , 8.22-8.27 (m, 2H), 8.41 (s, IH), 8.84—8.86 (m, IH), 8.90 (s,
IH), 10.56 (s, IH), 10.60 (s, IH). IH), 10.56 (s, IH), 10.60 (s, IH).
参考例 43： 7-ヒドロキシ -2-イソプロピルァミノ- 6-{2-メチル - 5-[5-メチル - 2-(4-メチル フエ-ル) -2H-ピラゾール -3-ィルカルバモイル]フエ-ル}キナゾリン（ィ匕合物 43) 工程 1 Reference Example 43: 7-hydroxy-2-isopropylamino-6- {2-methyl-5- [5-methyl-2- (4-methylphenol) -2H-pyrazole-3-ylcarbamoyl] phenol Lu} Quinazoline (I Compound 43) Process 1
3-ョード -4-メチル安息香酸（1.00 g, 3.89 mmol)を塩化チォ -ル（12.5 mL)に溶解 し、 80 °Cで 1.75時間攪拌した後、減圧下塩ィ匕チォニルを留去した。反応混合物を塩 ィ匕メチレン（10.0 mL)に溶解し、 5-ァミノ- 3-メチル -l-(p-トリル)ピラゾール（0.728 g, 3.89 mmol)及び Ν,Ν-ジイソプロピルェチルァミン（0.678 mL, 3.89 mmol)の塩化メチ レン（10.0 mL)溶液に加えた後、室温で一晩攪拌した。反応混合物に水を加え、酢 酸ェチルで抽出した後、有機層を飽和重曹水、飽和塩ィ匕アンモ-ゥム水溶液及び水 で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下、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（酢酸ェチル /へキサン = 1/4)で精製することで 3_ョード -4- メチル -N- [5-メチル -2- (p-トリル)- 2H-ピラゾール- 3-ィル]ベンズアミド（1.44 g, 86%) を得た。  3-iodo-4-methylbenzoic acid (1.00 g, 3.89 mmol) was dissolved in chlorochloride (12.5 mL) and stirred at 80 ° C. for 1.75 hours, and then the salt was dissolved under reduced pressure. The reaction mixture was dissolved in salt methylene (10.0 mL) and 5-amino-3-methyl-l- (p-tolyl) pyrazole (0.728 g, 3.89 mmol) and Ν, Ν-diisopropylethylamine (0.678) were dissolved. (mL, 3.89 mmol) in methylene chloride (10.0 mL) and then stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4) to give 3_odo-4-methyl-N- [5-methyl-2- (p -Tolyl) -2H-pyrazol-3-yl] benzamide (1.44 g, 86%) was obtained.
JH NMR (270 MHz, CDC1 ) δ (ppm) 2.34 (s, 3H), 2.43 (s, 3H), 2.47 (s, 3H), 6.61 (s, J H NMR (270 MHz, CDC1) δ (ppm) 2.34 (s, 3H), 2.43 (s, 3H), 2.47 (s, 3H), 6.61 (s,
3  Three
IH), 7.27-7.41 (m, 5H), 7.53 (dd, J = 7.9, 1.9 Hz, IH), 7.85 (br s, IH), 8.19 (d, J = 1.9 Hz, IH).  IH), 7.27-7.41 (m, 5H), 7.53 (dd, J = 7.9, 1.9 Hz, IH), 7.85 (br s, IH), 8.19 (d, J = 1.9 Hz, IH).
工程 2 Process 2
3-ョード -4-メチル -N- [5-メチル -2- (p-トリル)- 2H-ピラゾール- 3-ィル]ベンズアミド（ 1.54 g, 3.57 mmol)及びビス (ピナコラート)ジボロンを DMF (11.9 mL)に溶解し、酢酸 カリウム（1.05 g, 10.7 mmol)及び [Ι, -ビス (ジフエ-ルホスフイノ)フエ口セン]ジクロロ パラジウム（197 mg, 0.241 mmol)をカ卩えた後、アルゴン雰囲気下 95 °Cでー晚攪拌し た。反応混合物に酢酸ェチル、水を加え、不溶物をセライトで濾別した後、酢酸ェチ ルで抽出した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下、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（酢酸ェチル /へキサン = 1/4→1 /3)で精製することで、 4-メチル -N- [5-メチル -2- (p-トリル) -2H-ピラゾール -3-ィル]- 。 べ )- ( -ェ 、 Ε- ε)- ¾^0)$^；^ ェ
Figure imgf000085_0001
3-iodo-4-methyl-N- [5-methyl-2- (p-tolyl) -2H-pyrazol-3-yl] benzamide (1.54 g, 3.57 mmol) and bis (pinacolato) diboron were added to DMF (11.9 After dissolving potassium acetate (1.05 g, 10.7 mmol) and [Ι, -bis (diphenylphosphino) pheocene] dichloropalladium (197 mg, 0.241 mmol) in an argon atmosphere, Stir with C. Ethyl acetate and water were added to the reaction mixture, the insoluble material was filtered off through celite, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 → 1/3) to give 4-methyl-N- [5-methyl-2- ( p-Tolyl) -2H-pyrazole-3-yl]- . B)-(-e, Ε-ε) -¾ ^ 0) $ ^ ； ^
Figure imgf000085_0001
。 べ "^c clE^— S—( ェ 、 E— S)— N、 ^ W^ ¾  . "^ C clE ^ — S— (, E— S) — N, ^ W ^ ¾
ΐ¾Χ ΐ¾Χ
(„呦 ^；] べ fi 、 ^ { -ェ [ ^ („呦 ^ ；] All fi, ^ {-e [^
Figure imgf000085_0002
[36 TO] •(HI 's -iq) 6 ·0ΐ '(Ηΐ 's) 02 Ϊ '(Ηΐ 98·8 '(Ηΐ '^Η Ζ·ΐ '0·8 = f 'ΡΡ) 8Ζ "Ζ '(Ηΐ 'ω) Wl-^Vl '(Ηΐ 's) OS'Z '(HS 'ω) 0^" -9S" '(Η2 'ω) - ·Ζ '(Ηΐ '^Η
Figure imgf000085_0002
[36 TO] • (HI 's -iq) 6 · 0ΐ' (Ηΐ 's) 02 Ϊ' (Ηΐ 98 · 8 '(Ηΐ' ^ Η Ζ · ΐ '0 · 8 = f' ΡΡ) 8Ζ "Ζ '(Ηΐ' ω) Wl- ^ Vl '(Ηΐ' s) OS'Z '(HS' ω) 0 ^ "-9S"'(Η2' ω)-· Ζ '(Ηΐ' ^ Η
0·8 = f 'Ρ) S0"Z '(Ηΐ 's) 8·9 '(Ηΐ ΖΖ'9 '(Ηΐ 'ω) 0Γ '(HS 62"2 '(HS 's ) ΖΖ'Ζ '(HS 's) 6Γ2 '(Η9 'ΖΗ ·9 = ΓΡ) 6ΐ·ΐ ( d) g (9ρ―。 SW。 'z LZ) 醒 HT 0 · 8 = f 'Ρ) S0 "Z' (Ηΐ 's) 8 · 9' (Ηΐ ΖΖ'9 '(Ηΐ' ω) 0Γ '(HS 62''2' (HS 's) ΖΖ'Ζ' ( HS 's) 6Γ2' (Η9 ' Ζ Η 9 = ΓΡ) 6 ΐ · ΐ (d) g ( 9 ρ―. SW.' Z LZ) Awakening H T
。 ε呦^ 翁^;
Figure imgf000085_0003
. ε 呦 ^ 翁 ^;
Figure imgf000085_0003
•(HI 's) 08·8 '(Ηΐ 's) Wl '(Ηΐ '^Η 8· ΐ = ΓΡ) Ζ9"Ζ '(Ηΐ 'ΖΗ 8·ΐ '2"8 = f 'ΡΡ) 8S'Z '(Η6 'ω) ΐ · - Ζ '(Η2 'ω) 8ΓΖ-3ΓΖ • (HI 's) 08 · 8' (Ηΐ 's) Wl' (Ηΐ '^ Η 8 · ΐ = ΓΡ) Ζ9 "Ζ' (Ηΐ 'ΖΗ 8 · ΐ' 2" 8 = f 'ΡΡ) 8S' Z '(Η6' ω) ΐ ·-Ζ '(Η2' ω) 8ΓΖ-3ΓΖ
'(Ηΐ 's) 90"Ζ '(Ηΐ 's) S9"9 '(HS 'ω) 9I'S- SI'S '(Ηΐ 'ω) 8S^-92^ '(HS 's) 8S '(Η  '(Ηΐ' s) 90 "Ζ '(Ηΐ' s) S9" 9 '(HS' ω) 9I'S- SI'S '(Ηΐ' ω) 8S ^ -92 ^ '(HS' s) 8S '(Η
S 's) '(HS 's) OS '(Η9 'ΖΗ 9·9 = f 'Ρ) ΐε·ΐ ( d) g ( 3Q0 'z O S) 醒 HT S 's)' (HS 's) OS' (Η9 ' Ζ Η 9 · 9 = f' Ρ) ΐε · ΐ (d) g (3Q0 'z OS) Wake H T
ベ fi 、 ^: ェ [ / ¾ / / - ε- /— ½ - -( / ェ ^ - - S - ^Fi, ^: ェ [/ ¾ / /-ε- / — ½--(/ ェ ^--S-^
- S]- S- ^ - S}- 9- - 4 べ:^- Z ¾^0)翁^; 3¾ェ
Figure imgf000085_0004
-S]-S- ^-S}-9--4 Total: ^-Z ¾ ^ 0) 翁 ^; 3¾
Figure imgf000085_0004
ε¾ι [ 0] ε¾ι [0]
•(Ηΐ 's -iq) S0'8 '(HI 'ZH 0·• (Ηΐ 's -iq) S0'8' (HI 'ZH 0
Ζ = ΓΡ) εθ·8 '(Ηΐ 'ZH VZ '6"Z = f 'PP) 08"Z '(HS WZ- SS'Z '(HI 's) Ζ9·9 '(HS ' s) L9'Z '(HS 's) '(HS 's) '( 's) SS'I ( d) g ( 3Q0 'z O S) 醒 HT Ζ = ΓΡ) εθ8 '(Ηΐ' ZH VZ '6 "Z = f' PP) 08" Z '(HS WZ- SS'Z' (HI 's) Ζ9 · 9' (HS 's) L9' Z '(HS' s) '(HS' s) '(' s ) SS'I (d) g (3Q0 'z OS) Awakening H T
°-M  ° -M
¾ (%8 's on)、^ Xベ:^ ( - ベ ^^^- S'S'I- ^ 4 - s's»)- ε t8  ¾ (% 8 's on), ^ X: ^ (-Be ^^^-S'S'I- ^ 4-s's »)-ε t8
8.CZTC/900Zdf/X3d ΐひ I/900Z OAV ^ / ( / - べ , ίί s)]- ε}- 9 -( ^ ^べ ε)- ^： /;^ 8.CZTC / 900Zdf / X3d ΐ ひ I / 900Z OAV ^ / (/ -Be, ίί s)]-ε} -9-(^ ^ be ε)-^: /; ^
^>-- ^¾^0) ^ ^ 3¾ェ Q) \ 、、 ¾f¾、 ^ べ c / [ / ェ ( / - S  ^>-^ ¾ ^ 0) ^ ^ 3¾e Q) \, ¾f¾, ^ c / [/ é (/-S
-ベ ^^^- s's'i- ^ 4 - s's t)- ε]- N- /fi ¾a¾ sv呦^  -Be ^^^-s's'i- ^ 4-s's t)-ε]-N- / fi ¾a¾ sv 呦 ^
ε¾ι 6ΐο] ε¾ι 6ΐο]
。 (½ν呦^^ ベ fi、 ^( ^ ^べ - ε)- rci i- 9- ^： べ:^- zw . (½ν 呦 ^^ be fi, ^ (^ ^ be-ε)-rci i- 9- ^: be: ^-zw
•(Ηΐ 'ZH 9 're =  • (Ηΐ 'ZH 9' re =
f 'PP) 2S"8 '(Ηΐ 'ω) 60·8- 90·8 '(Ηΐ 's -iq) III '(Ηΐ 'ω) Wl-ZUl '(Ηΐ 'ω) S9"Z-09 •Ζ '(Ηΐ 'ZH VI 'ΐ·8 = f 'ΡΡ) ΖΥΙ '(Ηΐ ZV L '(Ηΐ '^Η ε·ΐ 'Γ3 = f 'ΡΡ) 06·9 '(Hf f 'PP) 2S "8' (Ηΐ 'ω) 60 · 8- 90 · 8' (Ηΐ 's -iq) III' (Ηΐ 'ω) Wl-ZUl' (Ηΐ 'ω) S9" Z-09 • Ζ '(Ηΐ' ZH VI 'ΐ ・ 8 = f' ΡΡ) ΖΥΙ '(Ηΐ ZV L' (Ηΐ '^ Η ε · ΐ' Γ3 = f 'ΡΡ) 06 ・ 9' (Hf
'ω) 'ω) '(Η2ΐ SS'I ( d) g ( 3Q0 'z OOS) 醒 HT 'ω)' ω) '(Η2ΐ SS'I (d) g (3Q0' z OOS) Awakening H T
。 べ^ c [ -ェ ( — ベ ^ 拳
Figure imgf000086_0001
. Be ^ c [-e (— Be ^ Fist
Figure imgf000086_0001
1 ェ  1
(S 呦^：] べ fi 、 ^ { -ェ [ ^ (S 呦 ^:] All fi, ^ {-e [^
( / - べ;^ ίί , ίί s)]- ε}- 9-^^ 、 - ζ -( ^ ^べ - ε)- s： e^p}% [96 TO] (/ -Be; ^ ίί, ίί s)]-ε}-9-^^,-ζ-(^^ be-ε)-s: e ^ p}% [96 TO]
•(HI 's) SS'OI '(Ηΐ 's) ZZ'Ol '(Ηΐ 's) 68·8 '(Η ΐ 'ZH re = f 'Ρ) S2"8 '(Ηΐ 's) S6"Z '(HI '^H Z'S = f 'P) Z '(HI 's) S9"Z '(HI '^H • (HI 's) SS'OI' (Ηΐ 's) ZZ'Ol' (Ηΐ 's) 68/8' (Η ΐ 'ZH re = f' Ρ) S2 "8 '(Ηΐ' s) S6" Z '(HI' ^ HZ'S = f 'P) Z' (HI 's) S9 "Z' (HI '^ H
VI 'Z'Z = f 'PP) OVL '(HI 'ZH 6"Z = f 'P) 2S" '(Ηΐ ZZ'L-ZZ'L '(HI 's -iq)  VI 'Z'Z = f' PP) OVL '(HI' ZH 6 "Z = f 'P) 2S"' (Ηΐ ZZ'L-ZZ'L '(HI' s -iq)
'(Ηΐ 'ZH S TS = f 'PP) ZO'L '(HI 's) S8'9 '(HI '(H 'ω) ΐθΤ- δΤ '(Ηΐ' ZH S TS = f 'PP) ZO'L' (HI 's) S8'9' (HI '(H' ω) ΐθΤ- δΤ
'(Η9 'ω) 6S"T-9S"T '(Η9 'ΖΗ 9·9 = ΓΡ) 8ΐ·ΐ ( d) g ( p-OS O 'z LZ) 醒 HT '(Η9' ω) 6S "T-9S" T '(Η9' Ζ Η 9 · 9 = ΓΡ) 8ΐ · ΐ (d) g (p-OS O 'z LZ) Awakening H T
•(HI 's -iq) 9S T '(HZ • (HI 's -iq) 9S T' (HZ
S2"8-02"8 '(Ηΐ 9Z"Z-SZ"Z '(Ηΐ 'ω) OS'Z— S 'Z '(H2 'ω) Z'L-fVL '(Ηΐ 'ω) 66·9- Ζ6·9 'ω) ΐ9·ε— 9S'S '(Η9 'ω) 29"T-SS"T ( d) 9 ( OS 'z LZ) 醒 HT S2 "8-02" 8 '(Ηΐ 9Z "Z-SZ"Z' (Ηΐ 'ω) OS'Z— S' Z '(H2' ω) Z'L-fVL '(Ηΐ' ω) 66 -Ζ6 · 9 'ω) ΐ9 · ε— 9S'S' (Η9 'ω) 29 "T-SS" T (d) 9 (OS' z LZ) Awakening H T
8L£Zl£/900Zdr/13d ΐひ I/900Z OAV ミノ]フエ二ル}キナゾリン (ィ匕合物 A55)を得た。 8L £ Zl £ / 900Zdr / 13d ΐ ひ I / 900Z OAV Mino] phenyl} quinazoline (I compound A55) was obtained.
1H NMR (270 MHz, CDCl ) δ (ppm) 0.97 (t, J = 7.4 Hz, 6H), 1.48—1.78 (m, 4H), 3.5  1H NMR (270 MHz, CDCl) δ (ppm) 0.97 (t, J = 7.4 Hz, 6H), 1.48—1.78 (m, 4H), 3.5
3  Three
7-3.61 (m, 4H), 3.81—3.84 (m, 4H), 4.02—4.15 (m, IH), 5.02—5.06 (m, IH), 5.23 (s, 2H), 6.88 (d, J = 5.4 Hz, IH), 7.04 (s, IH), 7.12 (s, IH), 7.30-7.43 (m, 7H), 7.61(s, IH), 7.65-7.71 (m, IH), 7.81 (s, IH), 7.81 (s, IH), 8.32 (d, J = 5.1 Hz, IH), 8.83 ( s, IH).  7-3.61 (m, 4H), 3.81—3.84 (m, 4H), 4.02—4.15 (m, IH), 5.02—5.06 (m, IH), 5.23 (s, 2H), 6.88 (d, J = 5.4 Hz, IH), 7.04 (s, IH), 7.12 (s, IH), 7.30-7.43 (m, 7H), 7.61 (s, IH), 7.65-7.71 (m, IH), 7.81 (s, IH) , 7.81 (s, IH), 8.32 (d, J = 5.1 Hz, IH), 8.83 (s, IH).
工程 4 Process 4
化合物 A55を用い、参考例 32の工程 2と同様の方法でィ匕合物 45を得た。  Compound 45 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A55.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 0.88 (t, J = 7.4 Hz, 6H), 1.47—1.60 (m, 4H), JH NMR (270 MHz, DMSO— d) δ (ppm) 0.88 (t, J = 7.4 Hz, 6H), 1.47—1.60 (m, 4H),
6  6
3.52-3.55 (m, 4H), 3.58—3.65 (m, IH), 3.71-3.75 (m, 4H), 6.83 (s, IH), 6.94—6.97 ( m, IH), 7.14 (d, J = 5.0 Hz, IH), 7.27 (s, IH), 7.33 (d, J = 7.6 Hz, IH), 7.41 (dd, J = 7.7, 7.6 Hz, IH), 7.64 (s, IH), 7.76 (d, J = 7.7 Hz, IH), 7.95 (s, IH), 8.29 (d, J = 5.0 Hz, IH), 8.88 (s, IH), 10.36 (br s, IH), 10.52 (s, IH).  3.52-3.55 (m, 4H), 3.58—3.65 (m, IH), 3.71-3.75 (m, 4H), 6.83 (s, IH), 6.94—6.97 (m, IH), 7.14 (d, J = 5.0 Hz, IH), 7.27 (s, IH), 7.33 (d, J = 7.6 Hz, IH), 7.41 (dd, J = 7.7, 7.6 Hz, IH), 7.64 (s, IH), 7.76 (d, J = 7.7 Hz, IH), 7.95 (s, IH), 8.29 (d, J = 5.0 Hz, IH), 8.88 (s, IH), 10.36 (br s, IH), 10.52 (s, IH).
参考例 46 : 7-ヒドロキシ -2-イソプロピルァミノ- 6-{3-[2- (ピロリジン- 1-ィル)ピリジン- 4- ィルカルバモイル]フエ-ル}キナゾリン（ィ匕合物 46) Reference Example 46: 7-Hydroxy-2-isopropylamino-6- {3- [2- (pyrrolidin-1-yl) pyridine-4-ylcarbamoyl] phenol} quinazoline (Compound 46)
工程 1 Process 1
2-クロ口- 4--トロピリジン（2.0 g, 12.2 mmol)を THF (30 mL)に溶解し、ピロリジン（3 .25 mL, 38.9 mmol)を加えた後、 80 °Cでー晚攪拌した。反応混合物の不溶物を濾 別した後、減圧下、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 (酢酸 ェチル /へキサン =20/80)で精製し、 4--トロ- 2- (ピロリジン- 1-ィル)ピリジン（560 mg , 24%)を得た。  2-Chloro mouth-4-tropyridine (2.0 g, 12.2 mmol) was dissolved in THF (30 mL), pyrrolidine (3.25 mL, 38.9 mmol) was added, and the mixture was stirred at 80 ° C. After insoluble matters in the reaction mixture were filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20/80) to obtain 4-tro-2- (pyrrolidine-1-yl) pyridine (560 mg, 24%).
1H NMR (270 MHz, CDCl ) δ (ppm) 2.04—2.09 (m, 4H), 3.50—3.54 (m, 4H), 7.02 (d,  1H NMR (270 MHz, CDCl) δ (ppm) 2.04—2.09 (m, 4H), 3.50—3.54 (m, 4H), 7.02 (d,
3  Three
J = 1.8 Hz, IH), 7.15 (dd, J = 5.4, 1.6 Hz, IH), 8.33 (d, J = 5.4 Hz, IH).  J = 1.8 Hz, IH), 7.15 (dd, J = 5.4, 1.6 Hz, IH), 8.33 (d, J = 5.4 Hz, IH).
工程 2 Process 2
4-二トロ- 2- (ピロリジン- 1-ィル)ピリジン（560 mg, 2.90 mmol)をメタノール (21 mL)及 び塩化メチレン (8.3 mL)に溶解し、パラジウム炭素（50%含水， 560 mg)を加えた後、 水素雰囲気下室温で一時間攪拌した。反応混合物の不溶物を濾別した後、減圧下 、溶媒を留去し、 2- (ピロリジン- 1-ィル)ピリジン- 4-ィルァミン (474 mg, 91%)を得た。 (Z 呦^：] べ fi 、 ^ { -ェ [ ^ -έ / - べ ίί ( - ΐ-ベ ίίΰ ) - - ε}- 9- /^^ 、 - ζ- (,^ ^べ - ε)- s： [0020] 4-Nitro-2- (pyrrolidin-1-yl) pyridine (560 mg, 2.90 mmol) was dissolved in methanol (21 mL) and methylene chloride (8.3 mL), and palladium on carbon (containing 50% water, 560 mg). Then, the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The insoluble material in the reaction mixture was filtered off, and the solvent was evaporated under reduced pressure to give 2- (pyrrolidin-1-yl) pyridine-4-ylamine (474 mg, 91%). (Z 呦 ^:] All fi, ^ {-e [^ -έ / -Be ίί (-ΐ-Be ίίΰ)--ε}-9- / ^^, -ζ- (, ^ ^ Be-ε) -s: [0020]
"(Ηΐ 's "(Ηΐ 's
) S9 T '(Ηΐ 's) ΐε·0ΐ '(Ηΐ 's) 06·8 '(Ηΐ εΐ·8 '(Ηΐ 'ΖΗ Γ3 = f 'Ρ) 36"Ζ '(Ηΐ '^Η ) S9 T '(Ηΐ' s) ΐε · 0ΐ '(Ηΐ' s) 06 ・ 8 '(Ηΐ εΐ · 8' (Ηΐ 'ΖΗ Γ3 = f' Ρ) 36 "Ζ '(Ηΐ' ^ Η
8"Ζ = f 'Ρ) 06"Ζ '(Ηΐ 'ΖΗ S'Z = f 'Ρ) Ϊ8"Ζ '(Ηΐ 9ΓΖ '(Ηΐ 'ω) 09· - SS'Z '(Ηΐ 'ω  8 "Ζ = f 'Ρ) 06" Ζ' (Ηΐ 'ΖΗ S'Z = f' Ρ) Ϊ8 "Ζ '(Ηΐ 9ΓΖ' (Ηΐ 'ω) 09 ·-SS'Z' (Ηΐ 'ω
) Ζ0· - '(Η2 'ω) ΐ0· - 66·9 '(Ηΐ 's) Ζ8·9 '(Ηΐ 'ω) ZZ' -W '(Η 'ω) IZ'Z-WZ ) Ζ0 ·-'(Η2' ω) ΐ0 ·-66 · 9 '(Ηΐ' s) Ζ8 · 9 '(Ηΐ' ω) ZZ '-W' (Η 'ω) IZ'Z-WZ
'ω) Z6"T-26"T '(Η9 'ΖΗ S'9 = ΓΡ) 6ΐ·ΐ ( d) g ( OS 'z LZ) 醒 Ητ 'ω) Z6 "T-26"T' (Η9 ' Ζ Η S'9 = ΓΡ) 6ΐ · ΐ (d) g (OS' z LZ) Awakening Η τ
。 9呦^ 翁^; 拳 \ ¾f¾9SVi¾J^  . 9 呦 ^ 翁 ^; Fist \ ¾f¾9 SVi¾J ^
e¾x  e¾x
•(HI 's) εε·0ΐ '(Ηΐ 's) 66·8 '(Ηΐ ZZ'S '(Η  • (HI 's) εε · 0ΐ' (Ηΐ 's) 66 · 8' (Ηΐ ZZ'S '(Η
Ζ 'ω) 66· -06 '(Η2 'ω) ^8" -T8" '(Ηΐ 'ω) ΐ9·Ζ— 9S'Z '(Η2 'ω) 9^" -S^" Hf 'ω) es- -ss- '(Ηε '{ΗΖ <s) ΐε"3 '(ΗΪ ' 9ΐ' '(Η ζε'ε— ιε'ε Ζ 'ω) 66 · -06' (Η2 'ω) ^ 8 "-T8"' (Ηΐ 'ω) ΐ9 · Ζ— 9S'Z' (Η2 'ω) 9 ^ "-S ^"Hf' ω) es- -ss- '(Ηε' {ΗΖ <s ) ΐε "3 '(ΗΪ' 9ΐ '' (Η ζε'ε— ιε'ε
'ω) Z6"T-26"T '(Η9 'ΖΗ 9·9 = f 'Ρ) ΐ2"ΐ ( d) g ( OSWd 'z 00S) 醒 HT 'ω) Z6 "T-26"T' (Η9 ' Ζ Η 9 · 9 = f' Ρ) ΐ2 "ΐ (d) g (OSWd 'z 00S) Awakening H T
。 频 9  .频 9
SV呦^ べ fi 、 ェ [ / ¾ / -トべ f ( - ΐ-ベ ίίΰ ) - - ε}- 9- - 、^： べ:^- Ζ ¾^Ο)翁^; s¾i fi 拳 \ ¾f ¾、^ Xベ:^ [ — べ ( — ΐ—ベ ίίΰ )— a— N―、 E— ε、 ^osv呦^  SV 呦 ^ be fi, e [/ ¾ / -tobe f (-ΐ-Be ίίΰ)--ε}-9--, ^: be: ^-Ζ ¾ ^ Ο) 翁 ^; s¾i fi fist \ ¾f ¾, ^ XBe: ^ [— Be (— ΐ—Be ίίΰ) — a— N—, E— ε, ^ osv 呦 ^
ェ Ye
•(Ηΐ 'ω) ·8 '(Ηΐ 's -iq) 80·8 '(Ηΐ '8'S = f 'Ρ) WT8 '(Η • (Ηΐ 'ω) · 8' (Ηΐ 's -iq) 80 · 8' (Ηΐ '8'S = f' Ρ) WT8 '(Η
Ζ 'ω) 06"Z-S8"Z '(Ηΐ 'ω) 52- -6Γ '(Ηΐ '^Η 9·ΐ = f 'Ρ) '(Ηΐ '^Η 8·ΐ '8'S = f  Ζ 'ω) 06 "Z-S8" Z' (Ηΐ 'ω) 52- -6Γ' (Ηΐ '^ Η 9 · ΐ = f' Ρ) '(Ηΐ' ^ Η 8 · ΐ '8'S = f
'ΡΡ) 09·9 '(Η 'ω) iq-£-9V£ Hf 'ω) 20"2- 6"T ( d) g ( 3Q0 'z O S) 醒 HT xベ:^ [ - べ (ί ( - ΐ-ベ fici ) - ¾- N -、 E- ε ¾^ )翁^; ΐ¾ι ε 'ΡΡ) 09 · 9' (Η 'ω) iq- £ -9V £ Hf' ω) 20 "2-6" T (d) g (3Q0 'z OS) Awakening H T xBe: ^ [-Be ( ί (-ΐ-be fici)-¾- N-, E- ε ¾ ^) 翁 ^; ΐ¾ι ε
2¾ェ [6610] •(Ηΐ 2¾ [6610] • (Ηΐ
'ZH Z'S = f 'P) S8"Z '(HI 'ZH 6·ΐ 'Z"S = f 'PP) Z6' '(HI '^H 6·ΐ = f 'P) 8S"S '(H2 's jq) 96·ε ε ·ε— 8ε·ε '{ '^) 66·ΐ— 6·ΐ ( a) g ODQD 'z οοε) 醒 HT 'ZH Z'S = f' P) S8 "Z '(HI' ZH 6 · ΐ 'Z" S = f' PP) Z6 '' (HI '^ H 6 · ΐ = f' P) 8S "S '(H2 's jq) 96 · ε ε · ε— 8ε · ε'{'^) 66 · ΐ— 6 · ΐ (a) g ODQD' z οοε) Awakening H T
8L£ZU/900Zdr/13d ΐひ I/900Z OAV [ -ェ ( - ベ ^^^- s's'i- ^ 4 - s's w- ε]- N- , fi 8L £ ZU / 900Zdr / 13d ΐ ひ I / 900Z OAV [-E (-be ^^^-s's'i- ^ 4-s's w- ε]-N-, fi
Figure imgf000089_0001
[TOSO]
Figure imgf000089_0001
[TOSO]
•(HI 's) ΐε·0ΐ '(Ηΐ 's -iq) 98·8 '(Ηΐ '^Η Γ3 = f 'Ρ) 02"8 '(Ηΐ 's) S • (HI 's) ΐε · 0ΐ' (Ηΐ 's -iq) 98/8' (Ηΐ '^ Η Γ3 = f' Ρ) 02 "8 '(Ηΐ' s) S
6"Z '(Ηΐ 9L'L-£L'L '(Ηΐ 2^- - S" '(HI 's) C9"Z '(Ηΐ 'ω) εε· - 0S '(HS 'ω 6 "Z '(Ηΐ 9L'L- £ L'L' (Ηΐ 2 ^--S" '(HI' s) C9 "Z '(Ηΐ' ω) εε ·-0S '(HS' ω
) 00"Z-88"9 '(HI 's) ΐ8·9 '(Ηΐ 'ω) ½"S- 8"S Hf 'ω) ·ε- ·ε '(Η 'ω) 86·ΐ— S6'I ) 00 "Z-88" 9 '(HI' s) ΐ8 · 9 '(Ηΐ' ω) ½ "S-8" S Hf 'ω) · ε- · ε' (Η 'ω) 86 · ΐ— S6 'I
'ω) ZS'I- 9 ·ΐ '(Η9 'ΖΗ Z'L = f Ζ8 ( d) 9 ( OS 'z LZ) 醒 HT 'ω) ZS'I- 9 · ΐ' (Η9 ' Ζ Η Z'L = f Ζ8 (d) 9 (OS' z LZ) Awakening H T
。 呦^ 翁^;
Figure imgf000089_0002
.呦 ^ 翁 ^;
Figure imgf000089_0002
ε¾χ  ε¾χ
"(Ηΐ 's) "(Ηΐ 's)
S8'8 '(Ηΐ 'ΖΗ re = f 'Ρ) LZ'S '(HI ε8" '(HI 'ω) eL'L-SL'L '(HI L'L-L9'L S8'8 '(Ηΐ' ΖΗ re = f 'Ρ) LZ'S' (HI ε8 "'(HI' ω) eL'L-SL'L '(HI L'L-L9'L
'(HI 's) Z9'L '(HZ 'ω) ΖΥΙ-%τΐ '(Ηΐ 's) '(Ηΐ 's) S8'9 '(Ηΐ 'ω) 9 ·9- 9 '(Η2 '(HI' s) Z9'L '(HZ' ω) ΖΥΙ-% τΐ '(Ηΐ' s) '(Ηΐ' s) S8'9 '(Ηΐ' ω) 9 9-9 '(Η2
<s) s '(HI so's- IO'S '(HI π· -60· '(Η 'ω) ss's- 6 ·ε '(Η 'ω) wrs- ε <s ) s '(HI so's- IO'S' (HI π -60 ́ (Η 'ω) ss's-6 εε (Η' ω) wrs- ε
Ο'Ζ 'ω) 99·ΐ- SS'I '(Η9 'ΖΗ S'Z = f 86·0 ( d) g ( 3Q0 'z OOS) 醒 HT Ο'Ζ 'ω) 99 · ΐ- SS'I' (Η9 ' Ζ Η S'Z = f 86 · 0 (d) g (3Q0' z OOS) Awakening H T
°-Μ sv呦^ べ fi、 ^ { -ェ [ ^ -^ / - べ ίί ( - ΐ-ベ ίίΰ ) - ¾- ε}- 9- (,^ ^べ - ε)- ^： べ:^- ¾  ° -Μ sv 呦 ^ be fi, ^ {-e [^-^ /-be ίί (-ΐ- be ίίΰ)-¾- ε}-9- (, ^ ^ be-ε)-^: be: ^ -¾
^Ο)翁^; 3 ェ0)1^ 拳ヽ ¾f 邈べ^ r= / ^[ / ェ ( / - ベ ^ Ο) 翁 ^; 3 0 0) 1 ^ Fist ¾f ^ be ^ r = / ^ [/ é (/-
^^^- s's'i- ^ 4 - s's w- ε]- Ν -( / - ΐ -ベ;^ ri )- ¾a¾ sv呦^  ^^^-s's'i- ^ 4-s's w- ε]-Ν-(/-ΐ -be; ^ ri)-¾a¾ sv 呦 ^
•(HI 'ZH re = f 'Ρ) 9Z'S '(Ηΐ 'ω) 80·8- S0'8 '(Ηΐ 's -iq) 08· '(Ηΐ 'ω) ^Vl-Wl • (HI 'ZH re = f' Ρ) 9Z'S '(Ηΐ' ω) 80 · 8- S0'8 '(Ηΐ' s -iq) 08 · '(Ηΐ' ω) ^ Vl-Wl
'(Ηΐ 'ω) Ϊ9·Ζ- 6S.Z '(Ηΐ 'ω) ·Ζ- ΐ ·Ζ '(Ηΐ 'ω) 02" -SF '(Ηΐ 'ω) ΐ8·9- SZ'9 '(Η '(Ηΐ' ω) Ϊ9 · Ζ-6S.Z '(Ηΐ' ω) · Ζ- ΐ · Ζ '(Ηΐ' ω) 02 "-SF '(Ηΐ' ω) ΐ8 · 9- SZ'9 '( Η
'ω) g-£-6V£ 'ω) ΖΟΉΟ '( 's) ss'i ( a) g (ειつ αつ 'ζ LZ) 醒 HT 'ω) g- £ -6V £' ω) ΖΟΉΟ '(' s) ss'i (a) g (ε ι one α one 'ζ LZ) Awakening: H T
Figure imgf000089_0003
Figure imgf000089_0004
Figure imgf000089_0003
Figure imgf000089_0004
88 88
8L£Zl£/900Zdr/13d ΐひ I/900Z OAV ンズアミドを得た。 8L £ Zl £ / 900Zdr / 13d ΐ ひ I / 900Z OAV Nzamide was obtained.
1H NMR (270 MHz, CDCl ) δ (ppm) 1.35 (s, 12H), 1.61—1.73 (m, 6H), 3.23-3.27 (m,  1H NMR (270 MHz, CDCl) δ (ppm) 1.35 (s, 12H), 1.61—1.73 (m, 6H), 3.23-3.27 (m,
3  Three
4H), 7.09 (dd, J = 8.4, 2.4 Hz, IH), 7.16-7.19 (m, IH), 7.31 (d, J = 7.8 Hz, IH), 7. 43-7.46 (m, 2H), 7.57-7.59 (m, IH), 7.73-7.74 (m, IH), 7.80 (br s, IH), 8.09—8.12 (m, IH).  4H), 7.09 (dd, J = 8.4, 2.4 Hz, IH), 7.16-7.19 (m, IH), 7.31 (d, J = 7.8 Hz, IH), 7. 43-7.46 (m, 2H), 7.57 -7.59 (m, IH), 7.73-7.74 (m, IH), 7.80 (br s, IH), 8.09—8.12 (m, IH).
工程 2 Process 2
化合物A36及び3-ピぺリジノ-N-[3-(4,4,5,5-テトラメチル-l,3,2-ジォキサボロラン- 2-ィル)フエ-ル]ベンズアミドを用い、参考例 1の工程 5と同様の方法で 7-ベンジルォ キシ -2-イソプロピルァミノ- 6-{3-[3- (ピペリジノ)ベンゾィルァミノ]フエ-ル}キナゾリン（ 化合物 A58)を得た。  Reference Example 1 using Compound A36 and 3-piperidino-N- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) phenol] benzamide In the same manner as in Step 5, 7-benzyloxy-2-isopropylamino-6- {3- [3- (piperidino) benzoylamino] phenol} quinazoline (Compound A58) was obtained.
JH NMR (270 MHz, CDCl ) δ (ppm) 1.30 (d, J = 6.5 Hz, 6H), 1.59—1.71 (m, 6H), 3.2 J H NMR (270 MHz, CDCl) δ (ppm) 1.30 (d, J = 6.5 Hz, 6H), 1.59—1.71 (m, 6H), 3.2
3  Three
1-3.25 (m, 4H), 4.24-4.37 (m, IH), 5.09—5.11 (m, IH), 5.22 (s, 2H), 7.05-7.10 (m, 2H), 7.15-7.46 (m, 10H), 7.62 (s, IH), 7.66-7.70 (m, IH), 7.84-7.86 (m, 2H), 8.83 (s, IH).  1-3.25 (m, 4H), 4.24-4.37 (m, IH), 5.09—5.11 (m, IH), 5.22 (s, 2H), 7.05-7.10 (m, 2H), 7.15-7.46 (m, 10H ), 7.62 (s, IH), 7.66-7.70 (m, IH), 7.84-7.86 (m, 2H), 8.83 (s, IH).
工程 3 Process 3
化合物 A58を用い、参考例 32の工程 2と同様の方法でィ匕合物 48を得た。  Compound 48 was obtained in the same manner as in Step 2 of Reference Example 32 using Compound A58.
JH NMR (270 MHz, DMSO— d ) δ (ppm) 1.18 (d, J = 6.7 Hz, 6H), 1.56—1.64 (m, 6H), JH NMR (270 MHz, DMSO— d) δ (ppm) 1.18 (d, J = 6.7 Hz, 6H), 1.56—1.64 (m, 6H),
6  6
3.19-3.23 (m, 4H), 4.11-4.22 (m, IH), 6.85 (s, IH), 7.02 (d, J = 8.6 Hz, IH), 7.10 -7.16 (m, IH), 7.27-7.45 (m, 5H), 7.65 (s, IH), 7.76 (d, J = 7.3 Hz, IH), 7.96 (s, 1 H), 8.89 (s, IH), 10.17 (s, IH), 10.53 (br s, IH).  3.19-3.23 (m, 4H), 4.11-4.22 (m, IH), 6.85 (s, IH), 7.02 (d, J = 8.6 Hz, IH), 7.10 -7.16 (m, IH), 7.27-7.45 ( m, 5H), 7.65 (s, IH), 7.76 (d, J = 7.3 Hz, IH), 7.96 (s, 1 H), 8.89 (s, IH), 10.17 (s, IH), 10.53 (br s , IH).
参考例 49： 6-{3-[2-(4-フルォ口- 2-メチルフエ-ル)ピリジン- 4-ィルカルボ-ルァミノ] フエ-ル}- 7-ヒドロキシ- 2- (イソプロピルァミノ)キナゾリン（ィ匕合物 49) Reference Example 49: 6- {3- [2- (4-Fluoro-2-methylphenyl) pyridine-4-ylcarbo-lamino] phenol} -7-hydroxy-2- (isopropylamino) quinazoline ( 49)
工程 1 Process 1
4-フルォ口- 2-メチルフエ-ルボロン酸を用い、参考例 42の工程 1及び 2と同様の方 法で2-(4-フルォロ-2-メチルフヱ-ル)-N-[3-(4,4,5,5-テトラメチル-l,3,2-ジォキサ ボロラン- 2-ィル)フエ-ル]イソニコチン酸アミドを得た。  2- (4-Fluoro-2-methylphenol) -N- [3- (4-, 4-fluoro-2-methylphenylboronic acid was used in the same manner as in steps 1 and 2 of Reference Example 42. 4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl) phenol] isonicotinamide was obtained.
JH NMR (270 MHz, CDCl ) δ (ppm) 1.35 (s, 12H), 2.39 (s, 3H), 7.01-7.04 (m, 2H), J H NMR (270 MHz, CDCl) δ (ppm) 1.35 (s, 12H), 2.39 (s, 3H), 7.01-7.04 (m, 2H),
3  Three
7.14-7.10 (m, 2H), 7.39-7.46 (m, 2H), 7.62-7.64 (m, 2H), 7.78-7.85 (m, 2H), 8.05- ^^令 ^dT^ {-^y^
Figure imgf000091_0001
z m os晷攀 回 ΐ)醬攀蓁 M/— 、 ェ o)¾f»
Figure imgf000091_0002
z)Lzz- dYR 7.14-7.10 (m, 2H), 7.39-7.46 (m, 2H), 7.62-7.64 (m, 2H), 7.78-7.85 (m, 2H), 8.05- ^^ command ^ dT ^ {-^ y ^
Figure imgf000091_0001
zm os 晷 攀 times ΐ) 醬 攀 蓁 M / —, é o) ¾f »
Figure imgf000091_0002
z) Lzz- dYR
Z^ Zl-DdH^m 00Ϊ呦 #、 «ΐ呦^: ^ ^ ^ ^ΨΛ .Ο)^^ S'l、 Z ^ Zl-DdH ^ m 00Ϊ 呦 #, «ΐ 呦 ^: ^ ^ ^ ^ ΨΛ .Ο) ^^ S'l,
Figure imgf000091_0003
Figure imgf000091_0003
¾ [soso]  ¾ [soso]
\ΗΖ 'ω) Ζ3 ΐ-93 ΐ '(Ηΐ 06·8 '(Ηΐ '^Η Γ3 = f 'Ρ) \ ΗΖ 'ω) Ζ3 ΐ-93 93' (Ηΐ 06/8 '(Ηΐ' ^ Η Γ3 = f 'Ρ)
98·8 '(Ηΐ 's) 20"8 '(Ηΐ 66"Ζ '(Ηΐ '^Η S'l 'Γ3 = f 'ΡΡ) 98"Ζ '(Ηΐ 'ω) ΐ8· - 8ΓΖ ' (Ηΐ 's) 99"Ζ '(Ηΐ 'ΖΗ ε·9 ' ·8 = f 'ΡΡ) SS'Z '(Ηΐ '^Η 8"Ζ '8"Ζ = f 'ΡΡ) S^" '(Ηΐ '^Η 98 · 8 '(Ηΐ' s) 20 "8 '(Ηΐ 66" Ζ' (Ηΐ '^ Η S'l' Γ3 = f 'ΡΡ) 98 "Ζ' (Ηΐ 'ω) ΐ8 ·-8ΓΖ' (Ηΐ 's) 99 "Ζ' (Ηΐ 'ΖΗ ε · 9' · 8 = f 'ΡΡ) SS'Z' (Ηΐ '^ Η 8" Ζ' 8 "Ζ = f 'ΡΡ) S ^"' (Ηΐ ' ^ Η
8"Ζ = f 'Ρ) SS"Z ΗΖ 'ω) - SI'Z '(Ηΐ 'ω) 90· - '(Ηΐ 98·9 '(Ηΐ 'ω) QZ'f  8 "Ζ = f 'Ρ) SS" Z ΗΖ' ω)-SI'Z '(Ηΐ' ω) 90 ·-'(Ηΐ 98 · 9' (Ηΐ 'ω) QZ'f
-IVf '(HS 's) S£'Z '(Η9 'ΖΗ 9·9 = ΓΡ) 6ΐ·ΐ ( d) g ( OSWd 'z 00S) 醒 HT -IVf '(HS' s) S £ 'Z' (Η9 ' Ζ Η 9 · 9 = ΓΡ) 6ΐ · ΐ (d) g (OSWd' z 00S) Awakening H T
。 6 呦^ 翁^; s :r )^i^ 拳 w ^mv ^  . 6 呦 ^ 翁 ^; s: r) ^ i ^ fist w ^ mv ^
ε¾χ  ε¾χ
"(HS 'ω) 98·8- S8'8 '(Η9 'ω) 06"Z-T9"Z  "(HS 'ω) 98 · 8- S8'8' (Η9 'ω) 06" Z-T9 "Z
'(ΗΖ 'ω) S^- -22" '(Η 'ω) Ζ0· - 96·9 '(Η2 SS'S '(Ηΐ 'ω) irS-80"S '(Ηΐ 'ω) I  '(ΗΖ' ω) S ^--22 "'(Η' ω) Ζ0 ·-96 · 9 '(Η2 SS'S' (Ηΐ 'ω) irS-80" S' (Ηΐ 'ω) I
£'f- Z'f '(HS 's) 8S '(Η9 'ΖΗ Ζ·9 = f 'Ρ) OS"! ( d) g ( 3Q0 'z O S) 醒 HT £ 'f- Z'f' (HS 's) 8S' (Η9 ' Ζ Η 9 · 9 = f' Ρ) OS "! (D) g (3Q0 'z OS) Awakening H T
°
Figure imgf000091_0004
°
Figure imgf000091_0004
べ;^ ίί ( -ェ ^ - / - - ¾- S}- 9- 、^： べ:^- 翁^  Be; ^ ίί (-é ^-/--¾- S}-9-, ^: Be: ^-翁 ^
'ε'ΐ- ^ 4 - s's - ε]- N -( / -ェ ^ - ci / - - ¾α¾9εν呦 'ε'ΐ- ^ 4-s's-ε]-N-(/ -e ^-ci /--¾α¾9εν 呦
"(Ηΐ 'ZH V = f 'Ρ) 98·8 '(Ηΐ 'ω) Ζ0"8 "(Ηΐ 'ZH V = f' Ρ) 98 · 8 '(Ηΐ' ω) Ζ0" 8
06 06
8.CZTC/900Zdf/X3d ΐひ I/900Z OAV 産業上の利用可能性 8.CZTC / 900Zdf / X3d ΐ ひ I / 900Z OAV Industrial applicability
本発明により、 p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有する化 合物またはその薬理学的に許容される塩を有効成分として含有する局所投与剤等 が提供される。  INDUSTRIAL APPLICABILITY According to the present invention, a topical preparation or the like containing a compound having a p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof as an active ingredient is provided.

Claims

請求の範囲 The scope of the claims
[1] 局所投与された場合の p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有 する化合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿 中濃度に対して 350倍以上となる該 p38MAPK阻害作用を有する化合物またはその薬 理学的に許容される塩を有効成分として含有する該局所投与剤。  [1] The local concentration of a compound having p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or its pharmacologically acceptable salt when administered locally is 350 times or more of the plasma concentration. The topical administration agent comprising, as an active ingredient, a compound having a p38 MAPK inhibitory action or a pharmaceutically acceptable salt thereof.
[2] 局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩の該局所における濃度力 その血漿中濃度に対して 500倍以上となる 該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効成 分として含有する該局所投与剤。  [2] A compound having a P38 MAPK inhibitory action when administered locally or a local concentration of a pharmacologically acceptable salt thereof A compound having a P38 MAPK inhibitory action that is 500 times or more of its plasma concentration Or the topical administration agent containing the salt accept | permitted pharmacologically as an active ingredient.
[3] 局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩の該局所における濃度が、その血漿中濃度に対して 1000倍以上となる 該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効成 分として含有する該局所投与剤。  [3] Having a P38MAPK inhibitory action when the local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof is 1000 times or more of its plasma concentration when administered locally The topical administration agent comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient.
[4] 局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩の該局所における濃度力 その血漿中濃度に対して 2000倍以上となる 該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩を有効成 分として含有する該局所投与剤。  [4] A compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof locally when administered locally A compound having a P38 MAPK inhibitory action that is more than 2000 times its plasma concentration Or the topical administration agent containing the salt accept | permitted pharmacologically as an active ingredient.
[5] P38MAPK阻害作用を有する化合物力 フ ノール誘導体またはフ ノール構造を縮 環系に内包する縮環性複素環化合物である請求項 1〜4のいずれかに記載の局所 投与剤。  [5] The topical administration agent according to any one of claims 1 to 4, which is a compound power having a P38MAPK inhibitory action, a phenol derivative or a condensed heterocyclic compound containing a phenol structure in a condensed ring system.
[6] P38MAPK阻害作用を有する化合物が、式 (I)  [6] A compound having P38MAPK inhibitory activity is represented by the formula (I)
[化 14]  [Chemical 14]
Figure imgf000093_0001
Figure imgf000093_0001
[式中、 R1及び R2は同一または異なって、水素原子、置換もしくは非置換の低級アル キル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキ-ル 、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケ-ル、置 換もしくは非置換の低級アルカノィル、置換もしくは非置換の低級シクロアルキル力 ルポニル、置換もしくは非置換のァリール、置換もしくは非置換の複素環基または CO NR5aR5b (式中、 R5a及び R5bは同一または異なって、水素原子または置換もしくは非置 換の低級アルキルを表す)を表し、 [Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, Kill, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted A lower cycloalkyl group of sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or CO NR 5a R 5b (wherein R 5a and R 5b are the same or different and represent a hydrogen atom or substituted or unsubstituted Represents a substituted lower alkyl),
Xは結合、酸素原子、硫黄原子、 CR6aR6b (式中、 R6a及び R6bは同一または異なって、 水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキルまたは置換もし くは非置換の低級アルコキシを表す力、または R6a及び R6bが一緒になつて酸素原子を 表す)または NR7 (式中、 R7は水素原子、置換もしくは非置換の低級アルキルまたは 置換もしくは非置換の低級アルカノィルを表す)を表し、 X is a bond, oxygen atom, sulfur atom, CR 6a R 6b (wherein R 6a and R 6b are the same or different, hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl or substituted or unsubstituted) Or a NR 7 (wherein R 7 is a hydrogen atom, a substituted or unsubstituted lower alkyl, or a substituted or unsubstituted lower group), or R 6a and R 6b together represent an oxygen atom. Represents alkanoyl),
Xが結合または CR6aR6b (式中、 R6a及び R6bはそれぞれ前記と同義である)である場合、 R3は置換もしくは非置換の低級アルコキシ、置換もしくは非置換のァリール、置換もし くは非置換の芳香族複素環基または NR8aR8b (式中、 R 及び R8bは同一または異なつ て、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アル ケ -ル、置換もしくは非置換の低級アルキ -ル、置換もしくは非置換のシクロアルキ ル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換のァリールまたは置 換もしくは非置換の複素環基を表すか、または R及び R8bが隣接する窒素原子と一 緒になって置換もしくは非置換の複素環基を形成する）を表し、 When X is a bond or CR 6a R 6b (wherein R 6a and R 6b are as defined above), R 3 is a substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted. Is an unsubstituted aromatic heterocyclic group or NR 8a R 8b (wherein R and R 8b are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl, Represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or R and R 8b together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocyclic group)
Xが酸素原子、硫黄原子または NR7 (式中、 R7は前記と同義である）である場合、 R3は 置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を表し、 R4は水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もし くは非置換の低級ァルケ-ル、置換もしくは非置換の低級アルコキシ、置換もしくは 非置換のァリール、置換もしくは非置換の複素環基、 CONR9aR9b (式中、 R9a及び R9bは それぞれ前記 R8a及び R8bと同義である）または COR1Q (式中、 R1Qは水素原子、ヒドロキ シ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級ァルケ-ル、置 換もしくは非置換の低級アルキ-ル、置換もしくは非置換のシクロアルキル、置換もし くは非置換の低級アルコキシ、置換もしくは非置換のァリールまたは置換もしくは非 置換の複素環基を表す)を表す]で表される 2-アミノキナゾリン誘導体またはその薬 理学的に許容される塩である請求項 1〜4のいずれかに記載の局所投与剤。 When X is an oxygen atom, a sulfur atom or NR 7 (wherein R 7 is as defined above), R 3 represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group; R 4 is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted Heterocyclic group, CONR 9a R 9b (wherein R 9a and R 9b are as defined above for R 8a and R 8b respectively) or COR 1Q (wherein R 1Q is a hydrogen atom, hydroxy, substituted or unsubstituted) Lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted alkyl Reel or replacement or non 5. The topical administration agent according to any one of claims 1 to 4, which is a 2-aminoquinazoline derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
[7] R1が水素原子であり、 R2が置換もしくは非置換の低級アルキルである請求項 6記載の 局所投与剤。 7. The topical administration agent according to claim 6, wherein R 1 is a hydrogen atom, and R 2 is substituted or unsubstituted lower alkyl.
[8] Xが結合である請求項 6または 7記載の局所投与剤。  [8] The topical administration agent according to claim 6 or 7, wherein X is a bond.
[9] Xが C=0である請求項 6または 7記載の局所投与剤。 [9] The topical administration agent according to claim 6 or 7, wherein X is C = 0.
[10] R3が置換もしくは非置換のァリールである請求項 6〜9の 、ずれかに記載の局所投 与剤。 [10] according to claim 6 to 9 R 3 is Ariru substituted or unsubstituted, topical throw Azukazai according to any misalignment.
[11] R4が水素原子である請求項 6〜10のいずれかに記載の局所投与剤。 [11] Topical administration preparation according to any one of claims 6 to 10 R 4 is a hydrogen atom.
[12] R4がハロゲンまたは置換もしくは非置換のァリールである請求項 6〜 10のいずれかに 記載の局所投与剤。 [12] Topical administration preparation according to any one of claims. 6 to 10 R 4 is Ariru halogen or substituted or unsubstituted.
[13] P38MAPK阻害作用を有する化合物力 式 (IA) [13] P38MAPK inhibitory activity Compound (IA)
[化 15]  [Chemical 15]
Figure imgf000095_0001
Figure imgf000095_0001
{式中、 x、
Figure imgf000095_0002
R3及び R4はそれぞれ前記と同義であり、 {Where x,
Figure imgf000095_0002
R 3 and R 4 are as defined above,
R2aは置換もしくは非置換のァリール、置換もしくは非置換のァラルキル、置換もしくは 非置換の芳香族複素環基または CRUR12R13 [式中、 R11は水素原子または置換もしく は非置換の低級アルキルを表し、 R 2a is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic group, or CR U R 12 R 13 [wherein R 11 is a hydrogen atom or substituted or unsubstituted Represents lower alkyl of
R12及び R13は同一または異なって、水素原子、置換もしくは非置換の低級アルキル、 OR14 (式中、 R14は水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置 換の低級アルケニル、置換もしくは非置換の低級アルキ-ル、置換もしくは非置換の シクロアルキル、置換もしくは非置換のァリールまたは置換もしくは非置換の複素環 基を表す)、 S(O) R1½ (式中、 R1½は前記 R14と同義であり、 pは 0〜2の整数を表す)、 C R 12 and R 13 are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, OR 14 (wherein R 14 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl. Represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), S (O) R 1½ (wherein R 1½ Is synonymous with R 14 above, p represents an integer of 0-2), C
P P
OR14b (式中、 R14bは前記 R14と同義である）、 CO R14e (式中、 ま前記 R14と同義である OR 14b (wherein, R 14b has the same meaning as the R 14), in CO R 14e (Formula have the same meanings as or said R 14
2  2
)、 CONR15aR15b (式中、 R15a及び R15bはそれぞれ前記 R及び R8bと同義である)または S( O) NR15 15d (式中、 R15e及び R15dはそれぞれ前記 R及び R8bと同義である）を表すか、), CONR 15a R 15b (wherein R 15a and R 15b have the same meanings as R and R 8b , respectively) or S ( O) NR 15 15d (wherein R 15e and R 15d have the same meanings as R and R 8b , respectively),
2 2
または R12及び R13が隣接する炭素原子と一緒になつて置換もしくは非置換のシクロア ルキルまたは置換もしくは非置換の脂環式複素環基を形成する。ただし、 R11が水素 原子である場合、 R12及び R13は同時に水素原子にはならない]を表す }で表される 2- アミノキナゾリン誘導体またはその薬理学的に許容される塩である請求項 1〜4のい ずれかに記載の局所投与剤。 Or R 12 and R 13 together with the adjacent carbon atom form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted alicyclic heterocyclic group. However, when R 11 is a hydrogen atom, R 12 and R 13 do not become a hydrogen atom at the same time.] Or a pharmacologically acceptable salt thereof. The topical administration agent according to any one of 1 to 4.
[14] R1が水素原子である請求項 13記載の局所投与剤。 14. The topical administration agent according to claim 13, wherein R 1 is a hydrogen atom.
[15] R2aが CRUaR12aR13a (式中、 RUaは水素原子または置換もしくは非置換の低級アルキル を表し、 [15] R 2a is CR Ua R 12a R 13a (wherein R Ua represents a hydrogen atom or a substituted or unsubstituted lower alkyl,
R12a及び R13aは同一または異なって、水素原子または置換もしくは非置換の低級アル キルを表すか、または R12a及び R13aが隣接する炭素原子と一緒になつて置換もしくは 非置換のシクロアルキルまたは置換もしくは非置換の脂環式複素環基を形成する。 ただし、 RUaが水素原子である場合、 R12a及び R13aは同時に水素原子にはならない)で ある請求項 13または 14記載の局所投与剤。 R 12a and R 13a are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R 12a and R 13a together with an adjacent carbon atom are substituted or unsubstituted cycloalkyl or Forms a substituted or unsubstituted alicyclic heterocyclic group. However, when R Ua is a hydrogen atom, R 12a and R 13a do not simultaneously become a hydrogen atom).
[16] Xが結合である請求項 13〜 15のいずれかに記載の局所投与剤。 [16] The topical administration agent according to any one of claims 13 to 15, wherein X is a bond.
[17] Xが CR6aR6b (式中、 R6a及び R6bはそれぞれ前記と同義である）であり、 R3が置換もしくは 非置換のァリールである請求項 13〜 15の 、ずれかに記載の局所投与剤。 [17] X is CR 6a R 6b (wherein R 6a and R 6b are as defined above), and R 3 is a substituted or unsubstituted aryl. The topical administration agent described.
[18] R6a及び R6bが一緒になつて酸素原子を表す請求項 17記載の局所投与剤。 18. The topical administration according to claim 17, wherein R 6a and R 6b together represent an oxygen atom.
[19] R4が水素原子である請求項 13〜18のいずれかに記載の局所投与剤。 [19] Topical administration preparation according to any one of claims 13 to 18 R 4 is a hydrogen atom.
[20] R4がハロゲンまたは置換もしくは非置換のァリールである請求項 13〜18のいずれか に記載の局所投与剤。 [20] Topical administration preparation according to any one of claims 13 to 18 R 4 is Ariru halogen or substituted or unsubstituted.
[21] P38MAPK阻害作用を有する化合物力 式 (IB) [21] P38MAPK inhibitory activity (IB)
[化 16]  [Chemical 16]
Figure imgf000096_0001
〈式中、 R4及び Xはそれぞれ前記と同義であり、
Figure imgf000096_0001
Wherein R 4 and X are as defined above,
qは 0または 1を表し、  q represents 0 or 1,
rは 0〜4の整数を表し、  r represents an integer from 0 to 4,
Yは酸素原子、 C=0、 NR17 (式中、 R17は水素原子、スルフィ入カルボキシ、置換もしく は非置換の低級アルキル、置換もしくは非置換の低級アルカノィル、置換もしくは非 置換の低級アルコキシカルボ-ルまたは置換もしくは非置換の低級アルキルスルホ -ルを表す)または CHR18{式中、 R18は水素原子、ヒドロキシ、アミ入カルボキシ、ス ルフィ入置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ 、モノもしくはジ (置換もしくは非置換の低級アルキル)アミ入置換もしくは非置換の低 級アルカノィル、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置 換の低級アルキルスルホ -ル、 NR19COR2° [式中、 R19は水素原子または置換もしくは 非置換の低級アルキルを表し、 R2°はァミノ、置換もしくは非置換の低級アルキル、置 換もしくは非置換の低級アルコキシまたはモノもしくはジ (置換もしくは非置換の低級 アルキル)アミノを表す]または NR19aS(0) R2°a (式中、 R19a及び R2°aはそれぞれ前記 R19 Y is an oxygen atom, C = 0, NR 17 (wherein R 17 is a hydrogen atom, sulfiated carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxy Carb or substituted or unsubstituted lower alkyl sulfol) or CHR 18 (wherein R 18 is a hydrogen atom, hydroxy, amino-substituted carboxy, sulfur-substituted substituted or unsubstituted lower alkyl, substituted or unsubstituted Substituted lower alkoxy, mono or di (substituted or unsubstituted lower alkyl) amino-substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkyl sulfol, NR 19 COR 2 ° [wherein, R 19 represents a hydrogen atom or a substituted or unsubstituted lower alkyl, R 2 ° is Amino, lay be substituted Unsubstituted lower alkyl, substitution or unsubstituted lower alkoxy or mono- or di represents an amino (substituted or unsubstituted lower alkyl) or NR 19a S (0) R 2 ° a ( wherein, R 19a and R 2 ° a is R 19
2  2
及び R2°と同義である）を表し }を表し、 And R 2 °).
R3aは置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を 表し、 R 3a represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group,
R16はァミノ、ヒドロキシ、スルフィ入カルボキシ、置換もしくは非置換の低級アルキル 、置換もしくは非置換の低級アルコキシ、モノもしくはジ (置換もしくは非置換の低級ァ ルキル)アミ入置換もしくは非置換の低級アルカノィル、置換もしくは非置換の低級ァ ルコキシカルボ-ル、置換もしくは非置換の低級アルキルスルホ -ル、 NR21aCOR22a ( 式中、 R21a及び R22aはそれぞれ前記 R19及び R2°と同義である）または NR21bS(0) R22b (式 R 16 is amino, hydroxy, sulfi-substituted carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, mono- or di (substituted or unsubstituted lower alkyl) ami-substituted or unsubstituted lower alkanol, Substituted or unsubstituted lower alkoxy carbonyl, substituted or unsubstituted lower alkyl sulfonate, NR 21a COR 22a (wherein R 21a and R 22a are as defined above for R 19 and R 2 °, respectively) or NR 21b S (0) R 22b (Formula
2 中、 R21b及び R22bはそれぞれ前記 R19及び R2°と同義である）を表す。ただし、 rが 2〜4の 整数である場合は、それぞれの R16は同一でも異なって 、てもよ 、〉で表される 2-アミ ノキナゾリン誘導体またはその薬理学的に許容される塩である請求項 1〜4のいずれ かに記載の局所投与剤。 2, R 21b and R 22b are the same as R 19 and R 2 °, respectively. However, when r is an integer of 2 to 4, each R 16 may be the same or different, and is a 2-aminoquinazoline derivative represented by> or a pharmacologically acceptable salt thereof. The topical administration agent according to any one of claims 1 to 4.
[22] Xが結合である請求項 21記載の局所投与剤。  [22] The topical administration agent according to claim 21, wherein X is a bond.
[23] R4が水素原子である請求項 21または 22記載の局所投与剤。 [24] 式 (IC) [23] R 4 is topical agent according to claim 21 or 22, wherein a hydrogen atom. [24] Formula (IC)
[化 17]  [Chemical 17]
Figure imgf000098_0001
Figure imgf000098_0001
(式中、 Rla及び R2bは同一または異なって、水素原子、置換もしくは非置換の低級ァ ルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換のシクロアルキ ルまたは置換もしくは非置換のシクロアルケ-ルを表し、 (Wherein R la and R 2b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted cycloalkenyl; Represents
R3bは置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を 表し、 R 3b represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group,
R4aは水素原子またはハロゲンを表し、 R 4a represents a hydrogen atom or halogen,
Xaは酸素原子または硫黄原子を表す)で表される 2-アミノキナゾリン誘導体またはそ の薬理学的に許容される塩。 X a 2-aminoquinazoline derivative or its pharmacologically acceptable salt represented by an oxygen atom or a sulfur atom).
[25] Rla及び R2bが同一または異なって水素原子または置換もしくは非置換の低級アルキ ルである請求項 24記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容され る塩。 [25] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to [24], wherein R la and R 2b are the same or different and each is a hydrogen atom or a substituted or unsubstituted lower alkyl.
[26] Rlaが水素原子であり、 R2bが置換もしくは非置換の低級アルキルである請求項 24記 載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 26. The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 24, wherein R la is a hydrogen atom, and R 2b is substituted or unsubstituted lower alkyl.
[27] Rlaが水素原子であり、 R2bが 2-プロピルである請求項 24記載の 2-アミノキナゾリン誘 導体またはその薬理学的に許容される塩。 27. The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 24, wherein R la is a hydrogen atom and R 2b is 2-propyl.
[28] R3bが置換もしくは非置換のァリールである請求項 24〜27のいずれかに記載の 2-ァ ミノキナゾリン誘導体またはその薬理学的に許容される塩。 [28] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 24 to 27, wherein R 3b is a substituted or unsubstituted aryl.
[29] R3bがフエニルである請求項 24〜27のいずれかに記載の 2-アミノキナゾリン誘導体ま たはその薬理学的に許容される塩。 [29] The 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to any one of claims 24 to 27, wherein R 3b is phenyl.
[30] R½が水素原子である請求項 24〜29のいずれかに記載の 2-アミノキナゾリン誘導体 またはその薬理学的に許容される塩。 [30] The 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to any one of claims 24 to 29, wherein R ½ is a hydrogen atom.
[31] Xaが酸素原子である請求項 24〜30のいずれかに記載の 2-アミノキナゾリン誘導体ま たはその薬理学的に許容される塩。 [31] The 2-aminoquinazoline derivative according to any one of claims 24 to 30, wherein X a is an oxygen atom. Or a pharmacologically acceptable salt thereof.
式（ID)  Expression (ID)
[化 18]
Figure imgf000099_0001
[Chemical 18]
Figure imgf000099_0001
(式中、 R2A及び R3Aはそれぞれ前記と同義である）で表される 2-アミノキナゾリン誘導 体またはその薬理学的に許容される塩。 (Wherein, R 2A and R 3A are as defined above) or a pharmacologically acceptable salt thereof.
[33] R2Aが CRUAR12AR13A (式中、 RUA、 R12A及び R13Aはそれぞれ前記と同義である）である請求 項 32記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 [33] The 2-aminoquinazoline derivative or the pharmacologically thereof according to claim 32, wherein R 2A is CR UA R 12A R 13A (wherein R UA , R 12A and R 13A are as defined above). Acceptable salt.
[34] R3Aが置換もしくは非置換のァリールである請求項 32または 33記載の 2-アミノキナゾリ ン誘導体またはその薬理学的に許容される塩。 [34] The 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to claim 32 or 33, wherein R 3A is a substituted or unsubstituted aryl.
[35] R3Aが置換もしくは非置換のフエ-ルである請求項 32または 33記載の 2-アミノキナゾ リン誘導体またはその薬理学的に許容される塩。 [35] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein R 3A is a substituted or unsubstituted file.
[36] R3Aが [36] R 3A
[化 19]  [Chemical 19]
Figure imgf000099_0002
Figure imgf000099_0002
[式中、 sは 0〜4の整数を表し、  [Wherein s represents an integer of 0 to 4,
R23は水素原子、ハロゲンまたは低級アルキルを表し、 R 23 represents a hydrogen atom, halogen or lower alkyl,
R24は低級アルキル、シクロアルキル、低級アルコキシ、ァリール、置換基 A力 選ば れる 1つ〜置換可能な数の置換基で置換されたァリール、芳香族複素環基または置 換基 A力 選ばれる 1つ〜置換可能な数の置換基で置換された芳香族複素環基を表 す。ただし、 sが 2〜4の整数である場合は、それぞれの R23は同一でも異なっていても よい； 置換基 A:ノヽロゲン、低級アルキル、ヒドロキシ低級アルキル、シクロアルキル、ァリー ル、 1つ〜置換可能な数のハロゲン及び Zもしくは 1つ〜置換可能な数の低級アルキ ルで置換されたァリール、 -NR25aR25b (式中、 R25a及び R25bは同一または異なって水素 原子、低級アルキルまたはシクロアルキルを表す力、または R25a及び R25bが隣接する 窒素原子と一緒になつて脂環式複素環基または 1つ〜置換可能な数の低級アルキ ルで置換された脂環式複素環基を形成する） ]である請求項 32または 33記載の 2-ァ ミノキナゾリン誘導体またはその薬理学的に許容される塩。 R 24 is selected from lower alkyl, cycloalkyl, lower alkoxy, aryl, substituent A force selected from 1 to aryl substituted with a substitutable number of substituents, aromatic heterocyclic group or substituent A force 1 Represents an aromatic heterocyclic group substituted with one to a substitutable number of substituents. Provided that when s is an integer from 2 to 4, each R 23 may be the same or different; Substituent A: Neurogen, lower alkyl, hydroxy lower alkyl, cycloalkyl, aryl, 1 to substitutable number of halogens and Z or 1 to substitutable number of lower alkyl substituted with- NR 25a R 25b (wherein R 25a and R 25b are the same or different and represent a hydrogen atom, lower alkyl or cycloalkyl, or R 25a and R 25b together with the adjacent nitrogen atom are cycloaliphatic A 2-aminoquinazoline derivative according to claim 32 or 33, or a pharmacologically thereof, which forms a cyclic group or an alicyclic heterocyclic group substituted with one to a substitutable number of lower alkyl). Acceptable salt.
[37] R24が- NR25aR25b (式中、 R25a及び R25bはそれぞれ前記と同義である)で置換されたフエ -ルまたは- NR25aR25b (式中、 R25a及び R25bはそれぞれ前記と同義である）で置換され たピリジルである請求項 36記載の 2-アミノキナゾリン誘導体またはその薬理学的に許 容される塩。 [37] R 24 is - (wherein, R 25a and R 25b have the same meanings as defined above) NR 25a R 25b is substituted with Hue - le or - NR 25a R 25b (wherein, R 25a and R 25b 37. The 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to claim 36, which is pyridyl substituted with the same meaning as defined above.
[38] R24が 1つ〜置換可能な数のハロゲン及び Zもしくは 1つ〜置換可能な数の低級アル キルで置換されたフエ-ルで置換されたフエ-ル、または 1つ〜置換可能な数のハロ ゲン及び Zもしくは 1つ〜置換可能な数の低級アルキルで置換されたフエ二ルで置 換されたピリジルである請求項 36記載の 2-アミノキナゾリン誘導体またはその薬理学 的に許容される塩。 [38] R 24 is substituted with 1 to substitutable number of halogens and Z or 1 to substitutable number of lower alkyl substituted phenyl, or 1 to substitutable 37. A 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 36, which is pyridyl substituted with any number of halogens and Z or phenyl substituted with 1 to a substitutable number of lower alkyl. Salt.
[39] R3aが [39] R 3a
[化 20]  [Chemical 20]
Figure imgf000100_0001
Figure imgf000100_0001
(式中、 s、 R23及び R24はそれぞれ前記と同義である）である請求項 32または 33記載 の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 34. The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 32 or 33, wherein s, R 23 and R 24 are as defined above.
[40] sが 1であり、 R23が低級アルキルであり、 R24がシクロアルキルである請求項 39記載の 2 -ァミノキナゾリン誘導体またはその薬理学的に許容される塩。 [40] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 39, wherein s is 1, R 23 is lower alkyl, and R 24 is cycloalkyl.
[41] 式 (IE) [化 21] [41] Formula (IE) [Chemical 21]
Figure imgf000101_0001
Figure imgf000101_0001
(式中、 Rla、 R2a及び R3aはそれぞれ前記と同義であり、 (Wherein, R la , R 2a and R 3a are as defined above,
R4bは置換もしくは非置換のァリールまたは置換もしくは非置換の芳香族複素環基を 表す)で表される 2-ァミノキナゾリン誘導体またはその薬理学的に許容される塩。 R 4b represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group) or a pharmacologically acceptable salt thereof.
[42] Rlaが水素原子であり、 R2aが CRUaR12aR13a (式中、 RUa、 R12a及び R13aはそれぞれ前記と 同義である）である請求項 41記載の 2-アミノキナゾリン誘導体またはその薬理学的に 許容される塩。 42. The 2-amino of claim 41, wherein R la is a hydrogen atom, and R 2a is CR Ua R 12a R 13a (wherein R Ua , R 12a and R 13a are as defined above). A quinazoline derivative or a pharmacologically acceptable salt thereof.
[43] R3aが置換もしくは非置換のァリールである請求項 41または 42記載の 2-アミノキナゾリ ン誘導体またはその薬理学的に許容される塩。 [43] The 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to claim 41 or 42, wherein R 3a is a substituted or unsubstituted aryl.
[44] R3aが置換もしくは非置換のフエ-ルである請求項 41または 42記載の 2-アミノキナゾ リン誘導体またはその薬理学的に許容される塩。 [44] The 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to claim 41 or 42, wherein R 3a is a substituted or unsubstituted file.
[45] R4bが置換もしくは非置換のァリールである請求項 41〜44のいずれかに記載の 2-ァ ミノキナゾリン誘導体またはその薬理学的に許容される塩。 [45] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 41 to 44, wherein R 4b is a substituted or unsubstituted aryl.
[46] R4bが置換もしくは非置換のフエ-ルである請求項 41〜44のいずれかに記載の 2-ァ ミノキナゾリン誘導体またはその薬理学的に許容される塩。 [46] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 41 to 44, wherein R 4b is a substituted or unsubstituted file.
[47] R4bが置換もしくは非置換の芳香族複素環基である請求項 41〜44のいずれかに記 載の 2-アミノキナゾリン誘導体またはその薬理学的に許容される塩。 [47] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 41 to 44, wherein R 4b is a substituted or unsubstituted aromatic heterocyclic group.
[48] R4bが置換もしくは非置換のピリジルである請求項 41〜44のいずれかに記載の 2-アミ ノキナゾリン誘導体またはその薬理学的に許容される塩。 [48] The 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 41 to 44, wherein R4b is substituted or unsubstituted pyridyl.
[49] p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有する化合物が、請求項[49] A compound having a p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action,
24〜48のいずれかに記載の 2-アミノキナゾリン誘導体またはその薬理学的に許容さ れる塩である請求項 1〜4のいずれかに記載の局所投与剤。 The topical administration agent according to any one of claims 1 to 4, which is the 2-aminoquinazoline derivative or a pharmacologically acceptable salt thereof according to any one of 24-48.
[50] p38MAPK (Mitogen- Activated Protein Kinase)阻害作用がァロステリック阻害に基づ く作用であることを特徴とする、請求項 1〜23及び 49のいずれかに記載の局所投与 剤。 [50] The topical administration according to any one of claims 1 to 23 and 49, wherein the p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action is an action based on allosteric inhibition. Agent.
[51] 局所投与された場合の p38MAPK (Mitogen- Activated Protein Kinase)阻害作用を有 する化合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿 中濃度に対して 350倍以上となる該 p38MAPK阻害作用を有する化合物またはその薬 理学的に許容される塩の有効量を投与する工程を含む、該局所投与による疾患の 治療方法。  [51] When administered locally, the local concentration of a compound having p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof is 350 times or more of the plasma concentration. A method for treating a disease by local administration, comprising a step of administering an effective amount of the compound having a p38 MAPK inhibitory action or a pharmaceutically acceptable salt thereof.
[52] 局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩の該局所における濃度力 その血漿中濃度に対して 500倍以上となる 該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩の有効量 を投与する工程を含む、該局所投与による疾患の治療方法。  [52] A compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof when locally administered The compound having a P38 MAPK inhibitory action is more than 500 times its plasma concentration Or a method for treating a disease by local administration, comprising a step of administering an effective amount of a pharmacologically acceptable salt thereof.
[53] 局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩の該局所における濃度が、その血漿中濃度に対して 1000倍以上となる 該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩の有効量 を投与する工程を含む、該局所投与による疾患の治療方法。  [53] The local concentration of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof when administered topically is 1000 times or more the plasma concentration thereof. A method for treating a disease by local administration, comprising a step of administering an effective amount of a compound or a pharmacologically acceptable salt thereof.
[54] 局所投与された場合の P38MAPK阻害作用を有する化合物またはその薬理学的に 許容される塩の該局所における濃度力 その血漿中濃度に対して 2000倍以上となる 該 P38MAPK阻害作用を有する化合物またはその薬理学的に許容される塩の有効量 を投与する工程を含む、該局所投与による疾患の治療方法。  [54] A compound having a P38 MAPK inhibitory action or a pharmacologically acceptable salt thereof locally when administered locally The compound having a P38 MAPK inhibitory action more than 2000 times its plasma concentration Or a method for treating a disease by local administration, comprising a step of administering an effective amount of a pharmacologically acceptable salt thereof.
[55] P38MAPK阻害作用を有する化合物力 フ ノール誘導体またはフ ノール構造を縮 環系に内包する縮環性複素環化合物である請求項 51〜54の 、ずれかに記載の治 療方法。  [55] The therapeutic method according to any one of claims 51 to 54, which is a compound power having a P38 MAPK inhibitory action, or a condensed heterocyclic compound containing a phenol derivative or a phenol structure in a condensed ring system.
[56] P38MAPK阻害作用を有する化合物力 請求項 6〜23のいずれかに記載の 2-ァミノ キナゾリン誘導体またはその薬理学的に許容される塩である請求項 51〜54のいず れかに記載の治療方法。  [56] Compound power having P38 MAPK inhibitory activity The 2-amino quinazoline derivative or the pharmacologically acceptable salt thereof according to any one of claims 6 to 23. Treatment methods.
[57] P38MAPK阻害作用を有する化合物力 請求項 24〜48のいずれかに記載の 2-ァミノ キナゾリン誘導体またはその薬理学的に許容される塩である請求項 51〜54のいず れかに記載の治療方法。 [57] Compound power having P38 MAPK inhibitory activity The 2-amino quinazoline derivative or the pharmacologically acceptable salt thereof according to any one of claims 24 to 48. Treatment methods.
[58] p38MAPK (Mitogen- Activated Protein Kinase)阻害作用がァロステリック阻害に基づ く作用であることを特徴とする、請求項 51〜 57記載の治療方法。 [58] Inhibition of p38MAPK (Mitogen-Activated Protein Kinase) is based on allosteric inhibition 58. The method of treatment according to any one of claims 51 to 57, wherein the method is an action.
[59] 局所投与剤の製造のための、局所投与された場合の p38MAPK(Mitogen-Activated Protein Kinase)阻害作用を有する化合物またはその薬理学的に許容される塩の該 局所における濃度が、その血漿中濃度に対して 350倍以上となる該 p38MAPK阻害作 用を有する化合物またはその薬理学的に許容される塩の使用。  [59] For the production of a topical preparation, the local concentration of a compound having a p38 MAPK (Mitogen-Activated Protein Kinase) inhibitory action or a pharmacologically acceptable salt thereof when administered locally is Use of a compound having a p38MAPK inhibitory action which is 350 times or more of the medium concentration or a pharmacologically acceptable salt thereof.
[60] 局所投与剤の製造のための、局所投与された場合の P38MAPK阻害作用を有する化 合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿中濃 度に対して 500倍以上となる該 P38MAPK阻害作用を有する化合物またはその薬理 学的に許容される塩の使用。  [60] For the production of a topical preparation, the local concentration of a compound having a P38 MAPK inhibitory effect or its pharmacologically acceptable salt when administered topically is compared to its plasma concentration. Use of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof that is 500 times or more.
[61] 局所投与剤の製造のための、局所投与された場合の P38MAPK阻害作用を有する化 合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿中濃 度に対して 1000倍以上となる該 P38MAPK阻害作用を有する化合物またはその薬理 学的に許容される塩の使用。  [61] For the production of a topical preparation, the local concentration of a compound having a P38MAPK inhibitory effect or its pharmacologically acceptable salt when administered topically is compared to its plasma concentration. Use of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof which is 1000 times or more.
[62] 局所投与剤の製造のための、局所投与された場合の P38MAPK阻害作用を有する化 合物またはその薬理学的に許容される塩の該局所における濃度が、その血漿中濃 度に対して 2000倍以上となる該 P38MAPK阻害作用を有する化合物またはその薬理 学的に許容される塩の使用。  [62] For the production of a topical preparation, the local concentration of a compound having a P38 MAPK inhibitory effect or its pharmacologically acceptable salt when administered topically is compared to its plasma concentration. Use of a compound having a P38MAPK inhibitory action or a pharmacologically acceptable salt thereof that is 2000 times or more.
[63] P38MAPK阻害作用を有する化合物力 フ ノール誘導体またはフ ノール構造を縮 環系に内包する縮環性複素環化合物である請求項 59〜62のいずれかに記載の使 用。  [63] The use according to any one of claims 59 to 62, wherein the compound has a P38MAPK inhibitory action and is a condensed heterocyclic compound encapsulating a phenol derivative or a phenol structure in a condensed ring system.
[64] P38MAPK阻害作用を有する化合物力 請求項 6〜23のいずれかに記載の 2-ァミノ キナゾリン誘導体またはその薬理学的に許容される塩である請求項 59〜62のいず れかに記載の使用。  [64] Compound power having P38 MAPK inhibitory action The 2-amino quinazoline derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 23. Use of.
[65] P38MAPK阻害作用を有する化合物力 請求項 24〜48のいずれかに記載の 2-ァミノ キナゾリン誘導体またはその薬理学的に許容される塩である請求項 59〜62のいず れかに記載の使用。  [65] Compound power having P38 MAPK inhibitory activity The 2-amino quinazoline derivative according to any one of claims 24-48 or a pharmacologically acceptable salt thereof, according to any one of claims 59-62. Use of.
[66] p38MAPK (Mitogen- Activated Protein Kinase)阻害作用がァロステリック阻害に基づ く作用であることを特徴とする、請求項 59〜65記載の使用。  [66] Use according to claims 59 to 65, wherein the p38MAPK (Mitogen-Activated Protein Kinase) inhibitory action is an action based on allosteric inhibition.
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