CA2962326A1 - Novel compounds - Google Patents
Novel compounds Download PDFInfo
- Publication number
- CA2962326A1 CA2962326A1 CA2962326A CA2962326A CA2962326A1 CA 2962326 A1 CA2962326 A1 CA 2962326A1 CA 2962326 A CA2962326 A CA 2962326A CA 2962326 A CA2962326 A CA 2962326A CA 2962326 A1 CA2962326 A1 CA 2962326A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- fluoro
- mmol
- pharmaceutically acceptable
- formula
- 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
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 249
- 150000003839 salts Chemical class 0.000 claims abstract description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 80
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
- 201000010099 disease Diseases 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 18
- 238000002560 therapeutic procedure Methods 0.000 claims description 16
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 13
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 9
- 230000003176 fibrotic effect Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 229940044551 receptor antagonist Drugs 0.000 claims description 5
- 239000002464 receptor antagonist Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000008485 antagonism Effects 0.000 claims description 3
- 230000009286 beneficial effect Effects 0.000 claims 2
- BUAYFDWYSYICGP-UHFFFAOYSA-N OC(=O)CC(CN1CCC(F)(CCC2=CC=C3CCCNC3=N2)C1)C1=C(F)C=CC(=C1)N1CCOCC1 Chemical compound OC(=O)CC(CN1CCC(F)(CCC2=CC=C3CCCNC3=N2)C1)C1=C(F)C=CC(=C1)N1CCOCC1 BUAYFDWYSYICGP-UHFFFAOYSA-N 0.000 claims 1
- HKDUWRRLEDNORE-UHFFFAOYSA-N OC(=O)CC(CN1CCC(F)(CCC2=CC=C3CCCNC3=N2)C1)C1=CC(=CC=C1)N1CCOCC1 Chemical compound OC(=O)CC(CN1CCC(F)(CCC2=CC=C3CCCNC3=N2)C1)C1=CC(=CC=C1)N1CCOCC1 HKDUWRRLEDNORE-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 98
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 239000000203 mixture Substances 0.000 description 86
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 77
- 235000002639 sodium chloride Nutrition 0.000 description 73
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 102000006495 integrins Human genes 0.000 description 37
- 108010044426 integrins Proteins 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
- -1 alkali metal salts Chemical class 0.000 description 31
- 239000007787 solid Substances 0.000 description 28
- 239000005557 antagonist Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- 230000002829 reductive effect Effects 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- 238000004296 chiral HPLC Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 235000019441 ethanol Nutrition 0.000 description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000002585 base Substances 0.000 description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 15
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 14
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 14
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 14
- 239000001099 ammonium carbonate Substances 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000010948 rhodium Substances 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- MDSGTKLDIYJRNX-UHFFFAOYSA-N benzyl 3-fluoro-3-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound OCC1(F)CCN(C1)C(=O)OCc1ccccc1 MDSGTKLDIYJRNX-UHFFFAOYSA-N 0.000 description 13
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 238000003352 cell adhesion assay Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 239000003446 ligand Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000006071 cream Substances 0.000 description 9
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000012453 solvate Substances 0.000 description 9
- OHGOMHOEZUWGOH-UHFFFAOYSA-N (3-morpholin-4-ylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(N2CCOCC2)=C1 OHGOMHOEZUWGOH-UHFFFAOYSA-N 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 206010016654 Fibrosis Diseases 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000004761 fibrosis Effects 0.000 description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- PFQFYBXOJSQFJB-FZKQIMNGSA-N tert-butyl (3R)-3-fluoro-3-[[(1R)-1-phenylethyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound N([C@H](C)C=1C=CC=CC=1)C(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1 PFQFYBXOJSQFJB-FZKQIMNGSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 229940123038 Integrin antagonist Drugs 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 235000019502 Orange oil Nutrition 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 239000001530 fumaric acid Substances 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000011976 maleic acid Substances 0.000 description 6
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 6
- 239000010502 orange oil Substances 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 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 5
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 150000001860 citric acid derivatives Chemical class 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 235000011087 fumaric acid Nutrition 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
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- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 150000002688 maleic acid derivatives Chemical class 0.000 description 5
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- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 230000037390 scarring Effects 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
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- 235000017281 sodium acetate Nutrition 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 208000028006 Corneal injury Diseases 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000001743 benzylic group Chemical group 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
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- 239000008187 granular material Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
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Classifications
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- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| GB1417011.2 | 2014-09-26 | ||
| PCT/EP2015/071777 WO2016046226A1 (en) | 2014-09-26 | 2015-09-22 | Novel compounds |
Publications (1)
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| CA2962326A1 true CA2962326A1 (en) | 2016-03-31 |
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| UY (1) | UY36315A (enExample) |
| WO (1) | WO2016046226A1 (enExample) |
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| GB201305668D0 (en) | 2013-03-28 | 2013-05-15 | Glaxosmithkline Ip Dev Ltd | Avs6 Integrin Antagonists |
| GB201417018D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| GB201417002D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compound |
| GB201417094D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| GB201604681D0 (en) * | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
| GB201604680D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
| EP3538528B1 (en) | 2016-11-08 | 2020-12-23 | Bristol-Myers Squibb Company | Pyrrole amides as alpha v integrin inhibitors |
| TW201819378A (zh) | 2016-11-08 | 2018-06-01 | 美商必治妥美雅史谷比公司 | 作為αｖ整合素抑制劑之含環丁烷及氮雜環丁烷之單及螺環化合物 |
| PL3538525T3 (pl) | 2016-11-08 | 2022-09-12 | Bristol-Myers Squibb Company | 3-podstawione kwasy propionowe jako inhibitory integryny alfa v |
| US10745384B2 (en) | 2016-11-08 | 2020-08-18 | Bristol-Myers Squibb Company | Indazole derivatives as αv integrin antagonists |
| EA201991121A1 (ru) | 2016-11-08 | 2019-11-29 | АЗОЛАМИДЫ И АЗОЛАМИНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ ИНТЕГРИНОВ αV | |
| EP3558303A4 (en) | 2016-12-23 | 2020-07-29 | Pliant Therapeutics, Inc. | AMINO ACID COMPOUNDS AND PROCESSES FOR USE |
| CA3054792A1 (en) | 2017-02-28 | 2018-09-07 | Morphic Therapeutic, Inc. | Inhibitors of .alpha.v.beta.6 integrin |
| MX394210B (es) | 2017-02-28 | 2025-03-04 | Morphic Therapeutic Inc | INHIBIDORES DE INTEGRINA AVß6. |
| CN107823208A (zh) * | 2017-10-25 | 2018-03-23 | 南京多宝生物科技有限公司 | 吗啉类化合物在制备治疗和预防肾纤维化药物中的应用 |
| KR102700471B1 (ko) | 2017-11-07 | 2024-08-28 | 브리스톨-마이어스 스큅 컴퍼니 | 알파 v 인테그린 억제제로서의 피롤로피라진 유도체 |
| CN108208177A (zh) * | 2017-11-28 | 2018-06-29 | 上海交通大学医学院附属新华医院 | 含丁酸类化合物的组合物及其应用 |
| FI3844162T3 (fi) | 2018-08-29 | 2025-03-27 | Morphic Therapeutic Inc | Alfa v beeta6 -integriinin estäjiä |
| JP7540998B2 (ja) | 2018-08-29 | 2024-08-27 | モーフィック セラピューティック，インコーポレイテッド | αｖβ６インテグリンの阻害 |
| TW202028179A (zh) | 2018-10-08 | 2020-08-01 | 美商普萊恩醫療公司 | 胺基酸化合物及使用方法 |
| WO2020074937A1 (en) * | 2018-10-09 | 2020-04-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of alpha-v-integrin (cd51) inhibitors for the treatment of cardiac fibrosis |
| CA3119807A1 (en) * | 2018-12-04 | 2020-06-11 | Sumitomo Dainippon Pharma Oncology, Inc. | Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| EP4525866A1 (en) * | 2022-05-18 | 2025-03-26 | Pliant Therapeutics, Inc. | Stabilization of integrin inhibitors |
| EP4605008A1 (en) | 2022-12-14 | 2025-08-27 | Alnylam Pharmaceuticals, Inc. | Alpha-v beta-6 integrin ligands for extrahepatic delivery |
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| WO1999030709A1 (en) | 1997-12-17 | 1999-06-24 | Merck & Co., Inc. | Integrin receptor antagonists |
| NZ504893A (en) | 1997-12-17 | 2002-10-25 | Merck & Co Inc | 5, 6, 7, 8-Tetrahydro-[1,8]-naphthyridin-2-yl derivatives useful as integrin receptor antagonists |
| CA2373937A1 (en) | 1999-06-02 | 2000-12-07 | Merck & Co., Inc. | Alpha v integrin receptor antagonists |
| AU748949B2 (en) | 1999-06-23 | 2002-06-13 | Merck & Co., Inc. | Integrin receptor antagonists |
| CA2386030A1 (en) | 1999-10-04 | 2001-04-12 | Merck & Co., Inc. | Integrin receptor antagonists |
| WO2001034602A2 (en) | 1999-11-08 | 2001-05-17 | Merck & Co., Inc. | Process and intermediates for the preparation of imidazolidinone alpha v integrin antagonists |
| JP2004511434A (ja) | 2000-06-15 | 2004-04-15 | ファルマシア・コーポレーション | インテグリン受容体アンタゴニストとしてのヘテロアリールアルカン酸 |
| DE60126496T2 (de) | 2000-07-26 | 2007-11-15 | Merck & Co., Inc. | Alpha v integrin-rezeptor-antagonisten |
| WO2002022616A2 (en) | 2000-09-14 | 2002-03-21 | Merck & Co., Inc. | Alpha v integrin receptor antagonists |
| EP1349548A4 (en) | 2001-01-03 | 2004-06-02 | Merck & Co Inc | METHOD AND COMPOSITIONS FOR TREATING PERIODONTOSIS |
| DE10112771A1 (de) | 2001-03-16 | 2002-09-26 | Merck Patent Gmbh | Inhibitoren des Integrins alpha¶v¶beta¶6¶ |
| US20040224986A1 (en) * | 2002-08-16 | 2004-11-11 | Bart De Corte | Piperidinyl targeting compounds that selectively bind integrins |
| CA2507699A1 (en) | 2002-12-20 | 2004-07-15 | Pharmacia Corporation | Heteroarylalkanoic acids as integrin receptor antagonists |
| US6932865B2 (en) | 2003-04-11 | 2005-08-23 | Lockheed Martin Corporation | System and method of making single-crystal structures through free-form fabrication techniques |
| RS53151B (sr) | 2007-03-23 | 2014-06-30 | Amgen Inc. | 3-supstituisani derivati hinolina ili hinoksalina i njihova upotreba kao inhibitora fosfatidilinozitol 3-kinaze (pi3k) |
| EP2211615A4 (en) | 2007-10-22 | 2010-10-13 | Glaxosmithkline Llc | PYRIDOSULFONAMIDE DERIVATIVES AS PI3 KINASE INHIBITORS |
| WO2011111880A1 (ko) | 2010-03-08 | 2011-09-15 | 주식회사 메디젠텍 | 세포핵에서 세포질로의 ｇｓｋ３의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 gsk3 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물 |
| GB201305668D0 (en) * | 2013-03-28 | 2013-05-15 | Glaxosmithkline Ip Dev Ltd | Avs6 Integrin Antagonists |
| WO2015048819A1 (en) | 2013-09-30 | 2015-04-02 | The Regents Of The University Of California | Anti-alphavbeta1 integrin compounds and methods |
| GB201417094D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| GB201417002D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compound |
| GB201417018D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| JP2018510139A (ja) | 2015-02-19 | 2018-04-12 | サイフルーア ライフ サイエンシズ インコーポレイテッド | フッ化テトラヒドロナフチリジニルノナン酸誘導体およびその使用法 |
| AU2016228852A1 (en) | 2015-03-10 | 2017-10-19 | The Regents Of The University Of California | Anti-alphavbeta1 integrin inhibitors and methods of use |
| GB201604589D0 (en) | 2016-03-18 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical compound |
| GB201604681D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
| GB201604680D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
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2014
- 2014-09-26 GB GBGB1417011.2A patent/GB201417011D0/en not_active Ceased
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2015
- 2015-09-22 ES ES15767476T patent/ES2704525T3/es active Active
- 2015-09-22 CA CA2962326A patent/CA2962326A1/en active Pending
- 2015-09-22 US US15/514,407 patent/US10000489B2/en not_active Expired - Fee Related
- 2015-09-22 JP JP2017516365A patent/JP6665169B2/ja not_active Expired - Fee Related
- 2015-09-22 AR ARP150103048A patent/AR101995A1/es unknown
- 2015-09-22 AU AU2015320859A patent/AU2015320859A1/en not_active Abandoned
- 2015-09-22 EP EP15767476.3A patent/EP3197893B1/en active Active
- 2015-09-22 KR KR1020177007734A patent/KR20170063590A/ko not_active Withdrawn
- 2015-09-22 TW TW104131367A patent/TW201629057A/zh unknown
- 2015-09-22 RU RU2017114346A patent/RU2017114346A/ru unknown
- 2015-09-22 CN CN201580051539.2A patent/CN107074849A/zh active Pending
- 2015-09-22 UY UY0001036315A patent/UY36315A/es not_active Application Discontinuation
- 2015-09-22 WO PCT/EP2015/071777 patent/WO2016046226A1/en not_active Ceased
- 2015-09-22 BR BR112017006253A patent/BR112017006253A2/pt not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP3197893A1 (en) | 2017-08-02 |
| WO2016046226A1 (en) | 2016-03-31 |
| KR20170063590A (ko) | 2017-06-08 |
| EP3197893B1 (en) | 2018-10-24 |
| US20170298063A1 (en) | 2017-10-19 |
| JP2017528503A (ja) | 2017-09-28 |
| RU2017114346A (ru) | 2018-11-02 |
| TW201629057A (zh) | 2016-08-16 |
| US10000489B2 (en) | 2018-06-19 |
| CN107074849A (zh) | 2017-08-18 |
| UY36315A (es) | 2016-04-29 |
| ES2704525T3 (es) | 2019-03-18 |
| GB201417011D0 (en) | 2014-11-12 |
| JP6665169B2 (ja) | 2020-03-13 |
| AR101995A1 (es) | 2017-01-25 |
| BR112017006253A2 (pt) | 2017-12-12 |
| AU2015320859A1 (en) | 2017-03-09 |
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