JP6387488B2 - 非選択的キナーゼ阻害剤 - Google Patents
非選択的キナーゼ阻害剤 Download PDFInfo
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 229940063649 survanta Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 208000008203 tachypnea Diseases 0.000 description 1
- 206010043089 tachypnoea Diseases 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
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- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
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- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical group O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
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- 230000008467 tissue growth Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
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- 238000000954 titration curve Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 108091006106 transcriptional activators Proteins 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000001173 tumoral effect Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 210000000596 ventricular septum Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、2013年1月10日出願の米国仮出願番号第61/751,217号及び米国仮出願番号61/889,887号に関する優先権を主張するものである。これらの全内容を、その全体において参照により本明細書に組み込む。
本発明は、国立衛生研究所によって授与された認可番号1R43HL102946−01及び2R44HL102946−02のもとで、合衆国政府の支援によってなされたものである。合衆国政府は本発明において特定の権利を有する。
を有する方法を提供する。
R1、R2及びR3は、同じであっても異なっていてもよく、H、C、N、O、S、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−C−N−C−基、−C−N−C(=O)−基、−C(=O)R8基、−N−C(=O)R8基、−C−N−C(=O)R8基、置換及び非置換R8基、R9、R10及びR11の1つ又は複数で置換された置換及び非置換R8基、置換及び非置換アミジニル基、置換及び非置換グアニジニル基、置換及び非置換の第一級、第二級及び第三級アルキル基、置換及び非置換アリール基、置換及び非置換アルケニル基、置換及び非置換アルキニル基、置換及び非置換ヘテロシクリル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から独立に選択され;
R4、R5、R6及びR7は、同じであっても異なっていてもよく、H、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−NH2、−C≡N、−C=N基、−C−N−C−基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル基、アルコキシ基、アリールオキシ基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、置換及び非置換ジアルキルアミノ基、置換及び非置換ジアリールアミノ基、置換及び非置換(アルキル)(アリール)アミノ基、−C(=O)H、−C(=O)−アルキル基、−C(=O)−アリール基、−C(=O)O−アルキル基、−C(=O)O−アリール基、−C(=O)NH2、−C(=O)NH(アルキル)基、−C(=O)NH(アリール)基、−C(=O)N(アルキル)2基、−C(=O)−アリール基、−C(=O)NH2、−C(=O)NH(アルキル)基、−C(=O)NH(アリール)基、−C(=O)N(アルキル)2基、−C(=O)N(アリール)2基、−C(=O)N(アルキル)(アリール)基、−C(=O)O−アルキル基、−C(=O)O−アリール基、−C(=O)−ヘテロシクリル基、−C(=O)−O−ヘテロシクリル基、−C(=O)NH(ヘテロシクリル)基、−C(=O)−N(ヘテロシクリル)2基、−C(=O)−N(アルキル)(ヘテロシクリル)基、−C(=O)−N(アリール)(ヘテロシクリル)基、置換及び非置換ヘテロシクリルアミノアルキル基、置換及び非置換ヒドロキシアルキル基、置換及び非置換アルコキシアルキル基、置換及び非置換アリールオキシアルキル基、及び置換及び非置換ヘテロシクリルオキシアルキル基、置換及び非置換ジヘテロシクリルアミノアルキル、置換及び非置換(ヘテロシクリル)(アルキル)アミノアルキル、置換及び非置換(ヘテロシクリル)(アリール)アミノアルキル、置換及び非置換アルコキシアルキル基、置換及び非置換ヒドロキシアルキル基、置換及び非置換アリールオキシアルキル基、及び置換及び非置換ヘテロシクリルオキシアルキル基;−(アルキル)(アリール)アミノアルキル基、−C(=O)−ヘテロシクリル基、−C(=O)−O−ヘテロシクリル基、−C(=O)NH(ヘテロシクリル)基、−C(=O)−N(ヘテロシクリル)2基、−C(=O)−N(アルキル)(ヘテロシクリル)基、−C(=O)−N(アリール)(ヘテロシクリル)基、置換及び非置換ヘテロシクリルアミノアルキル基、置換及び非置換ヒドロキシアルキル基、置換及び非置換アルコキシアルキル基、置換及び非置換アリールオキシアルキル基、及び置換及び非置換ヘテロシクリルオキシアルキル基、−NH(アルキル)基、−NH(アリール)基、−N(アルキル)2基、−N(アリール)2基、−N(アルキル)(アリール)基、−NH(ヘテロシクリル)基、−N(ヘテロシクリル)(アルキル)基、−N(ヘテロシクリル)(アリール)基、−N(ヘテロシクリル)2基、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換アルコキシ基、置換及び非置換アリールオキシ基、置換及び非置換ヘテロシクリル基、−NHOH、−N(アルキル)OH基、−N(アリール)OH基、−N(アルキル)O−アルキル基、−N(アリール)O−アルキル基、−N(アルキル)O−アリール基、及び−N(アリール)O−アリール基からなる群から独立に選択され;
R8は、R1、R2、R3、R4、R5、R6、R7、H、存在せず、−C=C、置換及び非置換ヘテロシクリル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル(R9)基、置換及び非置換ヘテロシクリル(R10)基、置換及び非置換ヘテロシクリル(R11)基、置換及び非置換ヘテロシクリル(R9)(R10)基、置換及び非置換ヘテロシクリル(R9)(R11)基、置換及び非置換ヘテロシクリル(R10)(R11)基、置換及び非置換ヘテロシクリル(R9)(R10)(R11)基、置換及び非置換−C(=O)−ヘテロシクリル(R9)基、置換及び非置換−C(=O)−ヘテロシクリル(R10)基、置換及び非置換−C(=O)−ヘテロシクリル(R11)基、置換及び非置換−C(=O)−ヘテロシクリル(R9)(R10)基、置換及び非置換−C(=O)−ヘテロシクリル(R9)(R11)基、置換及び非置換−C(=O)−ヘテロシクリル(R10)(R11)基、置換及び非置換−C(=O)−ヘテロシクリル(R9)(R10)(R11)基、置換及び非置換アリール(R9)基、置換及び非置換アリール(R10)基、置換及び非置換アリール(R11)基、置換及び非置換アリール(R9)(R10)基、置換及び非置換アリール(R9)(R11)基、置換及び非置換アリール(R10)(R11)基、置換及び非置換アリール(R9)(R10)(R11)基、置換及び非置換−C(=O)−アリール(R9)基、置換及び非置換−C(=O)−アリール(R10)基、置換及び非置換−C(=O)−アリール(R11)基、置換及び非置換−C(=O)−アリール(R9)(R10)基、置換及び非置換−C(=O)−アリール(R9)(R11)基、置換及び非置換−C(=O)−アリール(R10)(R11)基並びに置換/非置換−C(=O)−アリール(R9)(R10)(R11)基からなる群から選択され;
R9、R10及びR11は、同じであっても異なっていてもよく、存在せず、H、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−NH2、−C(=O)−、−C−N−R12、−C≡N、−C−N−C基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、−C=N基、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル基、アルコキシ基、アリールオキシ基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、及び置換及び非置換ジアルキルアミノ基、置換及び非置換アミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、置換及び非置換ジアルキルアミノ基、置換及び非置換ジアリールアミノ基、置換及び非置換(アルキル)(アリール)アミノ基、−C(=O)H、−C(=O)−アルキル基、−C(=O)−アリール基、−C(=O)O−アルキル基、−C(=O)O−アリール基、−C(=O)NH2、−C(=O)NH(アルキル)基、−C(=O)NH(アリール)基、−C(=O)N(アルキル)2基、−C(=O)−アリール基、−C(=O)NH2、−C(=O)NH(アルキル)基、−C(=O)NH(アリール)基、−C(=O)N(アルキル)2基、−C(=O)N(アリール)2基、−C(=O)N(アルキル)(アリール)基、−C(=O)O−アルキル基、−C(=O)O−アリール基、−C(=O)−ヘテロシクリル基、−C(=O)−O−ヘテロシクリル基、−C(=O)NH(ヘテロシクリル)基、−C(=O)−N(ヘテロシクリル)2基、−C(=O)−N(アルキル)(ヘテロシクリル)基、−C(=O)−N(アリール)(ヘテロシクリル)基、置換及び非置換ヘテロシクリルアミノアルキル基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から独立に選択され;
R12は、存在せず、H、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−NH2、−C(=O)−、−C−N−R12、−C≡N、−C−N−C基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、−C=N基、−C(=O)−基、−C(=O)−C−基、−C(=O)−C=C、−S(=O)2−基、−S(=O)2−C−基、−S(=O)2−C=C−基、−S(=O)2−C=C−CH3、アルコキシ基、アリールオキシ基、置換及び非置換アミジニル基、置換及び非置換グアニジニル基、置換及び非置換の第一級、第二級及び第三級アルキル基、置換及び非置換アリール基、置換及び非置換アルケニル基、置換及び非置換アルキニル基、置換及び非置換ヘテロシクリル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から選択され;
Q1は、直接結合、H、C、Cl、Br、F、I、−CN、−NO2、−CH3、−CF3、−NH2、−C(=O)−、−C−N−R12、−C≡N、−C−N−C基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、−C=N基、−C(=O)−基、−C(=O)−C−基、−C(=O)−C=C、−CF3、−C≡N、−C−N−C−基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、−OH、アルコキシ基、アリールオキシ基、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル基、アルコキシ基、アリールオキシ基、メトキシ基、ジメトキシ基、メトキシフェノール、メトキシフェノール基、ジメトキシフェノール、ジメトキシフェノール基、ジメトキシベンゼン、ジメトキシベンゼン基、メトキシメチルベンジル基、置換及び非置換アラルキル基、−NH2、置換及び非置換ヘテロシクリルアルキル基、置換/非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、及び置換及び非置換ジアルキルアミノ基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から選択され;
Q2は、存在せず、H、Q1、Q1(Q3)、−OH、アルコキシ基、アリールオキシ基からなる群から選択され;
Q3は、存在せず、直接結合、H、C、Cl、Br、F、I、−CN、−NO2、−CH3、−CF3、−NH2、−C(=O)−、−C−N−R12、−C≡N、−C−N−C基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、−C=N基、−C(=O)−基、−C(=O)−C−基、−C(=O)−C=C、−CF3、−C≡N、−C−N−C−基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、−OH、アルコキシ基、アルコキシ基、アリールオキシ基、メトキシ基、ジメトキシ基、メトキシフェノール、メトキシフェノール基、ジメトキシフェノール、ジメトキシフェノール基、ジメトキシベンゼン、ジメトキシベンゼン基、置換及び非置換アルキル基、置換及び非置換アリール基並びに置換及び非置換ヘテロシクリル基からなる群から選択される。上記段落(すなわち、[0009])の内容を以下で「QXR」と称する。
(式中、XはC、N、O、S及び−CNから独立に選択され;
R9、R10及びR11は、同じであっても異なっていてもよく、H、C、N、O、S、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−NH2、−C(=O)−、−C−N−R12、−C≡N、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル基、−OH、アルコキシ基、アリールオキシ基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、及び置換及び非置換ジアルキルアミノ基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から独立に選択され;
R12は、−C(=O)−基、−C(=O)−C−基、−C(=O)−C=C、−S(=O)2−基、−S(=O)2−C−基、−S(=O)2−C=C−基、−S(=O)2−C=C−CH3、−OH、アルコキシ基、アリールオキシ基、置換及び非置換アミジニル基、置換及び非置換グアニジニル基、置換及び非置換の第一級、第二級及び第三級アルキル基、置換及び非置換アリール基、置換及び非置換アルケニル基、置換及び非置換アルキニル基、置換及び非置換ヘテロシクリル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から選択される)
を有する。上記段落(すなわち、[0010])の内容を以下で「QXR2」と称する。
から選択される。
{式中、XはC、N、O、S又は−CNから独立に選択され;
R1、R2及びR3は、同じであっても異なっていてもよく、H、C、N、O、S、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−C−N−C−基、−C−N−C(=O)−基、−C(=O)R8基、−N−C(=O)R8基、−C−N−C(=O)R8基、置換及び非置換R8基、R9、R10及びR11の1つ又は複数で置換された置換及び非置換R8基、置換及び非置換アミジニル基、置換及び非置換グアニジニル基、置換及び非置換の第一級、第二級及び第三級アルキル基、置換及び非置換アリール基、置換及び非置換アルケニル基、置換及び非置換アルキニル基、置換及び非置換ヘテロシクリル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から独立に選択され;
R4、R5、R6及びR7は、同じであっても異なっていてもよく、H、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−NH2、−C≡N、−C=N基、−C−N−C−基、−C−N−C(=O)−基、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル基、アルコキシ基、アリールオキシ基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、置換及び非置換ジアルキルアミノ基、置換及び非置換ジアリールアミノ基、置換及び非置換(アルキル)(アリール)アミノ基、−C(=O)H、−C(=O)−アルキル基、−C(=O)−アリール基、−C(=O)O−アルキル基、−C(=O)O−アリール基、−C(=O)NH2、−C(=O)NH(アルキル)基、−C(=O)NH(アリール)基、−C(=O)N(アルキル)2基、−C(=O)−アリール基、−C(=O)NH2、−C(=O)NH(アルキル)基、−C(=O)NH(アリール)基、−C(=O)N(アルキル)2基、−C(=O)N(アリール)2基、−C(=O)N(アルキル)(アリール)基、−C(=O)O−アルキル基、−C(=O)O−アリール基、−C(=O)−ヘテロシクリル基、−C(=O)−O−ヘテロシクリル基、−C(=O)NH(ヘテロシクリル)基、−C(=O)−N(ヘテロシクリル)2基、−C(=O)−N(アルキル)(ヘテロシクリル)基、−C(=O)−N(アリール)(ヘテロシクリル)基、置換及び非置換ヘテロシクリルアミノアルキル基、置換及び非置換ヒドロキシアルキル基、置換及び非置換アルコキシアルキル基、置換及び非置換アリールオキシアルキル基、及び置換及び非置換ヘテロシクリルオキシアルキル基、置換及び非置換ジヘテロシクリルアミノアルキル、置換及び非置換(ヘテロシクリル)(アルキル)アミノアルキル、置換及び非置換(ヘテロシクリル)(アリール)アミノアルキル、置換及び非置換アルコキシアルキル基、置換及び非置換ヒドロキシアルキル基、置換及び非置換アリールオキシアルキル基、及び置換及び非置換ヘテロシクリルオキシアルキル基;−(アルキル)(アリール)アミノアルキル基、−C(=O)−ヘテロシクリル基、−C(=O)−O−ヘテロシクリル基、−C(=O)NH(ヘテロシクリル)基、−C(=O)−N(ヘテロシクリル)2基、−C(=O)−N(アルキル)(ヘテロシクリル)基、−C(=O)−N(アリール)(ヘテロシクリル)基、置換及び非置換ヘテロシクリルアミノアルキル基、置換及び非置換ヒドロキシアルキル基、置換及び非置換アルコキシアルキル基、置換及び非置換アリールオキシアルキル基、及び置換及び非置換ヘテロシクリルオキシアルキル基、−NH(アルキル)基、−NH(アリール)基、−N(アルキル)2基、−N(アリール)2基、−N(アルキル)(アリール)基、−NH(ヘテロシクリル)基、−N(ヘテロシクリル)(アルキル)基、−N(ヘテロシクリル)(アリール)基、−N(ヘテロシクリル)2基、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換アルコキシ基、置換及び非置換アリールオキシ基、置換及び非置換ヘテロシクリル基、−NHOH、−N(アルキル)OH基、−N(アリール)OH基、−N(アルキル)O−アルキル基、−N(アリール)O−アルキル基、−N(アルキル)O−アリール基並びに−N(アリール)O−アリール基からなる群から独立に選択され;
R8の構造は以下の式:
(式中、XはC、N、O、S又は−CNから独立に選択され;
R9、R10及びR11は、同じであっても異なっていてもよく、H、C、N、O、S、Cl、Br、F、I、−CN、−NO2、−OH、−CH3、−CF3、−NH2、−C(=O)−、−C−N−R12、−C≡N、−C−N−C(=O)−C−F、−C−N−C(=O)−C=C、置換及び非置換アルキル基、置換及び非置換アリール基、置換及び非置換ヘテロシクリル基、−OH、アルコキシ基、アリールオキシ基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換アルキルアミノ基、置換及び非置換アリールアミノ基、及び置換及び非置換ジアルキルアミノ基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から独立に選択され;
R12は、−C(=O)−基、−C(=O)−C−基、−C(=O)−C=C、−S(=O)2−基、−S(=O)2−C−基、−S(=O)2−C=C−基、−S(=O)2−C=C−CH3、−OH、アルコキシ基、アリールオキシ基、置換及び非置換アミジニル基、置換及び非置換グアニジニル基、置換及び非置換の第一級、第二級及び第三級アルキル基、置換及び非置換アリール基、置換及び非置換アルケニル基、置換及び非置換アルキニル基、置換及び非置換ヘテロシクリル基、置換及び非置換アミノアルキル基、置換及び非置換アルキルアミノアルキル基、置換及び非置換ジアルキルアミノアルキル基、置換及び非置換アリールアミノアルキル基、置換及び非置換ジアリールアミノアルキル基、置換及び非置換(アルキル)(アリール)アミノアルキル基、置換及び非置換ヘテロシクリルアルキル基、置換及び非置換シアノ基、置換及び非置換ピリミジニル基、置換及び非置換シアノ(アリール)基、置換及び非置換シアノ(ヘテロシクリル)基並びに置換及び非置換シアノ−ピリミジニル基からなる群から選択される)
を有し、
Q1又はQ2の構造は−CH3、−OH、−O−CH3、−C−N−C(=O)−C=C、−C−N−C(=O)−C−F、
からなる群から選択される}
を有する方法を提供する。
{式中、X、R1、R2、R3、R4、R5、R6、R7(並びにその中に含まれるような、R8、R9、R10、R11及びR12)、Q1及びQ2(及びその中に含まれるような、Q3)は上記の「XRQ3」から選択される}
種々の化合物が、例えば癌などの特定の疾患を治療するのに有用であることが分かっている。例えば、Gleevec(登録商標)(イマチニブメシラート又は「イマチニブ」)は、慢性骨髄性白血病(CML)及び消化管間質腫瘍(GIST)を治療するのに効力を示している化合物である。他の実験的薬物には、それぞれ、腎細胞癌腫及び白血病の治療のためのソラフェニブ及びPNU−166196が含まれる。特定の癌を治療するための医薬組成物の開発において大幅な進歩がなされているが;癌及び他の疾患、例えば肺動脈高血圧症(PAH)などの肺−血管疾患を防止及び/又は治療するために、新規な化合物、組成物、治療の方法、及び薬物を開発するためのモデル系が求められている。特に、血小板由来の成長因子(PDGF)受容体チロシンキナーゼは、PAHのための魅力的な治療標的である。PDGFシグナル伝達経路は、ヒト特発性PAH(iPAH)において、また、疾患の動物モデルにおいて活性化される。例えば、PDGFA、PDGFB、PDGFRα及びPDGFRβ mRNAの発現は、対照とする対象と比較して、iPAHを有する患者からの肺小動脈において増大し、ウエスタンブロット分析は、PAH肺におけるPDGFRβのタンパク質発現の有意な増大を示している。
一態様では、本開示は、以下の部に記載されており、WO2008/058341(これを、その全体において、且つあたかも本明細書で完全に示されているかのようにすべての目的のために、参照により本明細書に組み込む)に開示されているような手順を用いて容易に合成される構造I化合物の合成を提供する。さらに、構造Iの化合物は一般に、例えばジハロ複素環などの出発原料から調製される。第1のステップは、モノアミノ−モノハロ中間体を生成するための求核的芳香族置換である。求核的芳香族置換は一般に、エタノール、イソプロパノール、tert−ブタノール、ジオキサン、THF、DMF、エトキシエタノール、トルエン又はキシレンなどの溶媒中で、第一級又は第二級アミンをジハロゲン化複素環に付加させることによって実施される。反応は通常、過剰なアミン又は非求核的塩基、例えばトリエチルアミン若しくはジイソプロピルエチルアミン又は無機塩基、例えば炭酸カリウム若しくは炭酸ナトリウムの存在下、高温で実施される。
タンパク質キナーゼは、タンパク質中の特定の残基のリン酸化を触媒作用する酵素のファミリーである。そうした酵素は一般に3つのグループ、セリン及び/又はスレオニン残基を優先的にリン酸化するもの、チロシン残基を優先的にリン酸化するもの、及びチロシンとSer/Thr残基の両方をリン酸化するものに分類される。したがって、タンパク質キナーゼは、それらの受容体に対するサイトカインの作用を含む細胞外シグナルを細胞核へ伝達し、種々の生物学的事象の引き金を引くことに関与するシグナル伝達経路における重要な要素である。正常な細胞生理におけるタンパク質キナーゼの多くの役割には、増殖、分化、代謝、アポトーシス、細胞移動、有糸分裂誘発、転写、翻訳及び他のシグナル伝達過程を含む細胞周期のコントロールが含まれる。
一態様では、本開示は、対象においてキナーゼ、例えばRTKなどのチロシンキナーゼを阻害する化合物及び方法、及び/又は、対象における、キナーゼ、例えばRTKなどのチロシンキナーゼによって媒介される、又はそれに関連する生物学的状態の治療方法を提供する。いくつかの実施形態では、そのキナーゼは、Cdc2キナーゼ、AKT、c−Kit、c−ABL、ERK1/2、STAT3、p60src、VEGFR3、PDGFRα、PDGFRβ、FGFR3、PDGFR−αα、PDGFR−ββ、PDGFR−αβ、FLT−3、Fyn、Lck、Tie−2、GSK−3、Cdk2、Cdk4、MEK1、NEK−2、CHK2、CK1ε、Raf、CHK1、Rsk2、FMS(CSF−IR)、KDR、EphA2、EphA3、EphA8、FLT1、FLT4、HCK、PTK5、RET、SYK、DDR1、DDR2及びPAR−1である。同様に、いくつかの実施形態では、キナーゼは、チロシンキナーゼ、例えばCdc2キナーゼ、c−Kit、c−ABL、p60src、VEGFR3、PDGFRα、PDGFRβ、FGFR3、PDGFR−αα、PDGFR−ββ、PDGFR−αβ、FLT−3、Fyn、Lck及び/又はTie−2などである。この方法は、対象に、構造Iの化合物、前記化合物の互変異性体、前記化合物の薬学的に許容される塩、その互変異性体の薬学的に許容される塩、又はその混合物を投与するステップを含む。
一態様では、本開示は、構造1の化合物の少なくとも1つ及び薬学的に許容される担体を含む医薬組成物を提供する。本発明の組成物は以下で説明するような他の治療剤を含むことができ、医薬処方物の技術分野において周知のものなどの技術にしたがって、例えば、慣用的な固体若しくは液体のビヒクル又は賦形剤、並びに所望の投与方式に適した種類の医薬品添加物、例えば添加剤、結合剤、防腐剤、安定剤、香味剤等を用いることによって処方することができる。
一態様では、本開示は、1つ又は複数の疾患を治療するための、構造1(構造1は本明細書で説明されている)の化合物、前記化合物の互変異性体、前記化合物のエナンチオマー、異性体若しくは立体異性体、前記化合物、前記化合物の互変異性体、エナンチオマー、異性体若しくは立体異性体の薬学的に許容される塩、又はその任意の混合物を提供する。
Z−lyteキナーゼアッセイを、PK10453(構造2)によるPDGFRアルファ及びPDGFRベータ媒介リン酸化の阻害を判定するために実施した。10点の滴定曲線をモデル化してIC50を計算した(Invitrogen Select Screen(登録商標))。
雄のスプラーグドーリーラットにMCT 60mg/kg IPMCTを施し、3週間後、PK10453(構造2)又はビヒクル対照を吸入により投与した。4つの群:ビヒクル対照(4min暴露)、及び1日に3回2min(D2)、4min(D4)又は8min(D8)の暴露時間でのPK10453(構造2)の3つの処置群を試験した。これらのレジメンを2週間投与した。ビヒクルは上記したようにアンモニア蒸気で中和された、エアロゾル化した1Mトシル酸からなるものである。捕捉したエアロゾル粒子を水に溶解して調製した溶液のpHを用量毎に測定した。これは常に5.5〜6.0の範囲内にあった。この試験の最後に、RV収縮期圧を測定し、心腔を切開し計量した。
雄のスプラーグドーリーラットにMCT 60mg/kg IPを与えた。3週間後、ビヒクル(1Mトシル酸)、PK10453(構造2、1Mトシル酸中に20mg/ml遊離塩基で)又はイマチニブメシラート(ネブライザー溶液中に20mg/ml)を指定された群に、1日に3回2週間、8min吸入暴露させて投与した。試験の最後に、RVSP圧を測定し;肺と心臓をホルマリンに固定した。RVSPの測定のため、動物をイソフルランで鎮静させ、気管開口部を通して挿管し、TOPOVENT圧力制御された人工呼吸器(最大吸気圧18cm H2O、PEEP 5cm)で人工呼吸させた。胸骨切開後、Scisense社の高品質カテーテルを、右心室心尖部(RV apex)を通して挿入した。
肺全摘、及び肺動脈中へのTRM53Pテレメトリーモニター(Telemetry Research、New Zealand及びADInstruments、Colorado)の埋め込みをラットにおいて実施した。MCT後2週間で、PK10453(構造2)を1日に3回、1週間投与した。投薬は、MCT後、3週間ではなく2週間で開始した。その理由は、より挑戦的なこのモデルでは、動物はより速くPAHを発現し、MCTだけで処置した動物より早く苦痛(distress)を現わすからである(データは示さていない)。2つの群に、ビヒクル対照か又はPK10453(構造2)の4min暴露を施した。大気(動物用施設の高度にもとづくと大気圧716mmHgと推定される)中で、歩行動物において毎朝投与する前に、PA圧のサンプリングを5min実施した。プロトコル4(イマチニブvs.ビヒクル)では、動物にDSI PAC40送信機を取り付け、次いでモノクロタリン50mg/kg IP(ロットSLBB7802V)を施した。より少ない用量のMCTをこの試験のために用いた。その理由は、このロットのMCTを60mg/kg用いようと試みたが、体重減少と頻呼吸のため、高い割合の動物において早期の安楽死を必要とする結果となったためである。MCT IP注射2週間後、ビヒクル(ネブライザー溶液中に、メシラート3mg/ml又はイマチニブメシラート20mg/ml)を、9日間にわたって1日に3回、8min暴露で投与した。このプロトコルのため、毎朝投与する前に、テレメトリーデータを毎日10min得た。
PK10453(構造2)の特性評価
インビトロでのキナーゼアッセイによって、ATP KmでのPK10453についてのIC50は、PDGFR−αに対して35nMであり、PDGFR−βに対して10.1nMであることが実証された。イマチニブについて、ATP KmでのIC50は、PDGFR−αに対して71nMであり、PDGFR−βに対して607nMであった。図1を参照されたい。図2に例示したICWで示されるように、Ser473でのPDGFBB刺激AKTリン酸化についてのPK10453のIC50は、イマチニブについての1.8μMに対して0.13μMであった(p<0.01)。Thr308でのPDGFBB刺激AKTリン酸化についてのPK10453のIC50は、イマチニブについての.3.25μMに対して、0.43μMであった(p<0.001)。PK10453及びイマチニブのAKTのPDGFAA刺激リン酸化についてのIC50濃度には有意差はなかった。
Rd=[(AUC肺/AUC血漿)呼吸器]/[(AUC肺/AUC血漿)IV]
MCTモデル効力
RVSP値を図5Aに示す。ビヒクル群(n=6)では、RVSPは80.4±2.6mmHgであった。処置群について、D2(n=6)、51.4±6.5;D4(n=6)、44.4±3.8;及びD8(n=5)、37.1±4.5mmHg(p<0.001)。正常な対照群RVSPは28.5±2.6mmHg(n=3)であった。ビヒクル処置群と比較して、D4群においてRVSPの44%の低下があり、D8群においてRVSPの54%の低下があった。比(RV+IVS)/LV重量で測って、RV肥大の度合いの有意の減少もあった。図5Bを参照されたい。中隔はRVとLVで共有されているので、データはこの比で表している。しかし、RV/(IVS+LV)比を用いても同様の結果が示されている。
ラットMCT+PNモデルでの効力試験
テレメトリー試験。ラットMCT+PNモデルにおけるテレメトリー試験の結果を説明する。処置開始前0日目、ビヒクル群におけるPA収縮期圧は41.0±11.7mmHgであり、PK10453(構造2)群において43.1±3.5mmHg(p=NS)であった。5日間の処置後、PA収縮期圧は、ビヒクル群において69.4±12.9mmHgであり、PK10453群において47.3±3.0mmHgで有意に低かった(p<0.01)。処置8日目、ビヒクル群におけるPA収縮期圧は83.5±8.5であったが、PK10453群では47.3±4.9mmHgで有意に低かった(p<0.001)。
MCT+PNMCT+PNモデル効力
PVループ試験。ビヒクル対照と比較して、D4とD8の処置群の両方において、RV収縮終期圧(ESP)はより低く、RV駆出率(EF)はより高かった。D8群における心拍出量はビヒクル群と比較して増大した。表3を参照されたい。MCT60mg/kg IPに続いて7日後、試験動物に左肺全摘を施した。MCT投与2週間後、PK10453(構造2)又はビヒクルを、1日に3回、2週間にわたって吸入により与えた。この期間の最後にPVループを得た。表3に関して:V=ビヒクル;D4=4min吸入PK10453;D8=8min吸入PK10453;各群n=4;*p<0.001;**p<0.01;§p<0.05 vs.Vである。以下の表3を参照されたい。
PDGFシグナル伝達についての免疫組織化学検査。
前毛細血管肺細動脈においては、PDGFR−β経路を介したシグナル伝達が支配的であった。PDGFAAリガンド及びPDGFR−αについてのシグナルは存在したが、PDGFBB及びPDGFR−βについてのシグナルより定性的に低かった。リン酸化PDGFR−β(pPDGFR−β)は、新生内膜細胞及び血管周囲細胞において敷石状の外観を有しており、前毛細血管肺細動脈におけるホスホ−PDGFR−α(PDGFR−α)についてのシグナルより強かった。pPDGFR−β又はアルファについての最小シグナルが、前毛細血管肺細動脈の中膜層において検出された。図12A〜Fを参照されたい。より大きい(>50μm)血管では、pPDGFR−αについてのシグナルは中膜VSM細胞中に存在した。対照的に、pPDGFRβ中膜層シグナルは低かった。図13A〜Dを参照されたい。
NanoPro(登録商標)免疫アッセイ及びウエスタンブロット
pAKT/AKTについてのNanopro(登録商標)免疫アッセイを図14に示し、pSTAT3/STAT3について図15に示す。D4群とD8群の両方において、ビヒクルと比較して、pSTAT3/STAT3比の大幅な減少が見られた。図16は、肺ホモジネートにおける、ppERK1/ERK1、pERK1/ERK1、ppERK2/ERK2及びpERK2/ERK2に対する吸入PK10453(構造2)の効果を示す。D4群及びD8群において、ビヒクルと比較して、それぞれppERK1/ERK1及びpERK1/ERK1の大幅な減少が見られた。
PDGFAAはPDGFR−αを刺激するのに対して、PDGFBBはPDGFR−βと結合しそれを活性化させる。
図17は、ヒト胎児肺線維芽細胞における、ERK1及びERK2のPDGFAA vs.PDGFBB刺激リン酸化に対するイマチニブ、PK10453(構造2)及びPK10571(構造2a)の効果を示す。ジリン酸化ERK1と全ERK1(ppERK1/ERK1)の比はPDGFAA又はPDGFBB刺激で増大し、1μM及び10μMの濃度のイマチニブ、PK10453及びPK10571で有意に減少した。ジリン酸化ERK2と全ERK2(ppERK2/ERK2)の比はPDGFAA又はPDGFBB刺激(10ng/ml)で増大し、1uM及び10uMの濃度のイマチニブ、PK10453及びPK10571で有意に減少した。PDGF BB刺激後、ジリン酸化ERK1と全ERK1(ppERK1/ERK1)、及びジリン酸化ERK2と全ERK2(ppERK2/ERK2)の比は、イマチニブと比較して、1uMのPK10453及びPK10571で、より効率的に減少した。したがって、PK10453及びPK10571は、イマチニブと比較して、PDGF BB刺激のERK1及びERK2リン酸化のより強力な阻害剤である。
PK10453(構造2)、PK10467(構造3)、PK10468(構造4)、PK10569(構造5)及びPK10571(構造2a)は、線維芽細胞においてPDGFBB刺激AKTリン酸化を阻害するのに、イマチニブと比較して、より低いIC50濃度を有する。
細胞培養液中で成長させたヒト胎児肺線維芽細胞を、肺動脈高血圧症、肺線維症及び関連障害において起こる線維芽細胞増殖のモデルとして使用する。図18A〜Dを参照されたい。これらのデータは、PK10453、PK10467、PK10468、PK10569及びPK10571は、イマチニブと比較して、PDGFベータ受容体によって媒介されるシグナル伝達のより強力な阻害剤であることを強調している。これらのデータは、PK10453、PK10467、PK10468、PK10569及びPK10571で達成できる肺動脈高血圧症、肺線維症及び関連障害のための治療として、PDGFアルファ受容体シグナル伝達に加えてPDGFベータ受容体シグナル伝達を効果的に阻害することの重要性を示している。上記及び本出願を通して使用するように、PKの化合物及び構造の表示は、以下のように互換的に使用される:PK10453=構造2;PK10571=構造2a;PK10467=構造3;PK10468=構造4;及びPK10569=構造5。図18A〜Dを参照されたい。
体重、全身BP及びプレチスモグラフィー試験
ビヒクルと比較して、処置群において、対ビヒクル群で、より遅い体重減少速度の傾向があった。図19を参照されたい。図20に示すように、処置7日目で、MCT PK10453群(n=3)における131±10mmHgに対して、収縮期BPは、MCTビヒクル群(n=3)において111±21mmHgであった。ラットMCT+PNMCT+PNモデルにおいて、PK10453/ビヒクル投与1日目及び15日目に、2チャンバープレチスモグラフィーを測定した。結果を表4に示す。PK10453での処置は、4min暴露群(D4)において、ビヒクルと比較して、毎分換気量(MV)のより小さい低下を伴い、最大吸気流(PIF)及び最大呼気流(PEF)の大幅な改善を伴った。
考察及び適用実施形態
PDGFシグナル伝達経路は、ヒト肺動脈高血圧症(PAH)において、また、疾患の動物モデルにおいて活性化されることが分かった。この試験では、新規の非選択的な吸入PDGF受容体阻害剤、PK10453(構造2)は、PAHのラットモノクロタリン(MCT)モデルとラットMCT+肺全摘(+PN)モデルの両方において肺高血圧症を低減させるであろうという仮説をテストした。1日に3回2週間、4(D4)min暴露及び8(D8)min暴露で吸入によって送達されたPK10453は、ラットMCTとラットMCT+PNの両方のモデルにおいて右心室収縮期圧(RVSP)を低下させた:ビヒクルMCT群(n=6)のRVSPは80.4±2.6mmHg;D4 MCT群(n=6)において44.4±5.8mmHg;D8 MCT群(n=5)において37.1±4.5mmHg(p<0.001 vs.ビヒクル)であり;ビヒクルMCT+PN群(n=9)のRVSPは75.7±7.1mmHg;D4 MCT+PN群(n=10)において40.4±2.7mmHg、D8 MCT+PN群(n=8)において43.0±3.0mmHg(p<0.001)であった。ラットMCT+PNモデルにおいて、肺動脈圧の連続テレメトリーモニタリングも、PK10453がPAHの進行を防止することを実証している。吸入によって与えられたイマチニブは、MCTモデルにおいて同等に効果的であったが、MCT+PNモデルにおいては効果的ではなかった。
Claims (17)
- 肺障害を治療するのに使用のための化合物であって、該化合物は、以下の式又はその薬学的に許容される塩である、上記化合物:
- キナーゼを阻害するのに使用するための化合物であって、該化合物は、以下の式又はその薬学的に許容される塩である、上記化合物:
- 前記肺障害が炎症と関連する、請求項1の使用のための化合物。
- 前記肺障害が、心臓血管機能に関連する、請求項1の使用のための化合物。
- 前記肺障害が、肺高血圧症である、請求項1の使用のための化合物。
- 前記肺障害が、肺動脈性高血圧症である、請求項1の使用のための化合物。
- 前記肺障害が、間質性肺疾患に関連する肺高血圧症である、請求項1の使用のための化合物。
- 前記肺障害が、肺線維症である、請求項1の使用のための化合物。
- 前記化合物が、受容体チロシンキナーゼを阻害する、請求項2の使用のための化合物。
- 受容体チロシンキナーゼの阻害が、AKTの低下した活性化をもたらす、請求項9の使用のための化合物。
- 前記受容体チロシンキナーゼが、c−Kitである、請求項9の使用のための化合物。
- 前記受容体チロシンキナーゼが、血小板由来成長因子受容体である、請求項9の使用のための化合物。
- 前記化合物が、0.01mg/kg〜100mg/kgの量で投与するために処方される、請求項1〜12のいずれか一項の使用のための化合物。
- 前記化合物が、対象への投与後の対象の血漿中の化合物の1〜5000ng/kgのC max を提供するように処方される、請求項1〜13のいずれか一項の使用のための化合物。
- 前記化合物が、吸入投与用に処方される、請求項1〜14のいずれか一項の使用のための化合物。
- 前記化合物が、経口投与のために処方される、請求項1〜14のいずれか一項の使用のための化合物。
- 前記化合物が、乾燥粉末として投与のために処方される、請求項1〜16のいずれか一項の使用のための化合物。
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JP2018158931A (ja) * | 2013-01-10 | 2018-10-11 | プルモキネ、インコーポレイテッド | 非選択的キナーゼ阻害剤 |
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DK3007689T3 (en) | 2018-06-14 |
CN105142624A (zh) | 2015-12-09 |
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US10246438B2 (en) | 2019-04-02 |
AU2014205483B2 (en) | 2017-11-30 |
AU2020289802A1 (en) | 2021-01-21 |
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US20190248761A1 (en) | 2019-08-15 |
WO2014110200A1 (en) | 2014-07-17 |
EP3007689B1 (en) | 2018-03-07 |
EP3007689A4 (en) | 2016-07-13 |
CA2897651C (en) | 2021-09-21 |
CN109568319A (zh) | 2019-04-05 |
AU2023201605A1 (en) | 2023-04-13 |
AU2023201605B2 (en) | 2024-08-29 |
ES2675720T3 (es) | 2018-07-12 |
JP2016506418A (ja) | 2016-03-03 |
CA2897651A1 (en) | 2014-07-17 |
JP2018158931A (ja) | 2018-10-11 |
JP6547042B2 (ja) | 2019-07-17 |
US20150353527A1 (en) | 2015-12-10 |
AU2014205483A1 (en) | 2015-08-27 |
US10532994B2 (en) | 2020-01-14 |
AU2018201406A1 (en) | 2018-03-15 |
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