WO2006137421A1 - Agent pour administration topique - Google Patents

Agent pour administration topique 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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Prior art keywords
substituted
unsubstituted
compound
acceptable salt
lower alkyl
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PCT/JP2006/312378
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English (en)
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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Publication of WO2006137421A1 publication Critical patent/WO2006137421A1/fr

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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

La présente invention concerne un agent pour administration topique qui comprend un composé ayant un effet d’inhibition sur la P38MAPK (protéine kinase activée par des agents mitogènes) ou un sel pharmaceutique de celui-ci comme ingrédient actif, où la concentration du composé ou du sel au point d’administration topique est 350 fois ou plus supérieure à celle du plasma sanguin, lorsque l’agent est administré de façon topique. Dans l’agent pour une administration topique, le composé ayant un effet d’inhibition sur la P38MAPK peut être, par exemple, un dérivé phénolique ou un composé hétérocyclique accolé ayant une structure phénolique dans le système de cycles accolés.
PCT/JP2006/312378 2005-06-21 2006-06-21 Agent pour administration topique WO2006137421A1 (fr)

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Cited By (6)

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WO2007117607A3 (fr) * 2006-04-06 2007-12-21 Novartis Vaccines & Diagnostic Quinazolines pour l'inhibition de pdk1
WO2008050808A1 (fr) * 2006-10-24 2008-05-02 Kyowa Hakko Kirin Co., Ltd. Dérivé de 2-aminoquinazoline
WO2009131173A1 (fr) * 2008-04-23 2009-10-29 協和発酵キリン株式会社 Dérivé de 2-aminoquinazoline
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117607A3 (fr) * 2006-04-06 2007-12-21 Novartis Vaccines & Diagnostic Quinazolines pour l'inhibition de pdk1
US7932262B2 (en) 2006-04-06 2011-04-26 Novartis Ag Quinazolines for PDK1 inhibition
WO2008050808A1 (fr) * 2006-10-24 2008-05-02 Kyowa Hakko Kirin Co., Ltd. Dérivé de 2-aminoquinazoline
WO2009131173A1 (fr) * 2008-04-23 2009-10-29 協和発酵キリン株式会社 Dérivé de 2-aminoquinazoline
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US9695132B2 (en) 2013-03-15 2017-07-04 Celgene Car Llc Heteroaryl compounds and uses thereof
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10189794B2 (en) 2013-03-15 2019-01-29 Celgene Car Llc Heteroaryl compounds and uses thereof
US10618902B2 (en) 2013-03-15 2020-04-14 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10774052B2 (en) 2013-03-15 2020-09-15 Celgene Car Llc Heteroaryl compounds and uses thereof

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