IL188181A - Monohydrate of 2- (6-methyl-pyridine-2-yl) -3-) 6-amido-quinoline-4-yl) -6,5-dihydro-h4-pyrrolo [2,1- b] pyrazole as an anti-drug Cancerous and pharmaceuticals containing it - Google Patents
Monohydrate of 2- (6-methyl-pyridine-2-yl) -3-) 6-amido-quinoline-4-yl) -6,5-dihydro-h4-pyrrolo [2,1- b] pyrazole as an anti-drug Cancerous and pharmaceuticals containing itInfo
- Publication number
- IL188181A IL188181A IL188181A IL18818107A IL188181A IL 188181 A IL188181 A IL 188181A IL 188181 A IL188181 A IL 188181A IL 18818107 A IL18818107 A IL 18818107A IL 188181 A IL188181 A IL 188181A
- Authority
- IL
- Israel
- Prior art keywords
- methyl
- quinolin
- pyridin
- pyrrolo
- dihydro
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title claims description 4
- 230000001093 anti-cancer Effects 0.000 title 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 pyrazole monohydrate Chemical class 0.000 claims description 25
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 16
- 150000004682 monohydrates Chemical class 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 238000005481 NMR spectroscopy Methods 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 3
- 206010057644 Testis cancer Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 201000003120 testicular cancer Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 230000023750 transforming growth factor beta production Effects 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- JKLLRKDEWNJNFG-UHFFFAOYSA-N 4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carbonitrile Chemical compound CC1=CC=CC(C=2C(=C3CCCN3N=2)C=2C3=CC(=CC=C3N=CC=2)C#N)=N1 JKLLRKDEWNJNFG-UHFFFAOYSA-N 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000003756 stirring Methods 0.000 description 24
- 239000002002 slurry Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 17
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 17
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- KRFSUGPZCQQFPS-UHFFFAOYSA-N 4-[2-(6-methylpyridin-2-yl)-2-oxoethyl]quinoline-6-carbonitrile Chemical compound CC1=CC=CC(C(=O)CC=2C3=CC(=CC=C3N=CC=2)C#N)=N1 KRFSUGPZCQQFPS-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- PUZDXTZGYMAZCI-UHFFFAOYSA-N 4-methylquinoline-6-carbonitrile;hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(C)=CC=NC2=C1 PUZDXTZGYMAZCI-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- JUJGNTINMISJQF-UHFFFAOYSA-N O.C1=CNN2C=CC=C21 Chemical class O.C1=CNN2C=CC=C21 JUJGNTINMISJQF-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LTUUGSGSUZRPRV-UHFFFAOYSA-N 6-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=CC(C(O)=O)=N1 LTUUGSGSUZRPRV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 108091005682 Receptor kinases Proteins 0.000 description 2
- 102000043168 TGF-beta family Human genes 0.000 description 2
- 108091085018 TGF-beta family Proteins 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 238000005388 cross polarization Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012261 overproduction Methods 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMHSKYSHOIGDPE-UHFFFAOYSA-N pyridine;quinoline Chemical group C1=CC=NC=C1.N1=CC=CC2=CC=CC=C21 UMHSKYSHOIGDPE-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000007781 signaling event Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- CLVKUJLLENZMDL-UHFFFAOYSA-N 1,4-dihydropyrrolo[3,2-c]pyrazole Chemical class N1N=CC2=C1C=CN2 CLVKUJLLENZMDL-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- SOQBEKLZDZYWLR-UHFFFAOYSA-N 4-[1-(6-methylpyridin-2-yl)-2-(2-oxopyrrolidin-1-yl)iminoethyl]quinoline-6-carbonitrile Chemical compound CC1=CC=CC(C(C=NN2C(CCC2)=O)C=2C3=CC(=CC=C3N=CC=2)C#N)=N1 SOQBEKLZDZYWLR-UHFFFAOYSA-N 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- AXQBQWNSWXTDCR-UHFFFAOYSA-N 4-methylquinoline-6-carbonitrile Chemical compound C1=C(C#N)C=C2C(C)=CC=NC2=C1 AXQBQWNSWXTDCR-UHFFFAOYSA-N 0.000 description 1
- SDHJFGARGGXHBT-UHFFFAOYSA-N 6-methyl-5h-quinoline-6-carbonitrile;hydrochloride Chemical compound Cl.C1=CN=C2C=CC(C)(C#N)CC2=C1 SDHJFGARGGXHBT-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108091005735 TGF-beta receptors Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000014461 bone development Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical compound CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- CYWIZMOZBTXFIL-UHFFFAOYSA-N methyl 6-methylpyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(C)=N1 CYWIZMOZBTXFIL-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- XMGMFRIEKMMMSU-UHFFFAOYSA-N phenylmethylbenzene Chemical group C=1C=CC=CC=1[C]C1=CC=CC=C1 XMGMFRIEKMMMSU-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61P35/00—Antineoplastic agents
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70164105P | 2005-07-22 | 2005-07-22 | |
| PCT/US2006/025377 WO2007018818A1 (en) | 2005-07-22 | 2006-06-29 | A pyridin quinolin substituted pyrrolo [1,2-b] pyrazole monohydrate as tgf-beta inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL188181A0 IL188181A0 (en) | 2008-03-20 |
| IL188181A true IL188181A (en) | 2014-05-28 |
Family
ID=37450942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL188181A IL188181A (en) | 2005-07-22 | 2007-12-17 | Monohydrate of 2- (6-methyl-pyridine-2-yl) -3-) 6-amido-quinoline-4-yl) -6,5-dihydro-h4-pyrrolo [2,1- b] pyrazole as an anti-drug Cancerous and pharmaceuticals containing it |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US7872020B2 (https=) |
| EP (1) | EP1910370B1 (https=) |
| JP (1) | JP5242391B2 (https=) |
| BR (1) | BRPI0613639A2 (https=) |
| CA (1) | CA2616196C (https=) |
| DK (1) | DK1910370T3 (https=) |
| ES (1) | ES2542425T3 (https=) |
| HR (1) | HRP20150474T1 (https=) |
| HU (1) | HUE025209T2 (https=) |
| IL (1) | IL188181A (https=) |
| MX (1) | MX2008001020A (https=) |
| PL (1) | PL1910370T3 (https=) |
| PT (1) | PT1910370E (https=) |
| RS (1) | RS53999B1 (https=) |
| SI (1) | SI1910370T1 (https=) |
| WO (1) | WO2007018818A1 (https=) |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR081810A1 (es) | 2010-04-07 | 2012-10-24 | Bayer Cropscience Ag | Piridinilpirazoles biciclicos |
| DK2731949T3 (en) * | 2011-07-13 | 2018-06-14 | Tiumbio Co Ltd | 2-PYRIDYL-SUBSTITUTED IMIDAZOLS AS ALK5 AND / OR ALK4 INHIBITORS |
| WO2014072517A1 (en) | 2012-11-12 | 2014-05-15 | Institució Catalana De Recerca I Estudis Avançats | Methods and kits for the prognosis of colorectal cancer |
| LT2970890T (lt) | 2013-03-14 | 2020-07-10 | The Brigham And Women`S Hospital, Inc. | Kompozicijos ir būdai, skirti epitelinių kamieninių ląstelių padauginimui ir kultivavimui |
| WO2016037016A1 (en) | 2014-09-03 | 2016-03-10 | The Brigham And Women's Hospital, Inc. | Compositions, systems, and methods for generating inner ear hair cells for treatment of hearing loss |
| HK1247861A1 (zh) | 2015-01-30 | 2018-10-05 | President And Fellows Of Harvard College | 用於癌症治疗的肿瘤周围和肿瘤内部材料 |
| ES2918924T3 (es) | 2015-04-01 | 2022-07-21 | Rigel Pharmaceuticals Inc | Inhibidores de TGF-beta |
| US10669528B2 (en) | 2015-06-25 | 2020-06-02 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance |
| KR102738306B1 (ko) | 2015-12-15 | 2024-12-03 | 브리스톨-마이어스 스큅 컴퍼니 | Cxcr4 수용체 길항제 |
| CN108779437A (zh) | 2016-01-08 | 2018-11-09 | 麻省理工学院 | 分化的肠内分泌细胞和胰岛素产生细胞的制备 |
| US10201540B2 (en) | 2016-03-02 | 2019-02-12 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: I |
| US11260130B2 (en) | 2016-03-02 | 2022-03-01 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: IV |
| US10213511B2 (en) | 2016-03-02 | 2019-02-26 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| WO2017161001A1 (en) | 2016-03-15 | 2017-09-21 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion |
| CN109548403A (zh) | 2016-07-07 | 2019-03-29 | 苏州科睿思制药有限公司 | Galunisertib的晶型及其制备方法和用途 |
| EP3527570A4 (en) | 2016-10-14 | 2020-04-15 | Jiangsu Hengrui Medicine Co., Ltd. | FIVE-LINKED HETERARYARYLE CYCLE BRIDGE DERIVATIVE, METHOD FOR PREPARING SAME, AND MEDICAL USE THEREOF |
| US11066419B2 (en) | 2016-12-30 | 2021-07-20 | Frequency Therapeutics, Inc. | 1H-pyrrole-2,5-dione compounds and methods of using same |
| CN110582497B (zh) * | 2017-03-17 | 2022-03-11 | 杭州领业医药科技有限公司 | Galunisertib的晶型及其制备方法和药物组合物 |
| US10995083B2 (en) | 2017-03-21 | 2021-05-04 | Hangzhou Solipharma Co., Ltd. | Cocrystal of 2-(6-methyl-pyridine-2-yl)-3-yl-[6-amide-quinoline-4-yl]-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole, preparation method therefor, and pharmaceutical composition |
| WO2019042383A1 (zh) * | 2017-08-31 | 2019-03-07 | 苏州科睿思制药有限公司 | Galunisertib的晶型及其制备方法和用途 |
| WO2019105082A1 (zh) * | 2017-11-30 | 2019-06-06 | 苏州科睿思制药有限公司 | Galunisertib的晶型及其制备方法和用途 |
| WO2019137027A1 (zh) * | 2018-01-12 | 2019-07-18 | 苏州科睿思制药有限公司 | Galunisertib的晶型及其制备方法和用途 |
| JP2021518413A (ja) | 2018-03-20 | 2021-08-02 | アイカーン スクール オブ メディシン アット マウント サイナイ | キナーゼ阻害剤化合物及び組成物ならびに使用方法 |
| US20210254006A1 (en) | 2018-06-06 | 2021-08-19 | Ideaya Biosciences, Inc. | Methods of culturing and/or expanding stem cells and/or lineage committed progenitor cells using lactam compounds |
| CN113195707A (zh) | 2018-08-17 | 2021-07-30 | 频率治疗公司 | 用于通过上调jag-1来生成毛细胞的组合物和方法 |
| US11617745B2 (en) | 2018-08-17 | 2023-04-04 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by downregulating FOXO |
| WO2020142485A1 (en) | 2018-12-31 | 2020-07-09 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
| CN115282280A (zh) * | 2022-08-12 | 2022-11-04 | 中国科学技术大学 | TGF-β1信号抑制剂的新用途 |
| AU2024265078A1 (en) | 2023-05-04 | 2025-12-11 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| GB202309553D0 (en) | 2023-06-24 | 2023-08-09 | Ucl Business Ltd | Compostions and uses thereof |
| IL326136A (en) | 2023-08-07 | 2026-03-01 | Revolution Medicines Inc | RMC-6291 for use in the treatment of a disease or disorder associated with the RAS protein |
| US20250154171A1 (en) | 2023-10-12 | 2025-05-15 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
| US20250375445A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025265060A1 (en) | 2024-06-21 | 2025-12-26 | Revolution Medicines, Inc. | Therapeutic compositions and methods for managing treatment-related effects |
| WO2026006747A1 (en) | 2024-06-28 | 2026-01-02 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026015825A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Use of ras inhibitor for treating pancreatic cancer |
| WO2026015790A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015801A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026050446A1 (en) | 2024-08-29 | 2026-03-05 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026072904A2 (en) | 2024-09-26 | 2026-04-02 | Revolution Medicines, Inc. | Compositions and methods for treating lung cancer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1397364B1 (en) * | 2001-05-24 | 2007-07-25 | Eli Lilly And Company | Novel pyrrole derivatives as pharmaceutical agents |
| CA2506799A1 (en) | 2002-11-21 | 2004-06-10 | Eli Lilly And Company | Mixed lineage kinase modulators |
| UA80571C2 (en) * | 2002-11-22 | 2007-10-10 | Lilly Co Eli | Quinolinyl-pyrrolopyrazoles |
-
2006
- 2006-06-29 EP EP20060774280 patent/EP1910370B1/en active Active
- 2006-06-29 WO PCT/US2006/025377 patent/WO2007018818A1/en not_active Ceased
- 2006-06-29 HU HUE06774280A patent/HUE025209T2/en unknown
- 2006-06-29 JP JP2008522796A patent/JP5242391B2/ja not_active Expired - Fee Related
- 2006-06-29 SI SI200631924T patent/SI1910370T1/sl unknown
- 2006-06-29 HR HRP20150474TT patent/HRP20150474T1/hr unknown
- 2006-06-29 ES ES06774280.9T patent/ES2542425T3/es active Active
- 2006-06-29 RS RS20150319A patent/RS53999B1/sr unknown
- 2006-06-29 PT PT67742809T patent/PT1910370E/pt unknown
- 2006-06-29 PL PL06774280T patent/PL1910370T3/pl unknown
- 2006-06-29 BR BRPI0613639-7A patent/BRPI0613639A2/pt not_active Application Discontinuation
- 2006-06-29 US US11/995,938 patent/US7872020B2/en not_active Expired - Fee Related
- 2006-06-29 DK DK06774280.9T patent/DK1910370T3/en active
- 2006-06-29 CA CA2616196A patent/CA2616196C/en not_active Expired - Fee Related
- 2006-06-29 MX MX2008001020A patent/MX2008001020A/es active IP Right Grant
-
2007
- 2007-12-17 IL IL188181A patent/IL188181A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US20100120854A1 (en) | 2010-05-13 |
| JP5242391B2 (ja) | 2013-07-24 |
| CA2616196A1 (en) | 2007-02-15 |
| PL1910370T3 (pl) | 2015-09-30 |
| US7872020B2 (en) | 2011-01-18 |
| DK1910370T3 (en) | 2015-06-08 |
| WO2007018818A1 (en) | 2007-02-15 |
| EP1910370A1 (en) | 2008-04-16 |
| BRPI0613639A2 (pt) | 2012-02-22 |
| PT1910370E (pt) | 2015-06-30 |
| JP2009502780A (ja) | 2009-01-29 |
| ES2542425T3 (es) | 2015-08-05 |
| MX2008001020A (es) | 2008-03-25 |
| HRP20150474T1 (xx) | 2015-06-05 |
| EP1910370B1 (en) | 2015-04-22 |
| SI1910370T1 (sl) | 2015-06-30 |
| CA2616196C (en) | 2012-08-21 |
| HUE025209T2 (en) | 2016-03-29 |
| IL188181A0 (en) | 2008-03-20 |
| RS53999B1 (sr) | 2015-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1910370B1 (en) | A pyridin quinolin substituted pyrrolo [1,2-b] pyrazole monohydrate as tgf-beta inhibitor | |
| AU2020343671B2 (en) | RIP1 inhibitory compounds and methods for making and using the same | |
| DK3037424T3 (en) | NEW QUINOLIN-SUBSTITUTED COMPOUND | |
| RU2633694C2 (ru) | Дейтерированный фениламинопиримидин и фармацевтическая композиция, содержащая такое соединение | |
| JP2015180679A (ja) | ナトリウム４−｛［９−クロロ−７−（２−フルオロ−６−メトキシフェニル）−５Ｈ−ピリミド［５，４−ｄ］［２］ベンゾアゼピン−２−イル］アミノ｝−２−メトキシベンゾエートの結晶形 | |
| EP2985277A1 (en) | Dipyrromethene crystal and method for manufacturing same | |
| JP2015520186A (ja) | 増殖性疾患の治療にキナーゼ阻害剤として有用なジヒドロナフチリジン及び関連化合物 | |
| SK9622000A3 (en) | Inhibition of raf kinase using aryl and heteroaryl substituted heterocyclic ureas | |
| HUE029343T2 (en) | Quinolylpyrrolo-pyrimidyl fused ring compounds and salts thereof | |
| EP3892621A1 (en) | Haloallylamine compounds and application thereof | |
| JP2016517845A (ja) | ＰＥＲＫ阻害剤としての新規なＮ（２，３−ジヒドロ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−５−イル）−４−キナゾリンアミン誘導体およびＮ−（２，３−ジヒドロ−１Ｈ−インドール−５−イル）−４−キナゾリンアミン誘導体 | |
| EP3434674B1 (en) | ((4-(2-oxoimidazolidine-1-yl)pyrimidin-2-yl)amine derivatives as mutant idh inhibitors for treating cancer | |
| EP4332101A1 (en) | Methionine adenosyltransferase inhibitor, preparation method therefor and application thereof | |
| EP3854793A1 (en) | Aromatic heterocyclic compound with kinase inhibitory activity | |
| CN116217561A (zh) | 一类具有二甲基异吲哚酮结构的新型激酶抑制剂及其制备方法和用途 | |
| WO2014020531A1 (en) | Imidazo[1,2-b]pyridazin-6-amine derivatives as kinase jak-2 inhibitors | |
| TW202329952A (zh) | 克拉生坦(clazosentan)二鈉鹽之製備方法 | |
| WO2002094832A1 (en) | New benzylaminopyrimidines | |
| HK40053245A (en) | Haloallylamine compounds and application thereof | |
| HK1241358A1 (en) | Crystal of (s)-1-(2-hydroxyethyl)-4-methyl-n- [4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]- 1h-pyrrole-3-carboxamide | |
| AU2002338927A1 (en) | New benzylaminopyrimidines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| MM9K | Patent not in force due to non-payment of renewal fees |