CN1362953A - 用作erk抑制剂的吡唑组合物 - Google Patents
用作erk抑制剂的吡唑组合物 Download PDFInfo
- Publication number
- CN1362953A CN1362953A CN01800374A CN01800374A CN1362953A CN 1362953 A CN1362953 A CN 1362953A CN 01800374 A CN01800374 A CN 01800374A CN 01800374 A CN01800374 A CN 01800374A CN 1362953 A CN1362953 A CN 1362953A
- Authority
- CN
- China
- Prior art keywords
- compound
- cancer
- disease
- optional replacement
- carcinoma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims description 48
- 239000003112 inhibitor Substances 0.000 title description 37
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 56
- 201000010099 disease Diseases 0.000 claims abstract description 55
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
- 201000011510 cancer Diseases 0.000 claims abstract description 27
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 9
- 208000037803 restenosis Diseases 0.000 claims abstract description 7
- -1 aralkoxy Chemical group 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 53
- 108091000080 Phosphotransferase Proteins 0.000 claims description 30
- 102000020233 phosphotransferase Human genes 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000001931 aliphatic group Chemical group 0.000 claims description 23
- 230000002969 morbid Effects 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 102000001253 Protein Kinase Human genes 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 108060006633 protein kinase Proteins 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 230000002062 proliferating effect Effects 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- 206010036631 Presenile dementia Diseases 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 239000012472 biological sample Substances 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 208000026935 allergic disease Diseases 0.000 claims description 5
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 239000000523 sample Substances 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 201000009030 Carcinoma Diseases 0.000 claims description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 241000700605 Viruses Species 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 4
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
- 208000019423 liver disease Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 210000000214 mouth Anatomy 0.000 claims description 4
- 206010038038 rectal cancer Diseases 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 201000000498 stomach carcinoma Diseases 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 3
- 208000006029 Cardiomegaly Diseases 0.000 claims description 3
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 206010019842 Hepatomegaly Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 208000033065 inborn errors of immunity Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 208000028529 primary immunodeficiency disease Diseases 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 201000008261 skin carcinoma Diseases 0.000 claims description 3
- 208000003200 Adenoma Diseases 0.000 claims description 2
- 206010001233 Adenoma benign Diseases 0.000 claims description 2
- 102000003916 Arrestin Human genes 0.000 claims description 2
- 108090000328 Arrestin Proteins 0.000 claims description 2
- 206010004593 Bile duct cancer Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 206010023347 Keratoacanthoma Diseases 0.000 claims description 2
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 2
- 206010062038 Lip neoplasm Diseases 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 206010054184 Small intestine carcinoma Diseases 0.000 claims description 2
- 230000006044 T cell activation Effects 0.000 claims description 2
- 108090000190 Thrombin Proteins 0.000 claims description 2
- 208000033781 Thyroid carcinoma Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 206010062129 Tongue neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 2
- 208000015322 bone marrow disease Diseases 0.000 claims description 2
- 201000007455 central nervous system cancer Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 230000001066 destructive effect Effects 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 210000004907 gland Anatomy 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 210000002768 hair cell Anatomy 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 230000006698 induction Effects 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 208000003849 large cell carcinoma Diseases 0.000 claims description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 2
- 201000006721 lip cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 210000002751 lymph Anatomy 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000010198 papillary carcinoma Diseases 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims description 2
- 210000003800 pharynx Anatomy 0.000 claims description 2
- 201000008006 pharynx cancer Diseases 0.000 claims description 2
- 208000000649 small cell carcinoma Diseases 0.000 claims description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- 229960004072 thrombin Drugs 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 claims description 2
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims description 2
- 201000006134 tongue cancer Diseases 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 208000010576 undifferentiated carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 230000000973 chemotherapeutic effect Effects 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 7
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 5
- 208000027866 inflammatory disease Diseases 0.000 abstract description 3
- 239000003909 protein kinase inhibitor Substances 0.000 abstract 2
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 239000002585 base Substances 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 31
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 108091008611 Protein Kinase B Proteins 0.000 description 19
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 16
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 16
- 102000042838 JAK family Human genes 0.000 description 14
- 108091082332 JAK family Proteins 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 239000008194 pharmaceutical composition Substances 0.000 description 14
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 12
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 12
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 10
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 10
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 239000005441 aurora Substances 0.000 description 8
- 238000001952 enzyme assay Methods 0.000 description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 230000000699 topical effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108090000461 Aurora Kinase A Proteins 0.000 description 6
- 102100032311 Aurora kinase A Human genes 0.000 description 6
- 108020005199 Dehydrogenases Proteins 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000012824 ERK inhibitor Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 6
- 102000013009 Pyruvate Kinase Human genes 0.000 description 6
- 108020005115 Pyruvate Kinase Proteins 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 6
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000038624 GSKs Human genes 0.000 description 5
- 108091007911 GSKs Proteins 0.000 description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 208000006673 asthma Diseases 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 150000002081 enamines Chemical class 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000004770 neurodegeneration Effects 0.000 description 5
- 208000015122 neurodegenerative disease Diseases 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000002769 thiazolinyl group Chemical group 0.000 description 4
- 206010003497 Asphyxia Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 101100322915 Caenorhabditis elegans akt-1 gene Proteins 0.000 description 2
- 101100162366 Caenorhabditis elegans akt-2 gene Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000003226 mitogen Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000163 radioactive labelling Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical class C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical compound C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102100023033 Cyclic AMP-dependent transcription factor ATF-2 Human genes 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229940097420 Diuretic Drugs 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- YPINZEGNLULHHT-UHFFFAOYSA-N Fujimycin Natural products COC1CC(CCC1O)C=C(/C)C2OC(=O)C3CCCCCN3C(=O)C(=O)C4(O)OC(C(CC4C)OC)C(OC)C(C)CC(=CC(CC=C)C(=O)CC(O)C2C)C YPINZEGNLULHHT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 101000974934 Homo sapiens Cyclic AMP-dependent transcription factor ATF-2 Proteins 0.000 description 1
- 101000997829 Homo sapiens Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 101100457336 Homo sapiens MAPK12 gene Proteins 0.000 description 1
- 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 1
- 101000976899 Homo sapiens Mitogen-activated protein kinase 15 Proteins 0.000 description 1
- 101001052477 Homo sapiens Mitogen-activated protein kinase 4 Proteins 0.000 description 1
- 101000950710 Homo sapiens Mitogen-activated protein kinase 6 Proteins 0.000 description 1
- 101000950687 Homo sapiens Mitogen-activated protein kinase 7 Proteins 0.000 description 1
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 1
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 1
- 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 description 1
- 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 description 1
- 102100023483 Mitogen-activated protein kinase 15 Human genes 0.000 description 1
- 102100024189 Mitogen-activated protein kinase 4 Human genes 0.000 description 1
- 102100037801 Mitogen-activated protein kinase 6 Human genes 0.000 description 1
- 102100037805 Mitogen-activated protein kinase 7 Human genes 0.000 description 1
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 1
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
- HBOPVJJZFWIXOS-UHFFFAOYSA-M [Na][Zn]Cl Chemical compound [Na][Zn]Cl HBOPVJJZFWIXOS-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 210000005057 airway smooth muscle cell Anatomy 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 125000002078 anthracen-1-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([*])=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000000748 anthracen-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([H])=C([*])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- QABZOJKEJLITJL-UHFFFAOYSA-N but-3-enoic acid;ethenyl acetate Chemical compound CC(=O)OC=C.OC(=O)CC=C QABZOJKEJLITJL-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 239000011436 cob Substances 0.000 description 1
- 229960001678 colestyramine Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- BALGDZWGNCXXES-UHFFFAOYSA-N cyclopentane;propanoic acid Chemical compound CCC(O)=O.C1CCCC1 BALGDZWGNCXXES-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- ULLYUYLDAISRDE-SSPAHAAFSA-N heptanoic acid (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound C(CCCCCC)(=O)O.O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO ULLYUYLDAISRDE-SSPAHAAFSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000001511 high performance liquid chromatography nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000011177 media preparation Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- HXRAMSFGUAOAJR-UHFFFAOYSA-N n,n,n',n'-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine Chemical compound CN(C)C(N(C)C)OC(C)(C)C HXRAMSFGUAOAJR-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- 150000008135 α-glycosides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- 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
- A61P37/02—Immunomodulators
-
- 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
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychiatry (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Reproductive Health (AREA)
Abstract
本发明公开了用作蛋白激酶抑制剂的式(I)化合物,其中R1-4、Q和T如说明书中所述。这类化合物可用于治疗哺乳动物的能通过蛋白激酶抑制剂减轻的疾病状态,特别是诸如癌、炎性疾病、再狭窄和心血管疾病等疾病。
Description
本申请请求保护2000年2月5日提交的美国临时申请第60/180,506号、2000年10月24日提交的美国临时申请第60/242,935号和2000年3月24日提交的美国临时申请第60/191,956号的利益。
发明领域
本发明属于药物化学领域,并涉及属于蛋白激酶抑制剂、尤其是ERK抑制剂的吡唑化合物,含有这类化合物的组合物及其使用方法。这类化合物可用于治疗能通过蛋白激酶抑制剂减轻的癌和其他疾病状态。
发明背景
哺乳动物促***原活化蛋白(MAP)1激酶是介导胞内信号转导途径的丝氨酸/苏氨酸激酶(Cobb和Goldsmith,1995年,《生物化学杂志》270,14843;Davis,1995年,《Mol.Reprod.Dev.》42,459)。MAP激酶族的成员共享序列相似性和保守结构域,并包括ERK(胞外信号调节激酶)、JNK(Jun N端激酶)和p38激酶。JNK和p38激酶响应促炎细胞因子TNF-α和白介素-1并通过细胞应力诸如热震、高摩尔渗透压浓度、紫外线照射、脂多糖类和蛋白合成抑制剂而活化(Derijard等,1994年,《细胞》76,1025;Han等,1994年,《科学》265,808;Raingeaud等,1995年,《生物化学杂志》270,7420;Shapiro和Dinarello,1990年,《美国国家科学院院报》92年,12230)。与此对照,ERK通过促***原和生长因子活化(Bokemeyer等,1996年,《国际肾脏学》49,1187)。
ERK2是一种广泛分布的蛋白激酶,当Thr183和Tyr185被上游MAP激酶MEK1磷酸化时,它达到最大活性(Anderson等,1990年,《自然》343,651;Crews等,1992年,《科学》258,478)。一旦活化,ERK2就磷酸化许多调节蛋白,包括蛋白激酶Rsk90(Bjorbaek等,1995年,《生物化学杂志》270,18848)和MAPKAP2(Rouse等,1994年,《细胞》78,1027),以及转录因子诸如ATF2(Raingeaud等,1996年,《分子与细胞生物学》16,1247)、ElK-1(Raingeaud等,1996年)、c-Fos(Chen等,1993年,《美国国家科学院院报》90,10952)和c-Myc(Oliver等,1995年,《实验生物学与实验医学会会志》210,162)。ERK2还是依赖于Ras/Raf的途径的下游目标(Moodie等,1993年,《科学》260,1685),并可帮助从这些潜在的致癌蛋白交接信号。ERK2已显示在乳癌细胞的阴性生长对照中起作用(Frey和Mulder,1997年,《癌症研究》57,628),并且还报道了ERK2在人乳癌中的过度表达(Sivaraman等,1997年,《临床检查杂志》99,1478)。活化ERK2还牵涉到内皮素刺激的气道平滑肌细胞的增殖,提示了这种激酶在哮喘中的作用(Whelchel等,1997年,《美国呼吸细胞与分子生物学杂志》16,589)。
JNK族的(MAP)1激酶已涉及在介导对多种疾病的细胞反应中起作用,所述疾病包括癌(《致癌基因》1996年,13,135-42)、肝病(《肝脏学》1998年,28,1022-30)、心血管疾病(《循环系研究》1998年,83,167-78;《循环》1998年,97:1731-7;《生物化学杂志》1997年,272,28050-6;《循环系研究》1996年,79,162-73;《循环系研究》1996年,78,947-53;《临床检查杂志》1996年,97,508-14),和免疫学疾病(《免疫学杂志》1999年,162,3176-87;《欧洲免疫学杂志》1998年,28,3867-77;《实验医学杂志》1997年,186,941-53;《欧洲免疫学杂志》1996年,26,989-94,等等)。
Aurora2是和人的癌症诸如结肠癌、乳癌和其他固体肿瘤有牵连的丝氨酸/苏氨酸蛋白激酶。这种激酶据信与调节细胞周期的蛋白磷酸化事件有关。具体地说,Aurora2可在控制有丝***期间染色体的精确分离中起作用。细胞周期的错误调节可导致细胞增殖和其他异常。在人的结肠癌组织中,已发现了过度表达的Aurora2蛋白。参见Bischoff等,《欧洲分子生物学组织杂志》1998年,17,3052-3065;Schiumacher等,《细胞生物学杂志》1998年,143,1635-1646;Kimura等,《生物化学杂志》1997年,272,13766-13771。
糖原合酶激酶-3(GSK-3)是由各自由不同基因编码的α和β同种型构成的丝氨酸/苏氨酸蛋白激酶〔Coghlan等,《化学与生物学》7,793-803(2000);Kim和Kimmel,遗传学发展流行观点》10,508-514(2000)〕。GSK-3和多种疾病包括糖尿病、早老性痴呆、CNS疾病诸如躁狂抑郁性疾病和神经变性疾病、以及心肌突出肥大等有牵连〔WO99/65897;WO00/38675;和Haq等,《细胞生物学杂志》(2000)151,117〕。这些疾病可由其中GSK-3起作用的某些细胞信号途径的异常动作引起或导致这种异常。
KDR是也结合VEGF(血管内皮生长因子)的酪氨酸激酶受体(Neufeld等,1999年,《美国实验生物学会联合会会志》13,9)。VEGF与KDR受体的结合导致血管生成,这是毛细管从先存在的血管的萌芽。在引起肿瘤血管生成并允许癌性细胞迅速生长的各种癌中发现了高浓度的VEGF。因此,抑制VEGF活性是抑制肿瘤生长的一个手段,据显示这可以通过抑制KDR受体酪氨酸激酶实现。
AKT,也称作蛋白激酶B,是在促进各式各样的细胞类型的存活中起重要作用的丝氨酸/苏氨酸激酶〔Khwaja,A.,《自然》,33-34页(1990)〕。据Zang等人显示,人卵巢癌细胞显示出抬高浓度的AKT-1和AKT-2。抑制AKT导致这些人卵巢癌细胞的编程性细胞死亡,证明AKT可能是卵巢癌治疗〔Zang,Q.Y.等,《致癌基因》,19(2000)〕和其他增殖性疾病的重要目标。AKT途径也和运动神经元存活和神经再生有牵连〔Kazuhiko,N.等,《神经科学杂志》,20(2000)〕。
对于尚未得到满足的开发蛋白激酶抑制剂的医学需要有很高的需求,尤其是对于可用于治疗与ERK活化有关的各种疾病的ERK抑制剂,特别是考虑到对于这些疾病中的大多数来说目前可获得的、相当不够的治疗选择。
因此,仍然非常需要开发蛋白激酶的强抑制剂,包括ERK抑制剂,它们可用于治疗与蛋白激酶活化有关的各种疾病。
发明的描述
现已发现本发明化合物及其组合物是有效的蛋白激酶抑制剂,尤其是ERK的抑制剂。这些化合物具有通式I:或其药学上可接受的衍生物,其中:
R1选自R、卤素、N(R8)2、OR、NRCOR、NRCON(R8)2、CON(R8)2、SO2R、NRSO2R或SO2N(R8)2;
T选自价键或连接基;
R各自独立地选自氢或具有1至6个碳的可选取代的脂族基;
R2选自氢、CN、卤素、芳基、芳烷基、杂芳基、杂环基、具有1至6个碳的可选取代的无环脂族链基、或具有4至10个碳的可选取代的环脂族基;
R3选自R、OH、OR、N(R8)2、卤素或CN;
Q是价键、J、或可选取代的C1-6亚烷基链,其中该亚烷基链的最多两个非相邻碳各自可选地并独立地被J取代;
J选自-C(=O)-、-CO2-、-C(O)C(O)-、-NRCONR8-、-N(R)N(R8)-、-C(=O)NR8-、-NRC(=O)-、-O-、-S-、-SO-、-SO2-、-N(R)O-、-ON(R8)-、-OC(=O)N(R8)-、-N(R)COO-、-SO2N(R8)-、-N(R)SO2-或-N(R8)-;
R4选自-R8、-R5、-NH2、-NHR5、-N(R5)2或-NR5(CH2)yN(R5)2;
R5各自独立地选自R6、R7、-(CH2)yCH(R6)(R7)、-(CH2)yR6、-(CH2)yCH(R6)2、-(CH2)yCH(R7)2或-(CH2)yR7;
y是0-6;
R6各自是可选取代的基团,独立地选自脂族基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳基烷基、杂芳基烷氧基、杂环基、杂环基烷基或杂环基烷氧基;
R7各自独立地选自可选取代的羟基烷基、烷氧基烷基、芳氧基烷基或烷氧基羰基;
R8各自独立地选自R,或者同一氮上的两个R8与氮一起可选地构成具有1至3个杂原子的4至8元饱和或不饱和杂环;
并且各个可取代的环氮可选地被R、NR2、COR、CO2(C1-C6可选取代的烷基)、SO2(C1-C6可选取代的烷基)、CONR2和SO2NR2取代。
除非另有说明,否则本文中将采用以下定义。另外,取代基或变量的组合只有产生稳定的化合物时才是允许的。
本文中所用的术语“脂族”是指完全饱和或含有1个或多个不饱和单元的直链、支链或环C1-C12烃。例如,合适的脂族基包括取代或未取代的直链、支链或环烷基、烯基、炔基及其混合物,诸如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。单独使用或作为较大基团的一部分的术语“烷基”和“烷氧基”指的是含有1至12个碳原子的直链和支链。单独使用或作为较大基团的一部分的术语“烯基”和“炔基”将包括含有2至12个碳原子的直链和支链。术语“卤代烷基”、“卤代烯基”和“卤代烷氧基”是指根据具体情况被1个或多个卤素原子取代的烷基、烯基或烷氧基。术语“卤素”是指F、Cl、Br或I。术语“杂原子”是指N、O或S,并且将包括任何氧化形式的氮和硫,以及季铵化形式的任何碱性氮。
单独使用或作为较大基团的一部分如在“芳烷基”中所用的术语“芳基”指的是具有5至14个成员的芳环基,诸如苯基、苄基、1-萘基、2-萘基、1-蒽基和2-蒽基,以及杂环芳基或杂芳基诸如2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁二唑基、5-噁二唑基、2-噁唑基、4-噁唑基、5-噁唑基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、3-哒嗪基、2-噻唑基、4-噻唑基、5-噻唑基、5-四唑基、2-***基、5-***基、2-噻吩基或3-噻吩基。术语“芳环”也指被可选地取代的环。
芳基还包括稠合多环芳环***,其中碳环芳环或杂芳基环与一个或多个其他环稠合。实例包括四氢萘基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并噻唑基、苯并噁唑基、苯并咪唑基、异喹啉基、异吲哚基、吖啶基、苯并异噁唑基,等等。如本文中所用的,在术语“芳基”的范围内还包括这样的基团:其中一个或多个碳环芳环和/或杂芳基环与环烷基或非芳族杂环稠合,例如2,3-二氢化茚基或四氢苯并吡喃基。
非芳族杂环是其中一个或多个环碳在环中被杂原子诸如氮、氧或硫取代的非芳族碳环。环可以是5、6、7或8元环和/或与另一个环、诸如环烷基或芳环稠合。实例包括3-1H-苯并咪唑-2-酮、3-(1-烷基)-苯并咪唑-2-酮、2-四氢呋喃基、3-四氢呋喃基、2-四氢噻吩基、3-四氢噻吩基、2-吗啉基、3-吗啉基、4-吗啉基、2-硫代吗啉基、3-硫代吗啉基、4-硫代吗啉基、1-吡咯烷基、2-吡咯烷基、3-吡咯烷基、1-哌嗪基、2-哌嗪基、1-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、4-噻唑烷基、diazolonyl、N-取代diazolonyl、1-苯并[c]吡咯酮基、苯并噁烷、苯并***-1-基、苯并吡咯烷、苯并哌啶、苯并氧杂环戊烷基、苯并硫杂环戊烷基和benzothiane。术语“杂环”,无论是饱和的还是不饱和的,也指被可选取代的环。
芳基(碳环和杂环)或芳烷基,诸如苄基或苯乙基,可含有一个或多个取代基。芳基的不饱和碳原子上的适宜取代基的实例包括卤素、-R、-OR、-SR、被护OH(诸如酰氧基)、苯基(Ph)、取代Ph、-OPh、取代-OPh、-NO2、-CN、-N(R)2、-NRN(R)2、-NRCON(R)2、-NRCOR、-NRCO2(脂族的)、-CO2R、-COR、-C(O)C(O)R、-CON(R)2、-CONRN(R)2、-S(O)2R、-SON(R)2、-S(O)(脂族的)、-SO2N(R)2或-NRS(O)2R,其中R各自独立地选自氢、脂族基或取代脂族基。
脂族基或非芳族杂环可以含有一个或多个取代基。脂族基或非芳族杂环的饱和碳上的适宜取代基的实例包括上文中对不饱和碳列出的那些以及下列这些:=O、=S、=NNHR、=NNR2、=N-、OR、=NNHCOR、=NNHCO2(脂族的)、=NNHSO2(脂族的)或=NR,其中R各自独立地选自氢、脂族基或取代脂族基。
术语“亚烷基链”指的是可选取代的直链或支链碳链,它可以是完全饱和的或者具有一个或多个不饱和单元。可选取代基是如上文中对脂族基所述的。Q的C1-6亚烷基链的可选取代基包括上文中对脂族基所述的那些。
芳族或非芳族杂环上的可取代的氮可以是可选取代的。氮上的适宜取代基包括R、COR、N(R)2、CON(R)2、CONRN(R)2、S(O)2R和CO2R,其中R独立地选自氢、可选取代的芳基或脂族基。
术语“连接基”是指连接两部分化合物的有机部分。连接基一般由原子诸如氧或硫、单元诸如-NH-或-CH2-、或原子链诸如亚烷基链组成。连接基的分子质量一般在约14至200范围内。连接基的实例包括饱和或不饱和C1-6亚烷基链,它是可选取代的,并且其中该链的最多两个饱和碳可选地被-C(=O)-、-CONH-、-CONHNH-、-CO2-、-NHCO2-、-O-、-NHCONH-、-OC(=O)-、-OC(=O)NH-、-NHNH-、-NHCO-、-O-、-S-、-SO-、-SO2-、-NH-、-SO2NH-或NHSO2-取代。
对本领域技术人员来说显而易见的是,本发明的某些化合物可以互变异构形式存在,所有这类互变异构形式的化合物都在本发明的范围内。
除非另有说明,否则本文中描述的结构还意味着包括该结构的所有立体化学形式,即每个不对称中心的R和S构型。因此,本发明化合物的单一立体化学异构体以及对映体和非对映体的混合物也在本发明的范围内。除非另有说明,否则本文中描述的结构还意味着包括仅在存在一个或多个同位素富原子方面有所不同的化合物。例如,具有现在的结构但氢被氘或氚取代、或者碳被富集13C或14C的碳取代的化合物也在本发明范围内。本发明的一个实施方案涉及式II化合物:其中R1、R2、R3、R4、T和Q如上所述。
优选的化合物包括具有一项或多项、首选全部下列特征的那些:(a)Q是-CO-、-CO2-或-CONH-;(b)T是价键;(c)R1是氢或NHR;(d)R2是可选取代的芳环,更优选可选取代的苯环;(c)R3是氢;(e)R4选自R5、-NHR5、-N(R5)2、-NR5R6、-NHCHR5R6、或-NHCH2R5;和/或(f)R5是可选取代的基团,选自芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环基烷基、(CH2)yR6、(CH2)yR7、或(CH2)yCH(R6)(R7)。
R2苯基的取代基的实例包括卤素、硝基、烷氧基和氨基。
当R4为R5时,优选的R5基的实例包括吡咯烷-1-基、吗啉-1-基、哌啶-1-基和哌嗪-1-基,其中各个基团是可选取代的。当R4是-NHR5或-N(R5)2时,优选的R5基还包括(CH2)yR6、(CH2)yR7和(CH2)yCH(R6)(R7)。优选的R6和R7的实例包括吡啶-3-基、吡啶-4-基、咪唑基、呋喃-2-基、四氢呋喃-2-基、环己基、苯基、-CH2OH、-(CH2)2OH和异丙基,其中各个基团是可选取代的。其中R1和R3各自为氢的式II的例举性结构列在下表1中。表1.化合物II
本发明的另一个优选实施方案涉及式II-B化合物:其中T、R、R2和R4如上所述。
序号 | T-R2 | Q-R4 |
II-1 | 苯基 | CON(Me)2 |
II-2 | 苯基 | CO2Et |
II-3 | 3-NO2-苯基 | CONHNH2 |
II-4 | 苯基 | CO(吡咯烷-1-基) |
II-5 | 苯基 | CONHCH2(Ph) |
II-6 | 3-NO2-苯基 | CO2Et |
II-7 | 4-Cl-苯基 | CO2Et |
II-8 | 4-OMe-苯基 | CO2Et |
II-9 | 3-NH2-苯基 | CO2Et |
II-10 | 3-OMe-苯基 | CO2Et |
II-11 | 4-F-苯基 | CO2Et |
II-12 | 4-NO2-苯基 | CO2Et |
II-13 | 3-Cl-苯基 | CO2Et |
II-14 | 3-F-苯基 | CO2Et |
II-15 | 苯基 | CO2Et |
II-16 | 4-NH2-苯基 | CO2Et |
II-17 | 苯基 | CONHCH2CH2N(Me)2 |
II-18 | 苯基 | CONHCH2(吡啶-3-基) |
II-19 | 苯基 | CO(吗啉-1-基) |
II-20 | 苯基 | CONH(异丙基) |
II-179 | 4-OMe-苯基 | CONHCH2(吡啶-3-基) |
II-180 | 2,5-(OMe)2-苯基 | CONHCH2(吡啶-3-基) |
II-181 | 2,5-F2-苯基 | CONHCH2(吡啶-3-基) |
II-182 | 4-F-苯基 | CONHCH2(四氢呋喃-2-基) |
II-183 | 4-OMe-苯基 | CONHCH2(四氢呋喃-2-基) |
II-184 | 5-F-苯基 | CONHCH2(四氢呋喃-2-基) |
II-185 | 5-OMe-苯基 | CONHCH2(四氢呋喃-2-基) |
II-186 | 2,5-(OMe)2-苯基 | CONHCH2(四氢呋喃-2-基) |
II-187 | 5,6-F2-苯基 | CONHCH2(四氢呋喃-2-基) |
II-188 | 2,5-F2-苯基 | CONHCH2(四氢呋喃-2-基) |
II-189 | 4-F-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-190 | 4-OMe-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-191 | 5-F-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-192 | 5-OMe-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-193 | 3,6-(OMe)2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-194 | 4,5-F2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-195 | 5,6-F2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-196 | 3,6-F2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-197 | 4-F-苯基 | CO(吗啉-1-基) |
II-198 | 4-OMe-苯基 | CO(吗啉-1-基) |
II-199 | 5-F-苯基 | CO(吗啉-1-基) |
II-200 | 2,5-(OMe)2-苯基 | CO(吗啉-1-基) |
II-201 | 4,5-F2-苯基 | CO(吗啉-1-基) |
II-202 | 5,6-F2-苯基 | CO(吗啉-1-基) |
II-203 | 2,5-F2-苯基 | CO(吗啉-1-基) |
II-204 | 4-F-苯基 | CO(4-Me-哌啶-1-基) |
II-205 | 4-OMe-苯基 | CO(4-Me-哌啶-1-基) |
II-206 | 5-F-苯基 | CO(4-Me-哌啶-1-基) |
II-207 | 2,5-(OMe)2-苯基 | CO(4-Me-哌啶-1-基) |
II-208 | 4,5-F2-苯基 | CO(4-Me-哌啶-1-基) |
II-209 | 5,6-F2-苯基 | CO(4-Me-哌啶-1-基) |
II-210 | 3,6-F2-苯基 | CO(4-Me-哌啶-1-基) |
II-211 | 4-Cl-苯基 | CONHCH2(吡啶-4-基) |
II-212 | 4,5-(OMe)2-苯基 | CONHCH2(吡啶-4-基) |
II-213 | 4-苯并[1,3]二氧杂环戊烯-5-基 | CONHCH2(吡啶-4-基) |
II-214 | 4-Cl-苯基 | CONHCH2(吡啶-3-基) |
II-215 | 4,5-(OMe)2-苯基 | CONHCH2(吡啶-3-基) |
II-216 | 4-苯并[1,3]二氧杂环戊烯-5-基 | CONHCH2(吡啶-3-基) |
II-217 | 4-Cl-苯基 | CONHCH2(四氢呋喃-2-基) |
II-218 | 4,5-(OMe)2-苯基 | CONHCH2(四氢呋喃-2-基) |
II-219 | 4-苯并[1,3]二氧杂环戊烯-5-基 | CONHCH2(四氢呋喃-2-基) |
II-220 | 4-Cl-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-221 | 4,5-Cl2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-222 | 5-Cl-6-F-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-223 | 4-F-5-Cl-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-224 | 4,5-(OMe)2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-225 | 4-苯并[1,3]二氧杂环戊烯-5-基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-226 | 3,5-Cl2-苯基 | CONHCH2(1-Et-吡咯烷-2-基) |
II-227 | 4-Cl-苯基 | CO(吗啉-1-基) |
II-228 | 4,5-(OMe)2-苯基 | CO(吗啉-1-基) |
II-229 | 4-苯并[1,3]二氧杂环戊烯-5-基 | CO(吗啉-1-基) |
II-230 | 4-Cl-苯基 | CO(4-Me-哌啶-1-基) |
II-326 | 3-Cl-苯基 | NHCOCH2Ph |
II-327 | 3-Cl-苯基 | NHSO2-吗啉-1-基 |
II-328 | 3-Cl-苯基 | NHCONHCH2Ph |
II-329 | 3-Cl-苯基 | NHCO2-四氢呋喃-2-基 |
II-330 | CH2Ph | CONHCH2Ph |
II-331 | Me | CONHCH2Ph |
II-332 | 异丙基 | CONHCH2Ph |
II-333 | H | CON(Me)2 |
优选的II-B化合物包括具有一项或多项、首选全部下列特征的那些:(a)T是价键;(b)R3是氢;和/或(c)R2是可选取代的芳环,更优选可选取代的苯环。
其中R3为H的式II-B的例举性结构列在下表2中。
表2.化合物II-B
序号 | R | T-R2 | Q-R4 |
II-B-1 | H | 苯基 | CON(Me)2 |
II-B-2 | H | 苯基 | CO2Et |
II-B-3 | H | 3-NO2-苯基 | CONHNH2 |
II-B-4 | H | 苯基 | CO(吡咯烷-1-基) |
II-B-5 | Me | 苯基 | CONHCH2(Ph) |
II-B-6 | H | 3-NO2-苯基 | CO2Et |
II-B-7 | H | 4-Cl-苯基 | CO2Et |
II-B-8 | Me | 4-OMe-苯基 | CO2Et |
本发明化合物一般可以用本领域技术人员已知的制备类似化合物的方法加以制备,如通用方案I和II以及下文中所示的合成实施例所说明的。
方案I试剂和条件:(a)PhCH2COCl,AlCl3,CH2Cl2,2小时,室温(b)DMF,24小时,室温(c)(Me2N)2-Ot-Bu,THF,24小时,室温(d)H2NNH2,EtOH,12小时,回流
上述方案I显示了用于制备R2为可选取代的苯基时的本发明化合物的一般合成途径。在步骤(a)中,可选取代的苯甲酰氯在二氯甲烷和三氯化铝中与化合物1化合形成化合物2。苯环上的各种取代基都可经受该反应。合适的R2基的实例包括但不限于上文表1中列出的那些。
在DMF中用胺3处理化合物2而形成酰胺4。当胺3为伯胺时,该反应在室温下进行。当胺3为仲胺时,该反应在50℃下加热以使反应完全并得到酰胺4。
在步骤(c),通过在室温下用(Me2N)2-Ot-Bu处理酰胺4而形成烯胺5。另一方面,在步骤(c)形成烯胺5的反应也可以通过使用二甲基甲酰胺-二甲基乙缩醛(DMF-DMA)实现。使用DMF-DMA的反应需要抬高的温度以得到烯胺5,而使用(Me2N)2-OtBu则有在室温下进行反应以更高纯度得到烯胺5的优点。
在步骤(d),通过在抬高的温度下用水合肼处理烯胺5而形成吡唑化合物6。如表1中所例举的、用该方法合成的式II化合物通过制备HPLC(逆相,10→90%MeCN的水溶液,15分钟)分离。用于生产这些化合物的具体条件陈述在实施例中。
方案II试剂和条件:(a)3-Cl-PhCH2COCl,AlCl3,CH2Cl2,2小时,室温(b)DMF,24小时,室温(c)NBS,CCl4,回流(d)iPrOH,回流(e)甲酸,回流,2小时。
上述方案II显示了可用于制备式II-B化合物的一般合成方法,以化合物II-B-16为例。该方法是从Jira,T.等在《Pharmazie》第401-406页(1994)中公开的方法改良的。式II-B化合物也可以用与下列文献中公开的类似方法制备:Woller,J.等,《Pharmazie》第937-940页(1996);Rychmans,T.等,《四面体》第1729-1734页(1997);和Tupper,D.E.等,《合成》第337-341页(1997)。
按照另一个实施方案,本发明提供了抑制生物学样品中激酶活性的方法。该方法包括使所述生物学样品与本发明化合物接触的步骤。
本文中所用的术语“生物学样品”包括细胞培养物或其提取物;从哺乳动物得到的活组织检查物质或其提取物;以及血液、唾液、小便、粪便、***、眼泪、或其他体液或其提取物。术语“生物学样品”还包括活有机体,在这种情况下,“使本发明化合物与生物学样品接触”与术语“对哺乳动物给药所述化合物(或包含所述化合物的组合物)”是同义的。
本发明的另一个方面涉及哺乳动物的可通过用蛋白激酶抑制剂治疗而减轻的疾病状态的治疗方法,该方法包括对需要这种治疗的哺乳动物给药治疗有效量的式I化合物或其药学上可接受的衍生物,其中:
R1选自R、卤素、N(R8)2、OR、NRCOR、NRCON(R8)2、CON(R8)2、SO2R、NRSO2R或SO2N(R8)2;
T选自价键或连接基;
R各自独立地选自氢或具有1至6个碳的可选取代的脂族基;
R2选自氢、CN、卤素、芳基、芳烷基、杂芳基、杂环基、具有1至6个碳的可选取代的无环脂族链基、或具有4至10个碳的可选取代的环脂族基;
R3选自R、OH、OR、N(R8)2、卤素或CN;
Q是价键、J、或可选取代的C1-6亚烷基链,其中该亚烷基链的最多两个非相邻碳各自可选地并独立地被J取代;
J选自-C(=O)-、-CO2-、-C(O)C(O)-、-NRCONR8-、-N(R)N(R8)-、-C(=O)NR8-、-NRC(=O)-、-O-、-S-、-SO-、-SO2-、-N(R)O-、-ON(R8)-、-OC(=O)N(R8)-、-N(R)COO-、-SO2N(R8)-、-N(R)SO2-或-N(R8)-;
R4选自-R8、-R5、-NH2、-NHR5、-N(R5)2或-NR5(CH2)yN(R5)2;
R5各自独立地选自R6、R7、-(CH2)yCH(R6)(R7)、-(CH2)yR6、-(CH2)yCH(R6)2、-(CH2)yCH(R7)2或-(CH2)yR7;
y是0-6;
R6各自是可选取代的基团,独立地选自脂族基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳基烷基、杂芳基烷氧基、杂环基、杂环基烷基或杂环基烷氧基;
R7各自独立地选自可选取代的脂族基、羟基烷基、烷氧基烷基、芳氧基烷基或烷氧基羰基;
R8各自独立地选自R,或者同一氮上的两个R8与氮一起可选地构成具有1至3个杂原子的4至8元饱和或不饱和杂环;
并且各个可取代的环氮可选地被R、NR2、COR、CO2(C1-C6可选取代的烷基)、SO2(C1-C6可选取代的烷基)、CONR2和SO2NR2取代。
一个实施方案包括给药式II化合物。优选实施方案包括给药式II-A化合物,首选表1中所列的化合物。另一个优选实施方案包括给药式II-B化合物,更优选表2中所列的化合物。下面描述用于这类方法的药物组合物。
本发明方法尤其可用于治疗能通过使用ERK、JAK、JNK、Aurora、GSK、KDR或AKT的抑制剂来减轻的疾病状态。除非另有说明,否则本文中所用的术语“ERK”、“JAK”、“JNK”、“Aurora”、“GSK”、“KDR”和“AKT”指的是各个酶的所有同种型,包括但不限于:ERK1、ERK2、ERK3、ERK4、ERK5、ERK6、ERK7、JAK1、JAK2、JAK3、JAK4、JNK1、JNK2、JNK3、Auroral、Aurora2、GSK3-α、GSK3-β、KDR、AKT-1、AKT-2和AKT-3。
化合物作为蛋白激酶抑制剂、例如作为ERK抑制剂的活性可以在体外、在体内或在细胞系中进行测定。用ERK为例,体外测定包括测定活化ERK的激酶活性或ATP酶活性的抑制情况。另一项体外测定法定量测定抑制剂结合ERK的能力,并可通过在结合前对抑制剂进行放射性标记、分离抑制剂/ERK复合物和测定放射性标记结合的量来测量,或者通过进行竞争实验来测量,其中新的抑制剂与结合到已知放射性配体上的ERK一起培养。根据要抑制的ERK类型或同种型,可以使用任何类型或同种型的ERK。
根据酶测定法的测定,本发明化合物是ERK的强抑制剂。这些化合物还在细胞增殖测定中显示能抑制ERK。用于酶测定和细胞增殖测定的具体条件陈述在下文中的实施例中。
根据酶测定法的测定,本发明化合物还是JNK、Aurora、GSK、KDR和AKT的抑制剂。用于该测定的具体条件陈述在下文中的实施例中。不受理论的束缚,本发明化合物还预期能抑制其他蛋白激酶。
本发明的蛋白激酶抑制剂或其可药用盐可以配制成用于对动物或人给药的药物组合物。包含足以可检测地抑制蛋白激酶活性量的蛋白激酶抑制剂和药学上可接受的载体的、能有效地治疗或预防蛋白激酶介导的疾病的这些药物组合物是本发明的另一个实施方案。本文中所用的术语“可检测地抑制”是指含有所述抑制剂的样品和只含有蛋白激酶的样品间活性的可测量的变化。
本文中所用的术语“ERK介导的疾病”是指其中已知ERK起作用的任何疾病状态或其他有害病况。这类疾病非限制性地包括癌、中风、糖尿病、肝肿大、心血管疾病包括心肥大、早老性痴呆、囊纤维变性、病毒疾病、自身免疫疾病、动脉粥样硬化、再狭窄、牛皮癣、变应性疾病包括哮喘、炎症、神经病学疾病和与激素有关的疾病。术语“癌”包括但不限于下列癌:乳癌、卵巢癌、***、***癌、睾丸癌、生殖泌尿道癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡癌、未分化癌、***状癌、***瘤、黑素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、骨髓疾病、淋巴样疾病、何杰金氏病、毛细胞、口腔前庭和咽(口腔)癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑癌和中枢神经***癌,以及白血病。
本发明化合物还可用作相关激酶的抑制剂。术语“相关激酶”指的是具有与连接ERK结合位点的那些残基类似的残基的蛋白激酶。不希望受到理论的束缚,申请人推测这种抑制活性是由ERK和相关激酶的活性位点之间的紧密的结构相似性导致的。ERK序列与其他激酶的对齐可以从普通的软件程序诸如可从Genetics ComputerGroup购得的“bestfit”程序产生。这种程序使用Smith和Waterman在《应用数学进展》2;482(1981)中描述的局部同源性算法。
利用上述标准蛋白质序列对齐软件确定,受本发明化合物抑制的相关激酶将含有与ERK残基相对应的残基:I31、E33、G34、A35、Y36、G37、M38、V39、A52、K54、R67、T68、E71、L75、I84、I86、I103、Q105、D106、L107、M108、E109、D111、K114、D149、K151、S153、N154、L156、C166和D167,相似性得分为80%或更高。相似性得分可以使用标准氨基酸置换表确定,诸如由Dayhoff(Dayhoff,M.O.等,《蛋白质序列和结构图谱》,1979年)和Blosom-Henikoff(Blosom-Henikoff,S和Henikoff,J.D.,PNAS,1992,89:10915-10919)描述的那些。术语“相关激酶”还包括含有与下列ERK残基的相似性得分为80%或更高的残基的那些:I31、G37、A52、I103、E109和N154。
本发明化合物还可用作JAK族激酶的抑制剂。不希望受到理论的束缚,申请人推测这种抑制活性是由于如上述标准方法确定的ERK和JAK的活性位点之间的紧密的结构相似性导致的。
从用ERK结合抑制剂进行的内部X射线晶体结构实验来看,ERK活性部位中的三个氨基酸残基构成了与这些类型的抑制剂的关键氢键键合作用。这三个氨基酸残基是M108、D106和Q105。此氨基酸编号对应于Swiss-Prot资料库中的登记号#P28482。Swiss-Prot资料库是由瑞士日内瓦的欧洲生物信息学协会(EBI)发布的国际蛋白质序列资料库。该资料库可以在www.ebi.ac.uk/swissprot上找到。
M108和D106的主链原子以及伴随的相互作用是所有激酶共有的。M108提供氢键供体和受体,D106通过其主链CO提供氢键受体。能与活性部位中的一个或多个这些氢键键合基团形成氢键的抑制剂预期将与酶结合,并因此显示出抑制作用。
通过检查从上述软件程序获得的对齐数据,确定Q105谷氨酰胺残基和包括ERK和JAK的激酶子集有关。Q105提供关键的氢键接受侧链CO。模型化实验显示,对于ERK和JAK,Ht环的氢键供体在Q105残基远处的氢键键合部位中。由于这些类似的活化-位点相互作用,本发明的ERK抑制剂也抑制JAK。因此,这些化合物可用于治疗JAK介导的疾病。
本文中所用的术语“JAK介导的疾病”是指其中已知JAK起作用的任何疾病状态或其他有害病况。这类疾病非限制性地包括变应性疾病诸如哮喘和特应性皮炎、自身免疫疾病诸如SLE狼疮和牛皮癣、以及与器官移植有关的疾病。
本发明化合物还可用作JNK族激酶的抑制剂。因此,这些化合物可用于治疗JNK介导的疾病。本文中所用的术语“JNK介导的疾病”是指其中已知JNK起作用的任何疾病状态或其他有害病况。这类疾病非限制性地包括驱动编程性细胞死亡的神经变性疾病诸如早老性痴呆、帕金森氏病、ALS(肌萎缩性侧索硬化)、癫痫和癫痫发作、杭廷顿氏舞蹈病、外伤性脑损伤、以及缺血性和出血性中风、心脏病、免疫缺陷疾病、炎性疾病、变应性疾病、自身免疫疾病、破坏性骨疾病诸如骨质疏松症、增殖性疾病、传染病、病毒疾病、涉及细胞死亡的疾病和增生包括中风、心脏病发作和器官氧不足中的再充满/局部缺血、凝血酶诱导的血小板聚集、慢性骨髓性白血病(CML)、类风湿性关节炎、哮喘、骨关节炎、局部缺血、癌、肝脏疾病包括肝局部缺血、心脏病诸如心肌梗死和充血性心力衰竭、牵涉T细胞活化的病理性免疫疾病和神经变性疾病。
本发明化合物还可用作Aurora抑制剂。因此,这些化合物可用于治疗Aurora介导的疾病。本文中所用的术语“Aurora介导的疾病”是指其中已知Aurora起作用的任何疾病状态或其他有害病况。这类疾病非限制性地包括癌。术语“癌”包括但不限于下列癌:结肠癌和卵巢癌。
本发明化合物还可用作GSK族激酶的抑制剂。因此,这些化合物可用于治疗GSK介导的疾病。本文中所用的术语“GSK介导的疾病”是指其中已知GSK起作用的任何疾病状态或其他有害病况。这类疾病非限制性地包括糖尿病、早老性痴呆、神经变性疾病和CNS疾病诸如躁狂抑郁性疾病和精神***症。
本发明化合物还可用作KDR族激酶的抑制剂。因此,这些化合物可用于治疗KDR介导的疾病。本文中所用的术语“KDR介导的疾病”是指其中已知KDR起作用的任何疾病状态或其他有害病况。KDR介导的疾病或病况包括但不限于癌诸如脑癌、泌尿生殖道癌、淋巴***癌、胃癌、喉癌、肺癌、胰腺癌、乳癌、卡波济氏肉瘤和白血病;子宫内膜异位,良性***增生;血管疾病诸如再狭窄和动脉粥样硬化;自身免疫疾病诸如类风湿性关节炎和牛皮癣;眼病诸如增殖性或血管生成性视网膜病和黄斑变性;和炎性疾病诸如接触性皮炎、哮喘和迟发性过敏反应。
本发明化合物还可用作AKT族激酶的抑制剂。因此,这些化合物可用于治疗AKT介导的疾病。本文中所用的术语“AKT介导的疾病”是指其中已知AKT起作用的任何疾病状态或其他有害病况。AKT介导的疾病或病况包括但不限于增殖性疾病、癌和神经变性疾病。
除了本发明的化合物以外,本发明化合物的药学上可接受的衍生物或药物前体也可以用于组合物中来治疗或预防上述疾病。
“药学上可接受的衍生物或药物前体”是指本发明化合物的任何药学上可接受的盐、酯、酯的盐或其他衍生物,一旦对接受者给药,它们就能直接或间接提供本发明化合物或其抑制性活性代谢物或残余物。特别有利的衍生物或药物前体是当这类化合物对哺乳动物给药时能提高本发明化合物的生物利用度(例如通过使口服给药的化合物更容易地吸收到血液中)或能增强母化合物向与母物质有关的生物学房室(例如脑或淋巴***)的释放的那些。
本发明化合物的药学上可接受的药物前体非限制性地包括酯、氨基酸酯、磷酸酯、金属盐和磺酸酯。
本发明化合物的药学上可接受的盐包括从药学上可接受的无机和有机酸和碱衍生的那些。适宜的酸盐的实例包括乙酸盐、己二酸盐、藻酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐、酸式硫酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、月桂基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡糖庚酸盐、甘油磷酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、palmoate、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一烷酸盐。其他酸,诸如草酸,尽管自身不是药学上可接受的,但可以在得到本发明化合物和它们的药学上可接受的酸加成盐中作为中间体用于盐的制备。
从适宜的碱衍生的盐包括碱金属(例如钠和钾)盐、碱土金属(例如镁)盐、铵盐和N+(C1-4烷基)4盐。本发明还预想了本文中公开的化合物的任何碱性含氮基团的季铵化。季铵化可得到水或水溶或分散的产物。
可以用于这些药物组合物的药学上可接受的载体包括但不限于:离子交换剂、矾土、硬脂酸铝、卵磷脂、血清蛋白诸如人血清白蛋白、缓冲物质诸如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
本发明组合物可以口服给药、胃肠外给药、通过吸入喷雾给药、局部给药、直肠给药、经鼻给药、经颊给药、鞘内给药或经由植入贮器给药。本文中所用的术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、肝内、损害内和颅内注射或滴注技术。优选组合物口服、腹膜内或静脉内给药。
本发明组合物的无菌注射用形式可以是含水或油质的悬浮液。这些悬浮液可以按照本领域中的已知技术使用合适的分散剂或润湿剂和悬浮剂进行配制。无菌注射用制剂还可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌注射用溶液或悬浮液,例如用1,3-丁二醇制成溶液。在可接受的赋形剂和溶剂中可以采用的是水、Ringer溶液和等渗氯化钠溶液。另外,无菌的不挥发油常常用作溶剂或悬浮介质。为此目的,可以采用任何温和的不挥发油包括合成的一-或二-甘油酯。脂肪酸诸如油酸及其甘油酯衍生物可用于注射用制剂,天然的药学上可接受的油也可以,诸如橄榄油或蓖麻油,尤其是它们的聚氧乙基化变型。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂,诸如羧甲基纤维素或常用于配制药学上可接受的剂型包括乳剂和悬浮液的类似分散剂。为了制剂的目的,还可以使用其他常用表面活性剂诸如吐温类、司盘类和其他乳化剂或常用于制备药学上可接受的固体、液体或其他剂型的生物利用度增强剂。
本发明的药物组合物可以任何口服可接受的剂型口服给药,包括但不限于胶囊剂、片剂、含水悬浮液或溶液。就用于口服的片剂而言,常用载体包括乳糖和玉米淀粉。通常还加入润滑剂诸如硬脂酸镁。对于以胶囊形式的口服给药,有用的稀释剂包括乳糖和干燥玉米淀粉。当需要口服含水悬浮液时,将活性成分与乳化剂和悬浮剂混合。如果需要,还可加入某些甜味剂、调味剂或着色剂。
另一方面,本发明的药物组合物可以直肠给药用的栓剂形式给药。这些可以通过将药剂与适宜的在室温下为固体但在直肠温度下为液体并因此将在直肠中熔化而释放出药物的非刺激性赋形剂混合加以制备。这类物质包括椰子油、蜂蜡和聚乙二醇。
本发明的药物组合物还可以局部给药,尤其是当治疗目标包括通过局部应用就可容易地进入的区域或器官时,包括眼睛、皮肤或下肠道的疾病。合适的局部制剂可针对各种区域或器官容易地制备。
对于下肠道的局部应用可以用直肠栓剂制剂(参见上文)完成,或者用适宜的灌肠剂制剂完成。也可使用局部透皮贴片。
对于局部应用,药物组合物可以配制成合适的含有悬浮或溶于一种或多种载体中的活性成分的软膏剂。用于本发明化合物的局部给药的载体包括但不限于:矿物油、液体矿脂、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。另一方面,药物组合物可以配制成合适的含有悬浮或溶于一种或多种药学上可接受的载体中的活性成分的洗液或膏霜。适宜的载体包括但不限于矿物油、脱水山梨糖醇一硬脂酸酯、聚山梨醇酯60、鲸蜡基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。
对于眼科应用,药物组合物可以配制成在等渗的pH调节好的无菌盐水中的微粉化悬浮液,或者优选配制成在等渗的pH调节好的无菌盐水中的溶液,加或不加防腐剂诸如氯苄烷铵。另一方面,对于眼科应用,药物组合物可以配制成软膏剂诸如在凡士林中的。
本发明的药物组合物还可以通过鼻气雾剂或吸入给药。这类组合物按照药物制剂领域中众所周知的技术制备,并可制备成在盐水中的溶液,使用苯甲醇或其他适宜的防腐剂、增强生物利用度的吸收促进剂、碳氟化合物、和/或其他常规增溶剂或分散剂。
可以与载体物质结合生产单一剂型的本发明的蛋白激酶抑制剂的量将根据所治疗的主体、特定的给药方式变化。优选应配制组合物使得可以对接受这些组合物的病人给药剂量在约0.01-100mg/kg体重/天之间的抑制剂。
还应当理解:对于任何特定病人的具体剂量和治疗方案将取决于多种因素,包括所用的具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、***速率、药物组合、以及主治医师的判断和所治疗的特定疾病的严重程度。抑制剂的量还将取决于组合物中的特定化合物。
本发明的激酶抑制剂或其药物组合物还可以掺入到用于涂敷可植入医学装置诸如假体、人工瓣膜、血管移植物、斯滕特氏固定模和导管的组合物中。例如,血管斯滕特氏固定模已用于克服再狭窄(损伤后血管壁的再狭窄)。但是,使用斯滕特氏固定模或其他可植入装置的病人有形成凝血块或血小板活化的危险。这些不希望的作用可以通过用包含激酶抑制剂的组合物预先涂敷装置来防止或缓和。适宜的涂层和可植入包衣装置的一般制备记载在美国专利5,099,562;5,886,026和5,304,121中。涂层一般是生物相容性聚合材料诸如水凝胶聚合物、聚甲基二硅氧烷、聚己内酯、聚乙二醇、聚乳酸、乙烯基乙酸乙烯酯、及其混合物。涂层可以可选地进一步用适宜的氟聚硅氧烷、多糖、聚乙二醇、磷脂或其结合物的表层涂层覆盖,以便赋予组合物能可控释放的特性。用本发明的激酶抑制剂涂敷的可植入装置是本发明的另一个实施方案。
按照另一个实施方案,本发明提供了治疗或预防ERK、JAK、JNK、Aurora、GSK、KDR或AKT介导的病况或疾病状态的方法,它包括对病人给药上述一种药物组合物的步骤。本文中所用的术语“病人”是指哺乳动物,优选人。
优选该方法用于治疗或预防选自下列成员的病况或疾病状态:癌诸如乳癌、结肠癌、***癌、皮肤癌、胰腺癌、脑癌、生殖泌尿道癌、淋巴***癌、胃癌、喉癌和肺癌包括肺腺癌和小细胞肺癌、中风、糖尿病、肝肿大、心肥大、心血管疾病、早老性痴呆、囊纤维变性、和病毒疾病,或者任何上述具体疾病或紊乱。
根据要治疗或预防的特定病况或疾病状态,通常给药用于治疗或预防该病况的其他治疗剂可以与本发明的抑制剂一起给药。例如,化疗剂或其他抗增殖剂可以与本发明的抑制剂结合来治疗增殖性疾病和癌。已知化疗剂的实例包括但不限于阿霉素、***、长春新碱、环磷酰胺、氟尿嘧啶、托泊替堪、紫杉醇、干扰素和铂衍生物。
还可以与本发明的抑制剂结合给药的药剂的其他实例非限制性地包括抗炎剂诸如皮质类固醇、TNF阻滞剂、IL-1RA、硫唑嘌呤、环磷酰胺和柳氮磺胺吡啶;免疫调节剂和免疫抑制剂诸如环孢菌素、藤霉素、雷怕霉素、霉酚酸莫非替克、干扰素、皮质类固醇、环磷酰胺、硫唑嘌呤和柳氮磺胺吡啶;神经营养因子诸如乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥剂、离子通道阻滞剂、利鲁唑和抗帕金森氏病药剂;用于治疗心血管疾病的药剂诸如β阻滞剂、ACE抑制剂、利尿剂、硝酸盐、钙通道阻滞剂和他汀类;用于治疗肝脏疾病的药剂诸如皮质类固醇、考来烯胺、干扰素和抗病毒剂;用于治疗血液疾病的药剂诸如皮质类固醇、抗白血病药和生长因子;用于治疗糖尿病的药剂诸如胰岛素、胰岛素类似物、α葡萄糖甙酶抑制剂、双胍类和胰岛素敏化剂;以及用于治疗免疫缺陷疾病的药剂诸如γ球蛋白。
这些附加药剂可以作为多剂方案的一部分与含有抑制剂的组合物分开给药。另一方面,这些药剂可以是单一剂型的一部分,与抑制剂一起混合在单一组合物中。
2,2,2-三氯-1-(4-苯基乙酰基-1H-吡咯-2-基)-乙酮(1):在一个干燥烧瓶中,苯基乙酰氯(1当量)与2-三氯乙酰基吡咯(1当量)在最小量的二氯甲烷(DCM)中化合。在室温下,向所得溶液中加入三氯化铝(1当量)。2小时后,将该反应混合物直接加到硅胶柱上。用在己烷中的10%乙酸乙酯至50%乙酸乙酯梯度洗脱,得到化合物1,收率60%。1H NMR(CDCl3)δ4.0(s,2H),7.1-7.35(m,7H),9.7(brs,NH)。使用方法B进行的HPLC(如下文中实施例5所述)提供了4.9分钟的保留时间。LC/MS(M+1)330.2,(M-1)328.1。实施例2
4-苯基乙酰基-1H-吡咯-2-羧酸苄基酰胺(2):在室温下,向化合物1(1当量)的DMF溶液中加入苄胺(1.2当量)。24小时后,蒸除溶剂,粗产物2不经纯化就使用。使用方法B进行的HPLC(如下文中实施例5所述)提供了3.8分钟的保留时间。FIA/MS(M+1)319.3,(M-1)317.2。实施例3
4-(3-二甲氨基-2-苯基-丙烯酰基)-1H-吡咯-2-羧酸苄基酰胺(3):在室温下,向化合物2(1当量)的THF溶液中加入(Me2N)2CHOt-Bu(3当量)。24小时后,蒸除溶剂,粗产物3不经纯化就使用。1H NMR(CDCl3)δ4.4(s,2H),4.8(s,NH),6.8-7.4(m,13H)。实施例4
4-(4-苯基-1H-吡唑-3-基)-1H-吡咯-2-羧酸苄基酰胺(II-5):在室温下,向化合物3(1当量)的乙醇溶液中加入水合肼(3当量)并将所得混合物加热回流。12小时后,蒸除溶剂,粗产物用制备HPLC(逆相;10→90%MeCN的水溶液;15分钟)纯化,得到所需化合物II-5。LC/MS(M+1)343.3,(M-1)341.2。
实施例5
利用基本上与上述实施例1-4中所述的和方案I说明的类似方法,我们已制备了其他式II化合物。这些化合物的特性资料总结在下表3中,包括LC/MS,HPLC和1H NMR数据。
对于HPLC方法指定为“A”的化合物,采用以下方法:水∶MeCN,0.1%TFA(95∶5→0∶100)梯度洗脱22分钟,在1mL/分钟和214nm下进行。对于HPLC方法指定为“B”的化合物,采用以下方法:水∶MeCN,0.1%TFA(90∶10→0∶100)梯度洗脱8分钟,在1mL/分钟和214nm下进行。方法A和B各自使用大小为3.0×150mm的YMC ODS-AQ 55 120A柱。术语“Tret(分钟)”指的是使用指定HPLC方法得到的化合物的保留时间,以分钟计。
合适时,1H NMR数据也总结在下表3中,其中“Y”表示可以获得1H NMR数据并且该数据与结构一致。化合物编号对应于表1中所列的化合物编号。表3.选定化合物的特性资料
化合物号 | M+1 | M-1 | HPLC方法 | Tret(分) | 1H NMR |
II-41 | 407.4 | 405.4 | A | 8.6 | Y |
II-42 | 560.2 | 558.1 | A | 9.5 | - |
II-43 | - | - | A | 10.5 | - |
II-44 | 530.3 | 528.2 | A | 6.3 | - |
II-45 | - | - | A | 9.8 | - |
II-46 | - | - | A | 10.6 | - |
II-50 | 377.4 | - | A | 10.1 | Y |
II-52 | 530.2 | 528.2 | A | 10.3 | - |
II-53 | 378.4 | 376.3 | A | 7.4 | Y |
II-56 | 490.2 | 488.1 | A | 10.8 | - |
II-58 | - | - | A | 10.46 | - |
II-59 | - | - | A | 9.1 | - |
II-63 | 361.4 | 359.3 | A | 9.5 | Y |
II-65 | - | - | A | 10.0 | - |
II-67 | 378.4 | 376.3 | A | 7.4 | Y |
II-72 | 451.5 | 449.1 | A | 10.15 | Y |
II-80 | 374.4 | 372.3 | A | 6.6 | - |
II-83 | 435.3 | 433.4 | A | 10.3 | - |
II-85 | - | - | A | 10.6 | - |
II-86 | - | - | A | 9.3 | - |
II-88 | 380.4 | 378.3 | A | 6.9 | - |
II-89 | - | - | A | 10.5 | - |
II-91 | - | A | 9.6 | - | |
II-92 | 377.4 | 375.3 | A | 10.2 | Y |
II-94 | - | - | A | 9.0 | - |
II-97 | 342.1 | - | B | 3.8 | Y |
II-98 | 380.4 | 378.3 | A | 6.7 | - |
II-102 | - | - | A | 10.3 | - |
II-103 | - | - | A | 10.6 | - |
II-105 | - | - | A | 9.3 | - |
II-109 | - | - | A | 7.9 | - |
II-110 | - | - | A | 10.3 | - |
II-111 | 361.4 | 359.3 | A | 9.4 | Y |
II-113 | - | - | A | 10.6 | - |
C化合物号 | M+1 | M-1 | HPLC方法 | Tret(分) | 1H NMR |
II-116 | 380.2 | 378.4 | A | 6.9 | - |
II-117 | 373.4 | - | A | 9.0 | Y |
II-119 | 362.4 | 371.4 | A | 6.5 | - |
II-120 | 373.4 | 371.4 | A | 8.2 | - |
II-122 | - | - | A | 10.8 | - |
II-123 | - | - | A | 11.4 | - |
II-126 | - | - | A | 10.2 | - |
II-128 | - | - | A | 10.9 | - |
II-130 | - | - | A | 7.4 | - |
II-133 | - | - | A | 9.5 | - |
II-134 | 306.1 | - | B | 3.5 | Y |
II-135 | 353.4 | 351.4 | A | 7.7 | - |
II-137 | 313.3 | 311.2 | A | 6.4 | Y |
II-141 | 380.4 | 378.3 | A | 6.7 | - |
II-143 | 280.1 | - | B | 3.3 | Y |
II-144 | 336.4 | - | B | 3.5 | - |
II-145 | 373.4 | - | B | 2.8 | - |
II-146 | - | - | A | 10.5 | - |
II-147 | 362.4 | - | B | 3.5 | - |
II-148 | 327.3 | 325.2 | A | 9.2 | Y |
II-149 | 332.4 | - | B | 3.5 | - |
II-150 | 322.4 | - | B | 3.2 | - |
II-151 | 316.2 | 314.2 | A | 10.3 | Y |
II-152 | - | - | A | 6.6 | - |
II-153 | 323.4 | - | B | 2.3 | - |
II-154 | 343.4 | - | B | 2.8 | - |
II-158 | 294.3 | - | B | 3.4 | - |
II-159 | 335.4 | - | B | 2.7 | - |
II-161 | 389.3 | 387.2 | A | 8.9 | - |
II-162 | 300.3 | 298.2 | A | 9.5 | Y |
II-163 | 366.5 | 364.4 | B | 6.0 | - |
II-164 | 297.3 | - | A | 5.1 | Y |
II-165 | 322.3 | 325.2 | A | 9.7 | Y |
II-167 | 316.2 | 314.2 | A | 10.0 | Y |
II-168 | 312.3 | 310.2 | A | 8.6 | Y |
II-169 | 281.1 | - | B | 3.9 | Y |
II-170 | 312.3 | 310.2 | A | 9.1 | Y |
II-171 | 300.3 | 298.2 | A | 9.4 | Y |
C化合物号 | M+1 | M-1 | HPLC方法 | Tret(分) | 1HNMR |
II-172 | 297.3 | 295.7 | A | 5.5 | Y |
II-174 | 449.3 | 447.2 | A | 12.5 | Y |
II-175 | 477.3 | 475.3 | A | 14.0 | Y |
II-176 | 374.4 | 372.4 | A | 6.3 | - |
II-178 | 362.4 | 360.0 | A | 6.6 | - |
II-179 | 374.4 | 372.4 | A | 6.3 | - |
II-180 | 404.4 | 402.4 | A | 6.4 | - |
II-181 | 380.2 | 378.3 | A | 6.7 | - |
II-182 | 355.4 | 353.4 | A | 7.7 | - |
II-183 | 367.4 | 365.4 | A | 7.4 | - |
II-184 | 355.4 | 353.4 | A | 7.9 | - |
II-185 | 367.4 | 365.3 | A | 7.5 | - |
II-186 | 397.4 | 395.4 | A | 7.1 | - |
II-187 | 373.4 | 371.4 | A | 8.0 | - |
II-188 | 373.4 | 371.4 | A | 7.9 | - |
II-189 | 382.4 | 380.4 | A | 6.9 | - |
II-190 | 394.4 | 392.4 | A | 6.7 | - |
II-191 | 382.4 | 380.4 | A | 7.0 | - |
II-192 | 394.5 | 392.4 | A | 6.7 | - |
II-193 | 424.4 | 422.4 | A | 6.4 | - |
II-194 | 400.4 | 398.4 | A | 7.3 | - |
II-195 | 400.4 | 398.4 | A | 7.1 | - |
II-196 | 400.4 | 398.4 | A | 7.2 | - |
II-197 | 341.3 | 339.2 | A | 7.5 | - |
II-198 | 353.4 | 351.4 | A | 7.1 | - |
II-199 | 341.3 | 339.2 | A | 7.6 | - |
II-200 | 383.4 | 381.4 | A | 6.9 | - |
II-201 | 359.4 | 357.4 | A | 8.0 | - |
II-202 | 359.4 | 357.4 | A | 7.8 | - |
II-203 | 359.4 | 357.4 | A | 7.7 | - |
II-204 | 354.4 | 352.4 | A | 6.2 | - |
II-205 | 366.4 | 364.4 | A | 5.9 | - |
II-206 | 354.4 | .52.4 | A | 5.6 | - |
II-207 | 396.4 | 394.4 | A | 5.9 | - |
II-208 | 372.4 | 370.4 | A | 6.7 | - |
II-209 | 372.4 | 370.4 | A | 6.5 | - |
II-210 | 372.4 | 370.4 | A | 6.4 | - |
II-237 | - | - | A | 9.8 | - |
化合物号 | M+1 | M-1 | HPLC方法 | Tret(分) | 1H NMR |
II-238 | - | - | A | 11.6 | - |
II-239 | - | - | A | 11.3 | - |
II-240 | - | - | A | 7.5 | - |
II-241 | - | - | A | 12.0 | - |
II-242 | - | - | A | 11.7 | - |
II-243 | - | - | A | 11.6 | - |
II-244 | 389.4 | 387.3 | A | 10.2 | - |
II-245 | - | - | A | 10.6 | - |
II-246 | 365.4 | 363.4 | A | 7.5 | - |
II-247 | - | - | A | 7.2 | - |
II-248 | - | - | A | 8.0 | - |
II-249 | - | - | A | 7.7 | - |
II-267 | - | - | A | 10.7 | - |
II-268 | - | - | A | 10.0 | - |
II-269 | - | - | A | 12.2 | - |
II-270 | - | - | A | 12.3 | - |
II-271 | - | - | A | 9.3 | - |
II-272 | - | - | A | 12.7 | - |
II-273 | - | - | A | 12.7 | - |
II-274 | - | - | A | 3.8 | - |
II-275 | - | - | A | 10.3 | - |
II-276 | - | - | A | 8.4 | - |
II-277 | - | - | A | 10.6 | - |
II-278 | - | - | A | 12.8 | - |
II-279 | - | - | A | 11.4 | - |
II-280 | - | - | A | 7.9 | - |
II-281 | - | - | A | 11.5 | - |
II-282 | - | - | A | 8.6 | - |
II-283 | - | - | A | 8.4 | - |
II-284 | - | - | A | 12.2 | - |
II-290 | - | - | A | 11.4 | - |
II-291 | - | - | A | 9.7 | - |
II-292 | - | - | A | 9.1 | - |
II-293 | 481.3 | 479.3 | A | 8.3 | - |
II-294 | 455.4 | 453.3 | A | 6.9 | - |
II-295 | - | - | A | 7.5 | - |
II-296 | - | - | A | 8.9 | - |
II-298 | 353.4 | - | B | 2.8 | - |
化合物号 | M+1 | M-1 | HPLC方法 | Tret(分) | 1H NMR |
II-299 | 421.3 | 423.2 | A | 10.1 | - |
实施例6
ERK抑制测定:
通过分光光度偶联酶测定法(Fox等(1998)《蛋白质科学》7,2249)测定化合物对ERK2的抑制。在该测定中,固定浓度的活化ERK2(10mM)与在DMSO(2.5%)中的不同浓度的化合物一起在30℃下在含有10mM MgCl2、2.5mM磷酸烯醇丙酮酸、200μM NADH、150μg/mL丙酮酸激酶、50μg/mL乳酸脱氢酶和200μM erktide肽的0.1M HPEPS缓冲液,pH7.5中培养10分钟。监测在340nm下的吸光度的下降率。从该数据作为抑制剂浓度的函数来评估IC50。
表4显示了在ERK2抑制测定中选定的本发明化合物的活性结果。化合物编号对应于表1中的化合物编号。具有指定为“A”的活性的化合物提供1微摩尔以下的Ki值;具有指定为“B”的活性的化合物提供1至5微摩尔之间的Ki值;具有指定为“C”的活性的化合物提供大于5微摩尔的Ki值。表4.选定化合物的ERK2抑制活性
序号 | 活性 | 序号 | 活性 | 序号 | 活性 |
II-1 | A | II-2 | C | II-3 | A |
II-4 | A | II-5 | A | II-6 | A |
II-7 | C | II-8 | C | II-9 | C |
序号 | 活性 | 序号 | 活性 | 序号 | 活性 |
II-10 | C | II-11 | C | II-12 | C |
II-13 | A | II-14 | C | II-16 | C |
II-17 | C | II-18 | A | II-19 | A |
II-20 | A | II-21 | C | II-22 | A |
II-23 | A | II-24 | A | II-25 | C |
II-26 | A | II-27 | A | II-28 | A |
II-29 | C | II-30 | A | II-31 | C |
II-39 | A | II-40 | A | II-41 | A |
II-42 | A | II-43 | A | II-44 | A |
II-45 | A | II-46 | A | II-47 | A |
II-48 | A | II-49 | A | II-50 | A |
II-51 | A | II-52 | A | II-53 | A |
II-54 | A | II-55 | A | II-56 | A |
II-57 | A | II-58 | A | II-59 | A |
II-60 | A | II-61 | A | II-62 | A |
II-63 | A | II-64 | A | II-65 | A |
II-66 | A | II-67 | A | II-68 | A |
II-69 | A | II-70 | A | II-71 | A |
II-72 | A | II-73 | A | II-74 | A |
II-75 | A | II-76 | A | II-77 | A |
II-78 | A | II-79 | A | II-80 | A |
II-81 | A | II-82 | A | II-83 | A |
II-84 | A | II-85 | A | II-86 | A |
II-87 | A | II-88 | A | II-89 | A |
II-90 | A | II-91 | A | II-92 | A |
II-93 | A | II-94 | A | II-95 | A |
II-96 | A | II-97 | A | II-98 | A |
II-99 | A | II-100 | A | II-101 | A |
II-102 | A | II-103 | A | II-104 | A |
II-105 | A | II-106 | A | II-107 | A |
II-108 | A | II-109 | A | II-110 | A |
II-111 | A | II-112 | A | II-113 | A |
II-114 | A | II-115 | A | II-116 | B |
序号 | 活性 | 序号 | 活性 | 序号 | 活性 |
II-117 | B | II-118 | B | II-119 | B |
II-120 | B | II-121 | B | II-122 | B |
II-123 | B | II-124 | B | II-125 | B |
II-126 | B | II-127 | B | II-128 | B |
II-129 | B | II-130 | B | II-131 | B |
II-132 | B | II-133 | B | II-134 | B |
II-135 | B | II-136 | B | II-137 | B |
II-138 | B | II-139 | B | II-140 | B |
II-141 | B | II-142 | B | II-143 | B |
II-144 | B | II-145 | B | II-146 | B |
II-147 | B | II-148 | B | II-149 | B |
II-150 | B | II-151 | B | II-152 | B |
II-153 | B | II-154 | B | II-155 | B |
II-156 | B | II-157 | B | II-158 | B |
II-159 | B | II-160 | B | II-161 | C |
II-162 | C | II-163 | C | II-164 | C |
II-165 | C | II-166 | C | II-167 | C |
II-168 | C | II-169 | C | II-170 | C |
II-171 | C | II-172 | C | II-285 | B |
II-286 | C | II-287 | C | II-288 | B |
II-289 | C | II-290 | B | II-291 | C |
II-292 | C | II-293 | C | II-294 | C |
II-295 | C | II-296 | C | II-297 | C |
II-298 | C | II-299 | C |
实施例7
ERK抑制细胞增殖测定:
利用细胞增殖测定法测定化合物对ERK2的抑制。在该测定中,完全培养基通过向RPMI 1640培养基(JRH Biosciences)中加入10%胎牛血清和青霉素/链霉素溶液来制备。将结肠癌细胞(HT-29细胞系)加入到96孔平板的84个孔中,种植密度为10,000细胞/孔/150μL。通过在37℃下培养2小时使细胞附着到平板上。用完全培养基制备测试化合物的溶液,通过系列稀释得到以下浓度:20μM、6.7μM、2.2μM、0.74μM、0.25μM和0.08μM。将测试化合物溶液(50μL)加入到含有细胞的72个孔中。向其余的12个含有细胞的孔中仅加入完全培养基(200μL)构成对照组,以测量最大增殖。向剩余的12个空白孔中加入完全培养基构成载体对照组,以测量背景底数。平板在37℃下培养3天。将3H-胸苷储备溶液(1mCi/mL,NewEngland Nuclear,Boston,MA)用RPMI培养基稀释到20μCi/mL,然后将20μL该溶液加入到各个孔中。平板在37℃下再培养8小时,然后收获并使用液体闪烁计数器分析3H-胸苷摄取。
在结肠细胞增殖测定中抑制ERK并具有小于10μM的IC50的选定的本发明化合物包括:II-43、II-48和II-45。
实施例8
JAK抑制测定:
化合物对JAK的抑制可以利用G.R.Brown等在《Bioorg.Med.Chem.Lett.》2000年,第10卷,575-579页中描述的方法用以下方式测定。向先前在4℃下用Poly(Glu,Ala,Tyr)6∶3∶1涂敷然后用磷酸缓冲盐水0.05%和吐温(PBST)洗涤的Maxisorb平板中加入2μM ATP、5mM MgCl2和化合物的DMSO溶液。反应用JAK酶开始,平板在30℃下培养60分钟。然后这些平板用PBST洗涤,加入100μLHRP缀合4G10抗体,该平板在30℃下培养90分钟。平板再次用PBST洗涤,加入100μL TMB溶液,然后这些平板在30℃下再培养30分钟。加入硫酸(100μL,1M)终止反应,平板在450nM下读数,得到光学密度用于分析确定IC50值。
实施例9
JNK抑制测定:
用以下方式使用分光光度偶联酶测定法就化合物抑制JNK的能力对化合物进行筛选。向含有0.1M HPEPS缓冲液(pH7.5)、10mMMgCl2、2.5mM磷酸烯醇丙酮酸、200μM NADH、150μg/mL丙酮酸激酶、50μg/mL乳酸脱氢酶和200μM EGF受体肽(具有序列KRELVEPLTPSGEAPNQALLR)的测定储备缓冲溶液中加入化合物的不同浓度的DMSO溶液和固定浓度(10nM)的活化JNK。所得混合物在30℃下培养10分钟,然后通过加入10μM ATP引发反应。在30℃下在340nM下的吸光度的下降作为时间的函数加以监测,使所得数据与竞争性抑制动力学模型相配合来确定Ki。
表5显示了在JNK抑制测定中选定的本发明化合物的活性结果。化合物编号对应于表1中的化合物编号。具有指定为“A”的活性的化合物提供1微摩尔以下的Ki值;具有指定为“B”的活性的化合物提供1至5微摩尔之间的Ki值;具有指定为“C”的活性的化合物提供大于5微摩尔的Ki值。
表5.选定化合物的JNK抑制活性
序号 | 活性 | 序号 | 活性 |
II-39 | B | II-48 | A |
II-40 | A | II-51 | B |
II-43 | A | II-55 | A |
II-46 | A | II-104 | B |
II-47 | B | II-112 | C |
实施例10
Aurora抑制测定:
用以下方式使用标准偶联酶测定法就化合物抑制Aurora的能力对化合物进行筛选。向含有0.1M HPEPS,pH7.5、10mM MgCl2、25mMNaCl、2.5mM磷酸烯醇丙酮酸、300μM NADH、30μg/mL丙酮酸激酶、10μg/mL乳酸脱氢酶、40μM ATP和800μM肽(LRRASLG,AmericanPeptide,Sunnyvale,CA)的测定储备缓冲溶液中加入30μM化合物的DMSO溶液,所得混合物在30℃下培养10分钟。通过加入10μL70nM Aurora和1mM DTT引发反应。在30℃下使用BioRad Ultramark平板读数器(Hercules,CA)在5分钟读数时间里监测340nM下的吸光度而得到反应率。从该数据作为抑制浓度的函数来确定IC50。
表6显示了在Aurora2抑制测定中选定的本发明化合物的活性结果。化合物编号对应于表1中的化合物编号。具有指定为“A”的活性的化合物提供5微摩尔以下的IC50值;具有指定为“B”的活性的化合物提供5至10微摩尔之间的IC50值;具有指定为“C”的活性的化合物提供大于10微摩尔的IC50值。
表6.选定化合物的Aurora2抑制活性
序号 | 活性 | 序号 | 活性 | 序号 | 活性 |
II-48 | A | II-89 | A | II-211 | B |
II-51 | B | II-93 | A | II-212 | B |
II-54 | B | II-98 | B | II-213 | B |
II-57 | A | II-99 | A | II-214 | B |
II-61 | A | II-101 | A | II-215 | B |
II-64 | A | II-103 | B | II-216 | B |
II-66 | B | II-106 | B | II-218 | B |
II-70 | B | II-108 | B | II-228 | A |
II-72 | B | II-112 | A | II-252 | B |
II-76 | A | II-113 | A | II-254 | A |
II-77 | A | II-114 | A | II-255 | B |
II-80 | C | II-115 | A | II-258 | C |
II-81 | A | II-141 | A | II-259 | B |
II-82 | A | II-142 | A | II-260 | C |
II-85 | B | II-181 | B | II-262 | B |
II-88 | B | II-188 | C | II-266 | B |
实施例11
GSK-3抑制测定:
用以下方式使用标准偶联酶测定法(Fox等(1998)《蛋白质科学》7,2249)就化合物抑制糖原合成酶激酶3(GSK-3)的能力对化合物进行筛选。向含有0.1M HPEPS,pH7.5、10mM MgCl2、25mM NaCl、2.5mM磷酸烯醇丙酮酸、300μM NADH、1mM DTT、30μg/mL丙酮酸激酶、10μg/mL乳酸脱氢酶、300μM肽(HSSPHQp-SEDEEE,AmericanPeptide,Sunnyvale,CA)和60nM GSK-3的测定储备缓冲溶液中加入30μM化合物的DMSO溶液,所得混合物在30℃下培养5分钟。通过加入10μL ATP引发反应。在30℃下使用Molecular Devices平板读数器(Sunnyvale,CA)在5分钟读数时间里监测340nM下的吸光度而得到反应率。从该数据作为抑制浓度的函数来确定IC50。
表7显示了在GSK-3抑制测定中选定的本发明化合物的活性结果。化合物编号对应于表1中的化合物编号。具有指定为“A”的活性的化合物提供10微摩尔以下的IC50值;具有指定为“B”的活性的化合物提供10至20微摩尔之间的IC50值;具有指定为“C”的活性的化合物提供大于20微摩尔的IC50值。
表7.选定化合物的GSK-3抑制活性
序号 | 活性 | 序号 | 活性 | 序号 | 活性 |
II-89 | C | II-115 | C | II-263 | A |
II-93 | C | II-127 | B | II-271 | A |
II-94 | C | II-199 | C | II-278 | A |
II-99 | A | II-214 | C | - | - |
II-108 | B | II-227 | B | - | - |
实施例12KDR抑制测定:使用标准偶联酶测定法(Fox等,《蛋白质科学》,(1998)7,2249)就化合物抑制KDR的能力对化合物进行筛选。测定在200mMHPEPS,pH7.5、10mM MgCl2、25mM NaCl、1mM DTT和1.5%DMSO的混合物中进行。测定中的终底物浓度为300μM ATP(SigmaChemicals)和10μM聚E4Y(Sigma)。测定在37℃和30nM KDR下进行。偶联酶***各成分的终浓度为2.5mM磷酸烯醇丙酮酸、200μM NADH、30μg/mL丙酮酸激酶和10μg/mL乳酸脱氢酶。
制备含有上列所有试剂但不含ATP和测试化合物的测定储备缓冲溶液。将177μL该储备溶液置于96孔平板中,接着加入3μl含有测试化合物(化合物终浓度为30μM)的2mM DMSO储备液。平板在37℃下预培养约10分钟,反应通过加入20μl ATP(终浓度300μM)引发。使用Molecular Devices平板读数器(Sunnyvale,CA)在5分钟读数时间里在37℃下得到反应率。对与含有测定混合物和DMSO但不含测试化合物的标准孔相比显示大于50%抑制的化合物进行滴定,以确定IC50值。
在上述测定中在2μM浓度下抑制KDR并具有大于40%的抑制百分数的选定的本发明化合物包括:II-43、II-48、II-304和II-305。
实施例13
AKT抑制测定:
使用标准偶联酶测定法(Fox等,《蛋白质科学》,(1998)7,2249)就化合物抑制AKT的能力对化合物进行筛选。测定在100mMHPEPS,pH7.5、10mM MgCl2、25mM NaCl、1mM DTT和1.5%DMSO的混合物中进行。测定中的终底物浓度为170μM ATP(SigmaChemicals)和200μM肽(RPRAATF,American Peptide,Sunnyvale,CA)。测定在37℃和45nM AKT下进行。偶联酶***各成分的终浓度为2.5mM磷酸烯醇丙酮酸、300μM NADH、30μg/mL丙酮酸激酶和10μg/mL乳酸脱氢酶。
制备含有上列所有试剂但不含AKT、DTT和测试化合物的测定储备缓冲溶液。将56μL该储备溶液置于384孔平板中,接着加入1μl含有测试化合物(化合物终浓度为30μM)的2mM DMSO储备液。平板在30℃下预培养约10分钟,反应通过加入10μl酶(终浓度45nM)和1mM DTT引发。使用BioRad Ultramark平板读数器(Hercules,CA)在5分钟读数时间里在30℃下得到反应率。对与含有测定混合物和DMSO但不含测试化合物的标准孔相比显示大于50%抑制的化合物进行滴定,以确定IC50值。
抑制AKT的选定的本发明化合物包括:II-89、II-94和II-305。
虽然我们已描述了本发明的许多实施方案,但很明显,我们的基本实施例可以加以改变得到使用本发明化合物和方法的其他实施方案。因此,应当领会本发明的范围将由所附的权利要求书而不是已利用实施例进行表述的具体实施方案确定。
Claims (24)
R1选自R、卤素、N(R8)2、OR、NRCOR、NRCON(R8)2、CON(R8)2、SO2R、NRSO2R或SO2N(R8)2;
T选自价键或连接基;
R各自独立地选自氢或具有1至6个碳的可选取代的脂族基;
R2选自氢、CN、卤素、芳基、芳烷基、杂芳基、杂环基、具有1至6个碳的可选取代的无环脂族链基、或具有4至10个碳的可选取代的环脂族基;
R3选自R、OH、OR、N(R8)2、卤素或CN;
Q是价键、J、或可选取代的C1-6亚烷基链,其中该亚烷基链的最多两个非相邻碳各自可选地并独立地被J取代;
J选自-C(=O)-、-CO2-、-C(O)C(O)-、-NRCONR8-、-N(R)N(R8)-、-C(=O)NR8-、-NRC(=O)-、-O-、-S-、-SO-、-SO2-、-N(R)O-、-ON(R8)-、-OC(=O)N(R8)-、-N(R)COO-、-SO2N(R8)-、-N(R)SO2-或-N(R8)-;
R4选自-R8、-R5、-NH2、-NHR5、-N(R5)2或-NR5(CH2)yN(R5)2;
R5各自独立地选自R6、R7、-(CH2)yCH(R6)(R7)、-(CH2)yR6、-(CH2)yCH(R6)2、-(CH2)yCH(R7)2或-(CH2)yR7;
y是0-6;
R6各自是可选取代的基团,独立地选自脂族基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳基烷基、杂芳基烷氧基、杂环基、杂环基烷基或杂环基烷氧基;
R7各自独立地选自可选取代的脂族基、羟基烷基、烷氧基烷基、芳氧基烷基或烷氧基羰基;
R8各自独立地选自R,或者同一氮上的两个R8与氮一起可选地构成具有1至3个杂原子的4至8元饱和或不饱和杂环;
并且各个可取代的环氮可选地被R、NR2、COR、CO2(C1-C6可选取代的烷基)、SO2(C1-C6可选取代的烷基)、CONR2和SO2NR2取代;条件是当R1和R3各自为氢和当TR2是附着在吡唑环4位上的未取代苯环时QR4不是CON(CH3)2。
3、具有一项或多项以下特征的按照权利要求2的化合物:(a)Q是-CO-、-CO2-或-CONH-;(b)T是价键;(c)R1是氢或NHR;(d)R2是可选取代的芳环;(c)R3是氢;(e)R4选自R5、-NHR5、-N(R5)2、-NR5R6、-NHCHR5R6、或-NHCH2R5;或(f)R5是可选取代的基团,选自芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环基烷基、(CH2)yR6、(CH2)yR7、或(CH2)yCH(R6)(R7)。
5、具有以下特征的按照权利要求4的化合物:(a)T是价键;(b)R2是可选取代的芳环;(c)R4选自R5、-NHR5、-N(R5)2、-NR5R6、-NHCHR5R6、或-NHCH2R5;和(d)R5是可选取代的基团,选自芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环基烷基、(CH2)yR6、(CH2)yR7、或(CH2)yCH(R6)(R7)。
6、按照权利要求1的化合物,其中所述化合物选自表1中列出的那些,所述化合物不是编号1化合物。
8、按照权利要求7的化合物,其中所述化合物具有一项或多项以下特征:(a)T是价键;(b)R2是可选取代的芳环;(c)R4选自R5、-NHR5、-N(R5)2、-NR5R5、-NHCHR5R6、或-NHCH2R5;或(d)R5是可选取代的基团,选自芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环基烷基、(CH2)yR6、(CH2)yR7、或(CH2)yCH(R6)(R7)。
9、按照权利要求1的化合物,其中所述化合物选自表2中列出的那些。
10、包含足以可检测地抑制蛋白激酶活性量的权利要求1-9任一项所述的化合物和药学上可接受的载体的组合物,所述蛋白激酶选自ERK、JAK、JNK、Aurora、GSK、KDR、AKT或与此相关的蛋白激酶中的一个或多个。
11、按照权利要求10的组合物,其中所述化合物以药学上可接受的方式配制成用于对病人给药。
12、按照权利要求11的组合物,它进一步包含或者作为与所述化合物一起的多剂形式的一部分或者作为分离的剂型的治疗剂。
13、抑制生物学样品中蛋白激酶活性的方法,其中所述蛋白激酶选自ERK、JAK、JNK、Aurora、GSK、KDR、AKT或与此相关的蛋白激酶,该方法包括使所述样品与按照权利要求1-9任一项的化合物接触的步骤。
14、治疗病人的蛋白激酶介导的疾病状态的方法,其中所述蛋白激酶选自ERK、JAK、JNK、Aurora、KDR、AKT或与此相关的蛋白激酶中的一个或多个,该方法包括对所述病人给药按照权利要求11的组合物的步骤。
15、按照权利要求14的方法,还包括另外的对所述病人给药或者作为与所述化合物一起的多剂形式的一部分或者作为分离的剂型的治疗剂的步骤。
16、治疗病人的疾病状态的方法,其中所述疾病状态选自癌、中风、糖尿病、肝肿大、心血管疾病、早老性痴呆、囊纤维变性、病毒疾病、自身免疫疾病、动脉粥样硬化、再狭窄、牛皮癣、变应性疾病、炎症、神经病学疾病、与激素相关的疾病、与器官移植有关的疾病、免疫缺陷疾病、破坏性骨疾病、增殖性疾病、传染病、涉及细胞死亡的疾病、凝血酶诱导的血小板聚集、慢性骨髓性白血病(CML)、肝脏疾病、牵涉T细胞活化的病理性免疫疾病或CNS疾病,该方法包括对所述病人给药按照权利要求10的组合物的步骤。
17、按照权利要求16的方法,其中疾病状态是癌。
18、按照权利要求17的方法,其中疾病状态是选自下列种类的癌:乳癌、卵巢癌、***、***癌、睾丸癌、生殖泌尿道癌、食道癌、喉癌、成胶质细胞瘤、成神经细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡癌、未分化癌、***状癌、***瘤、黑素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、骨髓疾病、淋巴样疾病、何杰金氏病、毛细胞、口腔前庭和咽(口腔)癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑癌和中枢神经***癌,或白血病。
19、按照权利要求17或18的方法,还包括另外的对所述病人给药或者作为与所述化合物一起的多剂形式的一部分或者作为分离的剂型的化学治疗剂的步骤。
20、按照权利要求16的方法,其中疾病状态是心血管疾病。
21、按照权利要求20的方法,其中疾病状态是选自再狭窄、心肥大、动脉粥样硬化、心肌梗死或充血性心力衰竭的心血管疾病。
22、按照权利要求20或21的方法,还包括另外的对所述病人给药或者作为与所述化合物一起的多剂形式的一部分或者作为分离的剂型的用于治疗心血管疾病的治疗剂的步骤。
23、一种用于涂敷可植入装置的组合物,它包含按照权利要求1的化合物和适于涂敷所述可植入装置的载体。
24、一种用按照权利要求23的组合物包衣的可植入装置。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18050600P | 2000-02-05 | 2000-02-05 | |
US60/180,506 | 2000-02-05 | ||
US19195600P | 2000-03-24 | 2000-03-24 | |
US60/191,956 | 2000-03-24 | ||
US24293500P | 2000-10-24 | 2000-10-24 | |
US60/242,935 | 2000-10-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1362953A true CN1362953A (zh) | 2002-08-07 |
Family
ID=27391289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN01800374A Pending CN1362953A (zh) | 2000-02-05 | 2001-02-05 | 用作erk抑制剂的吡唑组合物 |
Country Status (19)
Country | Link |
---|---|
US (4) | US6528509B1 (zh) |
EP (1) | EP1200422A2 (zh) |
JP (1) | JP4783532B2 (zh) |
KR (1) | KR20010111298A (zh) |
CN (1) | CN1362953A (zh) |
AU (1) | AU782775B2 (zh) |
BG (1) | BG106054A (zh) |
BR (1) | BR0104424A (zh) |
CA (1) | CA2369504C (zh) |
CZ (1) | CZ20013540A3 (zh) |
HK (1) | HK1046276A1 (zh) |
HU (1) | HUP0202332A2 (zh) |
IL (1) | IL145757A (zh) |
LT (1) | LT4981B (zh) |
NO (1) | NO322745B1 (zh) |
NZ (1) | NZ514583A (zh) |
SK (1) | SK14082001A3 (zh) |
TR (1) | TR200103787T1 (zh) |
WO (1) | WO2001057022A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101370784B (zh) * | 2005-12-13 | 2012-10-10 | 先灵公司 | 用作胞外信号调节激酶抑制剂的化合物 |
Families Citing this family (117)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6207665B1 (en) * | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
BR0104424A (pt) * | 2000-02-05 | 2002-01-08 | Vertex Pharma | Composições de pirazol úteis como inibidores de erk |
US6436915B1 (en) | 2000-04-07 | 2002-08-20 | Kinetek Pharmaceuticals, Inc. | Pyrazole compounds |
WO2002014271A1 (fr) * | 2000-08-10 | 2002-02-21 | Mitsubishi Pharma Corporation | Dérivés de proline et leur utilisation comme médicaments |
DE60122176T2 (de) | 2000-09-15 | 2007-07-05 | Vertex Pharmaceuticals Inc., Cambridge | Isoxazole und ihre verwendung als erk-inhibitoren |
US7473691B2 (en) * | 2000-09-15 | 2009-01-06 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
WO2002022605A1 (en) * | 2000-09-15 | 2002-03-21 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US6660731B2 (en) * | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US7109199B2 (en) | 2000-09-22 | 2006-09-19 | Smithkline Beecham Corporation | Pyrazolopyridines and pyrazolopyridazines as antidiabetics |
US6989385B2 (en) * | 2000-12-21 | 2006-01-24 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
EP1364949A4 (en) | 2001-02-02 | 2005-11-23 | Takeda Pharmaceutical | INHIBITOR OF JNK |
JP4342939B2 (ja) | 2001-08-03 | 2009-10-14 | バーテックス ファーマシューティカルズ インコーポレイテッド | ピラゾール誘導キナーゼインヒビターおよびその使用 |
MXPA04001087A (es) * | 2001-08-03 | 2004-07-08 | Vertex Pharma | Derivados de pirazol como inhibidores de cinasa y uso de los mismos. |
MXPA04005204A (es) | 2001-11-30 | 2005-11-04 | Quadra Logic Tech Inc | Derivados de hidrazonipirazol y su uso como terpapeuticos. |
AU2003235798A1 (en) * | 2002-01-10 | 2003-07-24 | F. Hoffmann-La Roche Ag | Use of a gsk-3beta inhibitor in the manufacture of a medicament for increasing bone formation |
TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
RU2004126671A (ru) * | 2002-02-06 | 2005-04-10 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Гетероарилсоединения, полезные в качестве ингибиторов gsk-3 |
US20040009981A1 (en) * | 2002-03-15 | 2004-01-15 | David Bebbington | Compositions useful as inhibitors of protein kinases |
EP1506189A1 (en) | 2002-04-26 | 2005-02-16 | Vertex Pharmaceuticals Incorporated | Pyrrole derivatives as inhibitors of erk2 and uses thereof |
MY141867A (en) * | 2002-06-20 | 2010-07-16 | Vertex Pharma | Substituted pyrimidines useful as protein kinase inhibitors |
DE60313339T2 (de) * | 2002-07-31 | 2008-01-03 | Critical Outcome Technologies, Inc. | Protein tyrosin kinase inhibitoren |
EA200500299A1 (ru) | 2002-08-02 | 2005-08-25 | Вертекс Фармасьютикалз Инкорпорейтед | Пиразольные композиции, используемые в качестве ингибиторов gsk-3 |
EP1388541A1 (en) * | 2002-08-09 | 2004-02-11 | Centre National De La Recherche Scientifique (Cnrs) | Pyrrolopyrazines as kinase inhibitors |
AU2003273675A1 (en) * | 2002-10-09 | 2004-05-04 | Wayne R. Danter | Protein tyrosine kinase inhibitors |
CA2502685A1 (en) * | 2002-10-23 | 2004-05-06 | Exelixis, Inc. | Cdkl1 as modifier of branching morphogenesis and methods of use |
MXPA05006569A (es) * | 2002-12-20 | 2005-09-22 | Pharmacia Corp | Compuestos que inhiben la proteina cinasa-2 activada por la proteina cinasa activada por el mitogeno. |
US20050019366A1 (en) * | 2002-12-31 | 2005-01-27 | Zeldis Jerome B. | Drug-coated stents and methods of use therefor |
WO2004072029A2 (en) * | 2003-02-06 | 2004-08-26 | Vertex Pharmaceuticals Incorporated | Pyrazolopyridazines useful as inhibitors of protein kinases |
US20060172019A1 (en) * | 2003-03-07 | 2006-08-03 | Ralston Stuart H | Cannabinoid receptor inverse agonists and neutral antagonists as therapeutic agents for the treatment of bone disorders |
TWI372050B (en) | 2003-07-03 | 2012-09-11 | Astex Therapeutics Ltd | (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles |
AU2004261459B2 (en) | 2003-07-22 | 2008-06-26 | Astex Therapeutics Limited | 3, 4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) modulators |
DK1656372T3 (da) | 2003-07-30 | 2013-07-01 | Rigel Pharmaceuticals Inc | 2,4-pyrimidindiaminforbindelser til anvendelse til behandling eller forebyggelse af autoimmunsygdomme |
DE602004012578T2 (de) * | 2003-08-15 | 2008-12-11 | Vertex Pharmaceuticals Inc., Cambridge | Als inhibitoren von c-met geeignete pyrrolzusammensetzungen |
DE10354060A1 (de) * | 2003-11-19 | 2005-06-02 | Merck Patent Gmbh | Pyrrolderivate |
CN1902193B (zh) * | 2003-12-04 | 2011-07-13 | 沃泰克斯药物股份有限公司 | 可用作蛋白激酶抑制剂的喹喔啉 |
EP1694686A1 (en) * | 2003-12-19 | 2006-08-30 | Takeda San Diego, Inc. | Kinase inhibitors |
US7488817B2 (en) * | 2004-02-02 | 2009-02-10 | The Trustees Of The University Of Pennsylvania | Metal complex protein kinase inhibitors |
WO2005100342A1 (en) * | 2004-03-26 | 2005-10-27 | Vertex Pharmaceuticals, Incorporated | Pyridine inhibitors of erk2 and uses thereof |
WO2005105788A1 (en) * | 2004-04-23 | 2005-11-10 | Takeda San Diego, Inc. | Indole derivatives and use thereof as kinase inhibitors |
US7550598B2 (en) * | 2004-08-18 | 2009-06-23 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
JP2008516973A (ja) | 2004-10-15 | 2008-05-22 | タケダ サン ディエゴ インコーポレイテッド | キナーゼ阻害剤 |
FR2876582B1 (fr) * | 2004-10-15 | 2007-01-05 | Centre Nat Rech Scient Cnrse | Utilisation de derives de pyrrolo-pyrazines pour la fabrication de medicaments pour le traitement de la mucoviscidose et de maladies liees a un defaut d'adressage des proteines dans les cellules |
MX2007006103A (es) * | 2004-11-22 | 2007-07-20 | Vertex Pharma | Pirrolopirazinas y pirazolopirazinas de utilidad como inhibidores de proteinquinasas. |
AU2005321091B2 (en) * | 2004-12-30 | 2012-04-12 | Astex Therapeutics Limited | Pyrazole compounds that modulate the activity of CDK, GSK and Aurora kinases |
WO2006070202A1 (en) * | 2004-12-30 | 2006-07-06 | Astex Therapeutics Limited | Pyrazole derivatives having kinase modulating activity |
WO2006070198A1 (en) * | 2004-12-30 | 2006-07-06 | Astex Therapeutics Limited | Pyrazole derivatives as that modulate the activity of cdk, gsk and aurora kinases |
US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
TW200639163A (en) | 2005-02-04 | 2006-11-16 | Genentech Inc | RAF inhibitor compounds and methods |
JP5225079B2 (ja) | 2005-06-08 | 2013-07-03 | ライジェル ファーマシューティカルズ, インコーポレイテッド | Jak経路の阻害のための組成物および方法 |
US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
JP2007000061A (ja) * | 2005-06-23 | 2007-01-11 | Sumitomo Chemical Co Ltd | 昆虫由来のc−Junアミノ末端リン酸化酵素活性に関わる有害生物の生理状態に変化を与える薬剤 |
WO2007022384A2 (en) * | 2005-08-18 | 2007-02-22 | Vertex Pharmaceuticals Incorporated | Pyrazine kinase inhibitors |
US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
NZ594383A (en) * | 2005-11-03 | 2013-05-31 | Vertex Pharma | Aminopyrimidines useful as kinase inhibitors |
US8546404B2 (en) | 2005-12-13 | 2013-10-01 | Merck Sharp & Dohme | Compounds that are ERK inhibitors |
EP1968579A1 (en) | 2005-12-30 | 2008-09-17 | Astex Therapeutics Limited | Pharmaceutical compounds |
KR20080103996A (ko) | 2006-02-16 | 2008-11-28 | 쉐링 코포레이션 | Erk 억제제로서 피롤리딘 유도체 |
EP1991532B1 (en) | 2006-02-24 | 2017-01-11 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
TW200800203A (en) | 2006-03-08 | 2008-01-01 | Astrazeneca Ab | New use |
EP2049119A2 (en) | 2006-06-29 | 2009-04-22 | Astex Therapeutics Limited | Pharmaceutical combinations of 1-cyclopropyl-3-[3-(5-morphoolin-4-ylmethyl-1h-benzoimidazol-2-yl)-1h-1-pyrazol-4-yl]-urea |
EP2223925A1 (en) * | 2006-10-09 | 2010-09-01 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US20100120717A1 (en) | 2006-10-09 | 2010-05-13 | Brown Jason W | Kinase inhibitors |
NZ576750A (en) * | 2006-11-02 | 2012-01-12 | Vertex Pharma | Aminopyridines and aminopyrimidines useful as inhibitors of protein kinases |
EP2099787B1 (en) * | 2006-12-19 | 2010-07-21 | Vertex Pharmaceuticals, Inc. | Aminopyrimidines useful as inhibitors of protein kinases |
MX2009006864A (es) * | 2006-12-20 | 2009-08-28 | Schering Corp | Inhibidores novedosos de c jun-n-terminal cinasas. |
US8138191B2 (en) | 2007-01-11 | 2012-03-20 | Critical Outcome Technologies Inc. | Inhibitor compounds and cancer treatment methods |
JP5571387B2 (ja) | 2007-01-11 | 2014-08-13 | クリティカル・アウトカム・テクノロジーズ・インコーポレイテッド | 癌の治療のための化合物および方法 |
US8420690B2 (en) * | 2007-02-07 | 2013-04-16 | Glaxosmithkline Llc | Inhibitors of Akt activity |
UY30892A1 (es) * | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | Inhibidores de la actividad akt |
GB0702862D0 (en) * | 2007-02-14 | 2007-03-28 | Univ Aberdeen | Therapeutic compounds |
RU2009137390A (ru) * | 2007-03-09 | 2011-04-20 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Аминопиримидины, пригодные в качестве ингибиторов протеинкиназ |
CN101663295B (zh) * | 2007-03-09 | 2014-11-05 | 沃泰克斯药物股份有限公司 | 可用作蛋白激酶抑制剂的氨基嘧啶类化合物 |
NZ579483A (en) | 2007-03-09 | 2012-07-27 | Vertex Pharma | Aminopyridines useful as inhibitors of protein kinases |
WO2008124085A2 (en) * | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
MX2009011059A (es) | 2007-04-13 | 2009-11-26 | Vertex Pharma | Aminopirimidinas utiles como inhibidores de cinasas. |
MX2009011811A (es) * | 2007-05-02 | 2010-01-14 | Vertex Pharma | Aminopirimidinas utiles como inhibidores de cinasa. |
JP5389785B2 (ja) * | 2007-05-02 | 2014-01-15 | バーテックス ファーマシューティカルズ インコーポレイテッド | キナーゼ阻害剤として有用なチアゾールおよびピラゾール |
AU2008247594A1 (en) * | 2007-05-02 | 2008-11-13 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
JP2010528021A (ja) * | 2007-05-24 | 2010-08-19 | バーテックス ファーマシューティカルズ インコーポレイテッド | キナーゼのインヒビターとして有用なチアゾールおよびピラゾール |
CN101772501A (zh) * | 2007-06-18 | 2010-07-07 | 先灵公司 | 杂环化合物及其作为erk抑制剂的用途 |
NZ582879A (en) * | 2007-07-31 | 2012-03-30 | Vertex Pharma | Process for preparing 5-fluoro-1h-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof |
US8466151B2 (en) * | 2007-12-26 | 2013-06-18 | Critical Outcome Technologies, Inc. | Compounds and method for treatment of cancer |
EP2265607B1 (en) | 2008-02-15 | 2016-12-14 | Rigel Pharmaceuticals, Inc. | Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases |
MY152271A (en) | 2008-02-21 | 2014-09-15 | Merck Sharp & Dohme | Novel compounds that are erk inhibitors |
US8138339B2 (en) | 2008-04-16 | 2012-03-20 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
PT2323993E (pt) | 2008-04-16 | 2015-10-12 | Portola Pharm Inc | 2,6-diamino-pirimidina-5-il-carboxamidas como inibidores de quinasses syk ou jak |
WO2009131687A2 (en) | 2008-04-22 | 2009-10-29 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
US8106039B2 (en) * | 2008-04-30 | 2012-01-31 | The Trustees Of The University Of Pennsylvania | Metal complex phosphatidyl-inositol-3-kinase inhibitors |
EP2306825A4 (en) * | 2008-06-26 | 2011-12-28 | Glaxosmithkline Llc | HAMMER OF ACT ACTIVITY |
EP2303852A4 (en) * | 2008-06-26 | 2011-12-28 | Glaxosmithkline Llc | ACTIVITY INHIBITORS AKT |
EP2303277A4 (en) * | 2008-06-26 | 2011-08-17 | Glaxosmithkline Llc | HAMMER OF ACT ACTIVITY |
KR20110050549A (ko) * | 2008-09-03 | 2011-05-13 | 버텍스 파마슈티칼스 인코포레이티드 | 공-결정 및 이를 포함하는 제약 제제 |
EP2459195A1 (en) * | 2009-07-28 | 2012-06-06 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
MX2012008328A (es) | 2010-01-19 | 2012-08-08 | Astrazeneca Ab | Derivados de pirazina. |
CA2999435A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
US9102625B2 (en) | 2010-11-01 | 2015-08-11 | Portola Pharmaceuticals, Inc. | Nicotinamides as JAK kinase modulators |
MX363551B (es) | 2011-11-23 | 2019-03-27 | Portola Pharmaceuticals Inc Star | Compuestos derivados de pirazina como inhibidores de cinasa. |
WO2013109142A1 (en) | 2012-01-16 | 2013-07-25 | Stichting Het Nederlands Kanker Instituut | Combined pdk and mapk/erk pathway inhibition in neoplasia |
WO2013169858A1 (en) | 2012-05-08 | 2013-11-14 | The Broad Institute, Inc. | Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy |
WO2014058921A2 (en) | 2012-10-08 | 2014-04-17 | Portola Pharmaceuticals, Inc. | Substituted pyrimidinyl kinase inhibitors |
WO2015041534A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | P90rsk in combination with raf/erk/mek |
WO2015041533A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | Rock in combination with mapk-pathway |
US20170027940A1 (en) | 2014-04-10 | 2017-02-02 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
WO2015178770A1 (en) | 2014-05-19 | 2015-11-26 | Stichting Het Nederlands Kanker Instituut | Compositions for cancer treatment |
KR101600579B1 (ko) * | 2014-06-25 | 2016-03-07 | 한국생명공학연구원 | 피라졸 아마이드 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 |
WO2016123574A1 (en) | 2015-01-30 | 2016-08-04 | Biomed Valley Discoveries, Inc. | Crystalline forms of c21h22ci2n4o2 |
EP3355923B1 (en) | 2015-10-01 | 2022-02-23 | Stichting Het Nederlands Kanker Instituut- Antoni van Leeuwenhoek Ziekenhuis | Histone deacetylase inhibitors for use in the treatment of drug resistant melanoma |
AU2016368257C1 (en) * | 2015-12-07 | 2019-12-05 | Suzhou Sinovent Pharmaceuticals Co., Ltd. | Five-membered heterocyclic amides wnt pathway inhibitor |
WO2017099591A1 (en) | 2015-12-07 | 2017-06-15 | Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis | Treatment of inhibitor resistant braf-mutant cancers |
WO2017204626A1 (en) | 2016-05-24 | 2017-11-30 | Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis | Combination therapy - combined map2k4/map3k1 and mek/erk inhibition |
SG11202012241RA (en) * | 2018-06-08 | 2021-01-28 | Betta Pharmaceuticals Co Ltd | Erk inhibitor and use thereof |
US11739078B2 (en) * | 2019-02-22 | 2023-08-29 | Insilico Medicine Ip Limited | Methods of inhibiting kinases |
US20220213119A1 (en) | 2019-03-28 | 2022-07-07 | Jiangsu Hengrui Medicine Ca, Lid. | Thienoheterocyclic derivative, preparation method therefor and medical use thereof |
BR112021018924A2 (pt) | 2019-03-29 | 2022-02-01 | Jiangsu Hengrui Medicine Co | Derivado de heterocíclico pirrol, método de preparação do mesmo e aplicação do mesmo em medicamento |
TW202110848A (zh) | 2019-05-24 | 2021-03-16 | 大陸商江蘇恆瑞醫藥股份有限公司 | 取代的稠合雙環類衍生物、其製備方法及其在醫藥上的應用 |
EP4223758A4 (en) | 2020-09-29 | 2024-04-03 | Jiangsu Hengrui Pharmaceuticals Co Ltd | CRYSTALLINE FORM OF A PYRROLO-HETEROCYCLIC DERIVATIVE AND PREPARATION METHOD THEREFOR |
WO2022179528A1 (en) | 2021-02-24 | 2022-09-01 | Insilico Medicine Ip Limited | Analogs for the treatment of disease |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2707295A1 (fr) * | 1993-06-07 | 1995-01-13 | Rhone Poulenc Agrochimie | Fongicides pyrazoles substitués en position 3 par un hétérocycle. |
JP3734180B2 (ja) * | 1994-12-28 | 2006-01-11 | エーザイ株式会社 | 新規ピラゾール誘導体 |
GB9608435D0 (en) * | 1996-04-24 | 1996-06-26 | Celltech Therapeutics Ltd | Chemical compounds |
IL132736A0 (en) * | 1997-05-22 | 2001-03-19 | Searle & Co | 3(5)-Heteroaryl substituted pyrazoles as p38 kinase inhibitors |
US6514977B1 (en) * | 1997-05-22 | 2003-02-04 | G.D. Searle & Company | Substituted pyrazoles as p38 kinase inhibitors |
US6087381A (en) * | 1997-05-22 | 2000-07-11 | G. D. Searle & Company | Pyrazole derivatives as p38 kinase inhibitors |
BR0104424A (pt) * | 2000-02-05 | 2002-01-08 | Vertex Pharma | Composições de pirazol úteis como inibidores de erk |
-
2001
- 2001-02-05 BR BR0104424-9A patent/BR0104424A/pt not_active IP Right Cessation
- 2001-02-05 KR KR1020017012710A patent/KR20010111298A/ko not_active Application Discontinuation
- 2001-02-05 HU HU0202332A patent/HUP0202332A2/hu unknown
- 2001-02-05 CN CN01800374A patent/CN1362953A/zh active Pending
- 2001-02-05 TR TR2001/03787T patent/TR200103787T1/xx unknown
- 2001-02-05 CA CA002369504A patent/CA2369504C/en not_active Expired - Fee Related
- 2001-02-05 SK SK1408-2001A patent/SK14082001A3/sk unknown
- 2001-02-05 IL IL145757A patent/IL145757A/en not_active IP Right Cessation
- 2001-02-05 CZ CZ20013540A patent/CZ20013540A3/cs unknown
- 2001-02-05 NZ NZ514583A patent/NZ514583A/en unknown
- 2001-02-05 WO PCT/US2001/003911 patent/WO2001057022A2/en active IP Right Grant
- 2001-02-05 AU AU36723/01A patent/AU782775B2/en not_active Ceased
- 2001-02-05 JP JP2001557854A patent/JP4783532B2/ja not_active Expired - Fee Related
- 2001-02-05 EP EP01908911A patent/EP1200422A2/en not_active Withdrawn
- 2001-10-04 NO NO20014837A patent/NO322745B1/no not_active IP Right Cessation
- 2001-10-05 US US09/972,437 patent/US6528509B1/en not_active Expired - Lifetime
- 2001-10-17 LT LT2001103A patent/LT4981B/lt not_active IP Right Cessation
- 2001-10-26 BG BG106054A patent/BG106054A/xx unknown
-
2002
- 2002-08-22 US US10/225,719 patent/US6593357B1/en not_active Expired - Lifetime
- 2002-10-16 HK HK02107512.2A patent/HK1046276A1/zh unknown
-
2003
- 2003-01-02 US US10/335,793 patent/US6699865B2/en not_active Expired - Fee Related
- 2003-10-17 US US10/688,613 patent/US7056944B2/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101370784B (zh) * | 2005-12-13 | 2012-10-10 | 先灵公司 | 用作胞外信号调节激酶抑制剂的化合物 |
Also Published As
Publication number | Publication date |
---|---|
IL145757A0 (en) | 2002-07-25 |
JP2003522163A (ja) | 2003-07-22 |
US20030225151A1 (en) | 2003-12-04 |
KR20010111298A (ko) | 2001-12-17 |
US6528509B1 (en) | 2003-03-04 |
IL145757A (en) | 2007-12-03 |
CA2369504A1 (en) | 2001-08-09 |
SK14082001A3 (sk) | 2002-03-05 |
BR0104424A (pt) | 2002-01-08 |
WO2001057022A3 (en) | 2002-03-07 |
US20030040536A1 (en) | 2003-02-27 |
LT4981B (lt) | 2003-01-27 |
HK1046276A1 (zh) | 2003-01-03 |
NO20014837L (no) | 2001-12-04 |
NO322745B1 (no) | 2006-12-04 |
US6699865B2 (en) | 2004-03-02 |
US7056944B2 (en) | 2006-06-06 |
JP4783532B2 (ja) | 2011-09-28 |
NO20014837D0 (no) | 2001-10-04 |
NZ514583A (en) | 2004-05-28 |
TR200103787T1 (tr) | 2002-10-21 |
AU3672301A (en) | 2001-08-14 |
US20040102506A1 (en) | 2004-05-27 |
BG106054A (en) | 2002-06-28 |
LT2001103A (en) | 2002-10-25 |
WO2001057022A2 (en) | 2001-08-09 |
CZ20013540A3 (cs) | 2002-03-13 |
CA2369504C (en) | 2009-01-06 |
EP1200422A2 (en) | 2002-05-02 |
HUP0202332A2 (en) | 2002-10-28 |
AU782775B2 (en) | 2005-08-25 |
US6593357B1 (en) | 2003-07-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1362953A (zh) | 用作erk抑制剂的吡唑组合物 | |
AU782878B2 (en) | Pyrazole compositions useful as inhibitors of erk | |
JP4173738B2 (ja) | Erk2の複素環式インヒビターおよびその使用 | |
US6706711B2 (en) | Pyrazole derived kinase inhibitor | |
US6962936B2 (en) | Triazole-derived kinase inhibitors and uses thereof | |
EP1317453B1 (en) | Isoxazoles and their use as inhibitors of erk | |
DE60223790T2 (de) | Hemmer von c-jun-terminal kinase (jnk) und andere protein kinase | |
US6875789B2 (en) | Pyrazole-derived kinase inhibitors and uses thereof | |
JP4357295B2 (ja) | ピラゾール誘導キナーゼインヒビターとその使用 | |
US20020111353A1 (en) | Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases | |
US20040176271A1 (en) | Compostions useful as inhibitors of JAK and other protein kinases | |
US10059705B2 (en) | Acyclic cyanoethylpyrazolo pyridones as janus kinase inhibitors | |
EP1554269A1 (en) | Imidazoles, oxazoles and thiazoles with protein kinase inhibiting activities | |
US11407831B2 (en) | Pharmaceutical composition administered in combination with substituted dihydropyrrolopyrazole compound and immunotherapeutic agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |