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
-
- 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
-
- 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
- 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)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| GBGB1417011.2A GB201417011D0 (en) | 2014-09-26 | 2014-09-26 | Novel compounds |
| PCT/EP2015/071777 WO2016046226A1 (en) | 2014-09-26 | 2015-09-22 | Novel compounds |
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| CA2962326A1 true CA2962326A1 (en) | 2016-03-31 |
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| UY (1) | UY36315A (cg-RX-API-DMAC7.html) |
| WO (1) | WO2016046226A1 (cg-RX-API-DMAC7.html) |
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| GB201305668D0 (en) | 2013-03-28 | 2013-05-15 | Glaxosmithkline Ip Dev Ltd | Avs6 Integrin Antagonists |
| GB201417094D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| 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 |
| GB201604680D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
| GB201604681D0 (en) * | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
| US10851098B2 (en) | 2016-11-08 | 2020-12-01 | Bristol-Myers Squibb Company | Azole amides and amines as alpha v integrin inhibitors |
| CN110167935B (zh) | 2016-11-08 | 2022-05-27 | 百时美施贵宝公司 | 作为αV整合素抑制剂的3-经取代的丙酸 |
| RS61453B1 (sr) * | 2016-11-08 | 2021-03-31 | Bristol Myers Squibb Co | Amidi pirola kao inhibitori alfa v integrina |
| BR112019009129A2 (pt) | 2016-11-08 | 2019-07-16 | Bristol-Myers Squibb Company | compostos mono e espirocíclicos contendo ciclobutano e azetidina como inibidores de alfa v integrina |
| KR102506327B1 (ko) | 2016-11-08 | 2023-03-03 | 브리스톨-마이어스 스큅 컴퍼니 | αV 인테그린 길항제로서의 인다졸 유도체 |
| USRE50554E1 (en) | 2016-12-23 | 2025-08-26 | Pliant Therapeutics, Inc. | Amino acid compounds and methods of use |
| KR102605460B1 (ko) | 2017-02-28 | 2023-11-22 | 모픽 테라퓨틱, 인코포레이티드 | αvβ6 인테그린 억제제 |
| MA52117A (fr) | 2017-02-28 | 2022-04-06 | Morphic Therapeutic Inc | Inhibiteurs de l'intégrine (alpha-v) (bêta-6) |
| 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 |
| US11292802B2 (en) | 2017-11-07 | 2022-04-05 | Bristol-Myers Squibb Company | Substituted tetrahydropyrrolo[1,2-a]pyrazines as alpha v integrin inhibitors |
| 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 |
| CN112805001B (zh) | 2018-08-29 | 2024-07-23 | 莫菲克医疗股份有限公司 | 抑制αvβ6整联蛋白 |
| RS66733B1 (sr) * | 2018-08-29 | 2025-05-30 | Morphic Therapeutic Inc | Inhibitori alfa v beta6 integrina |
| 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 |
| US12351634B2 (en) * | 2018-10-09 | 2025-07-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of cilengitide for ameliorating cardiac fibrosis occurring in response to myocardial infarction |
| EP3890749B1 (en) * | 2018-12-04 | 2025-10-29 | Sumitomo Pharma America, Inc. | Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| WO2023225119A1 (en) * | 2022-05-18 | 2023-11-23 | Pliant Therapeutics, Inc. | Stabilization of integrin inhibitors |
| KR20250120424A (ko) | 2022-12-14 | 2025-08-08 | 알닐람 파마슈티칼스 인코포레이티드 | 간외 전달을 위한 알파-v 베타-6(αvβ6) 인테그린 리간드 |
| WO2025259743A1 (en) | 2024-06-12 | 2025-12-18 | Alnylam Pharmaceuticals, Inc. | Dual conjugate compounds for extrahepatic delivery |
| WO2025259747A2 (en) | 2024-06-12 | 2025-12-18 | Alnylam Pharmaceuticals, Inc. | Dystrophy myotonic protein kinase (dmpk) irna compositions and methods of use thereof |
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| AU736026B2 (en) | 1997-12-17 | 2001-07-26 | Merck & Co., Inc. | Integrin receptor antagonists |
| JP3585839B2 (ja) | 1997-12-17 | 2004-11-04 | メルク エンド カムパニー インコーポレーテッド | インテグリン受容体拮抗薬 |
| AU749351B2 (en) | 1999-06-02 | 2002-06-27 | Merck & Co., Inc. | Alpha V integrin receptor antagonists |
| CA2376077A1 (en) | 1999-06-23 | 2000-12-28 | Merck & Co., Inc. | Integrin receptor antagonists |
| JP2003510360A (ja) * | 1999-10-04 | 2003-03-18 | メルク エンド カムパニー インコーポレーテッド | インテグリン受容体拮抗薬 |
| WO2001034602A2 (en) | 1999-11-08 | 2001-05-17 | Merck & Co., Inc. | Process and intermediates for the preparation of imidazolidinone alpha v integrin antagonists |
| WO2001096334A2 (en) | 2000-06-15 | 2001-12-20 | Pharmacia Corporation | Heteroarylalkanoic acids as integrin receptor antagonists |
| 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 |
| JP2004517853A (ja) | 2001-01-03 | 2004-06-17 | メルク エンド カムパニー インコーポレーテッド | 歯周病の治療方法及び治療用組成物 |
| 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 |
| MXPA05006727A (es) | 2002-12-20 | 2005-09-08 | Pharmacia Corp | Acidos heteroarilalcanoicos como antagonistas de receptor de integrina. |
| US6932865B2 (en) | 2003-04-11 | 2005-08-23 | Lockheed Martin Corporation | System and method of making single-crystal structures through free-form fabrication techniques |
| PL2139882T3 (pl) | 2007-03-23 | 2014-05-30 | Amgen Inc | 3-podstawione pochodne chinoliny lub chinoksaliny i ich zastosowanie jako inhibitorów 3-kinazy fosfatydyloinozytolu (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 |
| 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 |
| WO2016134223A2 (en) | 2015-02-19 | 2016-08-25 | Scifluor Life Sciences, Inc. | Fluorinated tetrahydronaphthyridinyl nonanoic acid derivatives and uses thereof |
| US10214522B2 (en) | 2015-03-10 | 2019-02-26 | 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 |
| GB201604680D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
| GB201604681D0 (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 TW TW104131367A patent/TW201629057A/zh unknown
- 2015-09-22 UY UY0001036315A patent/UY36315A/es not_active Application Discontinuation
- 2015-09-22 KR KR1020177007734A patent/KR20170063590A/ko not_active Withdrawn
- 2015-09-22 WO PCT/EP2015/071777 patent/WO2016046226A1/en not_active Ceased
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- 2015-09-22 US US15/514,407 patent/US10000489B2/en not_active Expired - Fee Related
- 2015-09-22 RU RU2017114346A patent/RU2017114346A/ru unknown
- 2015-09-22 AU AU2015320859A patent/AU2015320859A1/en not_active Abandoned
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| GB201417011D0 (en) | 2014-11-12 |
| ES2704525T3 (es) | 2019-03-18 |
| RU2017114346A (ru) | 2018-11-02 |
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| US20170298063A1 (en) | 2017-10-19 |
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| WO2016046226A1 (en) | 2016-03-31 |
| EP3197893A1 (en) | 2017-08-02 |
| CN107074849A (zh) | 2017-08-18 |
| JP2017528503A (ja) | 2017-09-28 |
| AU2015320859A1 (en) | 2017-03-09 |
| AR101995A1 (es) | 2017-01-25 |
| JP6665169B2 (ja) | 2020-03-13 |
| UY36315A (es) | 2016-04-29 |
| EP3197893B1 (en) | 2018-10-24 |
| BR112017006253A2 (pt) | 2017-12-12 |
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