JP2021531234A - ヒトインテグリンα4β7のアンタゴニスト - Google Patents
ヒトインテグリンα4β7のアンタゴニスト Download PDFInfo
- Publication number
- JP2021531234A JP2021531234A JP2020555323A JP2020555323A JP2021531234A JP 2021531234 A JP2021531234 A JP 2021531234A JP 2020555323 A JP2020555323 A JP 2020555323A JP 2020555323 A JP2020555323 A JP 2020555323A JP 2021531234 A JP2021531234 A JP 2021531234A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- compound
- mmol
- compound according
- propanoate
- 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.)
- Granted
Links
- 239000005557 antagonist Substances 0.000 title abstract 2
- 108010043603 integrin alpha4beta7 Proteins 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 25
- -1 alkylene-cycloalkyl Chemical group 0.000 claims description 540
- 150000001875 compounds Chemical class 0.000 claims description 502
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 142
- 125000000217 alkyl group Chemical group 0.000 claims description 75
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 74
- 125000000623 heterocyclic group Chemical group 0.000 claims description 73
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- 210000004072 lung Anatomy 0.000 claims description 8
- 208000003167 cholangitis Diseases 0.000 claims description 7
- 208000037976 chronic inflammation Diseases 0.000 claims description 7
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 206010064212 Eosinophilic oesophagitis Diseases 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 6
- 208000005577 Gastroenteritis Diseases 0.000 claims description 6
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 6
- 201000000708 eosinophilic esophagitis Diseases 0.000 claims description 6
- 230000004761 fibrosis Effects 0.000 claims description 6
- 206010009887 colitis Diseases 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
- 206010009137 Chronic sinusitis Diseases 0.000 claims description 4
- 208000015943 Coeliac disease Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 230000003872 anastomosis Effects 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 208000007451 chronic bronchitis Diseases 0.000 claims description 4
- 208000027157 chronic rhinosinusitis Diseases 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 208000004396 mastitis Diseases 0.000 claims description 3
- 206010006262 Breast inflammation Diseases 0.000 claims description 2
- 208000027932 Collagen disease Diseases 0.000 claims description 2
- 208000002389 Pouchitis Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 208000008609 collagenous colitis Diseases 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 201000003146 cystitis Diseases 0.000 claims description 2
- 208000037902 enteropathy Diseases 0.000 claims description 2
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 claims description 2
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 claims description 2
- 235000019000 fluorine Nutrition 0.000 claims description 2
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 claims description 2
- 208000009326 ileitis Diseases 0.000 claims description 2
- 208000028774 intestinal disease Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 208000008275 microscopic colitis Diseases 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 238000010880 proctocolectomy Methods 0.000 claims description 2
- 201000000306 sarcoidosis Diseases 0.000 claims description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims 1
- 102000006495 integrins Human genes 0.000 abstract description 14
- 108010044426 integrins Proteins 0.000 abstract description 14
- 238000010586 diagram Methods 0.000 abstract 1
- 150000003384 small molecules Chemical class 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 411
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 377
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 312
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 262
- 239000000243 solution Substances 0.000 description 260
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 190
- 235000019439 ethyl acetate Nutrition 0.000 description 186
- 239000000047 product Substances 0.000 description 183
- 239000007787 solid Substances 0.000 description 163
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 131
- 239000002904 solvent Substances 0.000 description 124
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 121
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 113
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 110
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 107
- 239000003208 petroleum Substances 0.000 description 106
- 239000000706 filtrate Substances 0.000 description 101
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 98
- 239000012043 crude product Substances 0.000 description 97
- 238000005481 NMR spectroscopy Methods 0.000 description 96
- 239000000741 silica gel Substances 0.000 description 92
- 229910002027 silica gel Inorganic materials 0.000 description 92
- 239000003921 oil Substances 0.000 description 88
- 235000019198 oils Nutrition 0.000 description 88
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 83
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 82
- 239000011734 sodium Substances 0.000 description 78
- 238000002953 preparative HPLC Methods 0.000 description 77
- 238000002360 preparation method Methods 0.000 description 71
- 235000019260 propionic acid Nutrition 0.000 description 69
- 239000012230 colorless oil Substances 0.000 description 67
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 66
- 239000012044 organic layer Substances 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 56
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 53
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 53
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 42
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 36
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 25
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- 239000012071 phase Substances 0.000 description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 22
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
- 239000001257 hydrogen Substances 0.000 description 21
- 239000012299 nitrogen atmosphere Substances 0.000 description 20
- 238000004007 reversed phase HPLC Methods 0.000 description 20
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 19
- 229910000175 cerite Inorganic materials 0.000 description 19
- 238000003818 flash chromatography Methods 0.000 description 19
- 239000012267 brine Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 101150003085 Pdcl gene Proteins 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 14
- 150000002431 hydrogen Chemical class 0.000 description 14
- 238000012746 preparative thin layer chromatography Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- HMQMLTJHWDXRGZ-JTQLQIEISA-N (2S)-4-methyl-2-(4-methyl-2-oxopyridin-1-yl)pentanoic acid Chemical compound CC(C)C[C@H](N1C=CC(C)=CC1=O)C(O)=O HMQMLTJHWDXRGZ-JTQLQIEISA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 150000002632 lipids Chemical class 0.000 description 11
- 239000011777 magnesium Substances 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 11
- 241000209094 Oryza Species 0.000 description 10
- 235000007164 Oryza sativa Nutrition 0.000 description 10
- 235000009566 rice Nutrition 0.000 description 10
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 9
- 239000007821 HATU Substances 0.000 description 9
- FDBHAXKSSQPQMA-UHFFFAOYSA-N 3-amino-3-(5-bromopyridin-3-yl)propanoic acid Chemical compound OC(=O)CC(N)C1=CN=CC(Br)=C1 FDBHAXKSSQPQMA-UHFFFAOYSA-N 0.000 description 8
- YBDRFJXGJQULGH-UHFFFAOYSA-N 4-methyl-1h-pyridin-2-one Chemical compound CC1=CC=NC(O)=C1 YBDRFJXGJQULGH-UHFFFAOYSA-N 0.000 description 8
- 235000019502 Orange oil Nutrition 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 239000010502 orange oil Substances 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
- NNFDHJQLIFECSR-RXMQYKEDSA-N (2r)-2-bromo-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](Br)C(O)=O NNFDHJQLIFECSR-RXMQYKEDSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- NSJVYHOPHZMZPN-UHFFFAOYSA-N (2-methylphenyl)boronic acid Chemical compound CC1=CC=CC=C1B(O)O NSJVYHOPHZMZPN-UHFFFAOYSA-N 0.000 description 6
- VNVJUGIJJQSFIL-UHFFFAOYSA-N 3-(2,6-dimethylphenyl)pyridine Chemical compound CC1=CC=CC(C)=C1C1=CC=CN=C1 VNVJUGIJJQSFIL-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- VLDDKMRFFJQNTH-UHFFFAOYSA-N ethyl 2-iodo-4-methylpentanoate Chemical compound CCOC(=O)C(I)CC(C)C VLDDKMRFFJQNTH-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- ASWDQFLIXWPHMG-UHFFFAOYSA-N methyl 3-amino-3-(5-bromopyridin-3-yl)propanoate Chemical compound COC(=O)CC(N)C1=CN=CC(Br)=C1 ASWDQFLIXWPHMG-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 description 5
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical group CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- ONOYOAKWLSVXIA-UHFFFAOYSA-N ethyl 4-methyl-2-methylsulfonyloxypentanoate Chemical compound CCOC(=O)C(CC(C)C)OS(C)(=O)=O ONOYOAKWLSVXIA-UHFFFAOYSA-N 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- BAKAIPQSPNNZBV-HNNXBMFYSA-N methyl (3S)-3-amino-3-[5-(2,6-dimethylphenyl)pyridin-3-yl]propanoate Chemical compound N[C@@H](CC(=O)OC)C=1C=NC=C(C=1)C1=C(C=CC=C1C)C BAKAIPQSPNNZBV-HNNXBMFYSA-N 0.000 description 5
- IBEMQPCVVSSDDK-UHFFFAOYSA-N methyl 3-(5-bromopyridin-3-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound BrC=1C=C(C=NC=1)C(CC(=O)OC)NC(=O)OC(C)(C)C IBEMQPCVVSSDDK-UHFFFAOYSA-N 0.000 description 5
- BAKAIPQSPNNZBV-UHFFFAOYSA-N methyl 3-amino-3-[5-(2,6-dimethylphenyl)pyridin-3-yl]propanoate Chemical compound NC(CC(=O)OC)C=1C=NC=C(C=1)C1=C(C=CC=C1C)C BAKAIPQSPNNZBV-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 150000002894 organic compounds Chemical class 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- RUKHEOCYZLWSQX-UHFFFAOYSA-N 2-bromo-4,4,4-trifluorobutanoic acid Chemical compound OC(=O)C(Br)CC(F)(F)F RUKHEOCYZLWSQX-UHFFFAOYSA-N 0.000 description 4
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- LXGQHDUCNDGTDB-PAMNCVQHSA-N [2-[(8s,9r,10s,13s,14s,16s,17r)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate;[2-[(8s,9r,10s,13s,14s,16s,17r)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11, Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)CC2O.C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)CC2O LXGQHDUCNDGTDB-PAMNCVQHSA-N 0.000 description 4
- FGWUBRSSTMXPQD-NSHDSACASA-N [5-[(1S)-3-methoxy-1-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]pyridin-3-yl]boronic acid Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CC(=O)OC)C=1C=C(C=NC=1)B(O)O FGWUBRSSTMXPQD-NSHDSACASA-N 0.000 description 4
- 125000002015 acyclic group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- NNWUEBIEOFQMSS-UHFFFAOYSA-N (+)-(S)-2-methylpiperidine Natural products CC1CCCCN1 NNWUEBIEOFQMSS-UHFFFAOYSA-N 0.000 description 3
- ZXDTWWZIHJEZOG-UHFFFAOYSA-N (2,6-dimethylphenyl)boronic acid Chemical compound CC1=CC=CC(C)=C1B(O)O ZXDTWWZIHJEZOG-UHFFFAOYSA-N 0.000 description 3
- QPUATBDOZGZNNK-VIFPVBQESA-N (2S)-4-methyl-2-(2-oxopyridin-1-yl)pentanoic acid Chemical compound CC(C)C[C@H](N1C=CC=CC1=O)C(O)=O QPUATBDOZGZNNK-VIFPVBQESA-N 0.000 description 3
- NHZXOLWTNRHMNV-LBPRGKRZSA-N (2S)-4-methyl-2-(4-oxoquinazolin-3-yl)pentanoic acid Chemical compound CC(C[C@@H](C(=O)O)N1C=NC2=CC=CC=C2C1=O)C NHZXOLWTNRHMNV-LBPRGKRZSA-N 0.000 description 3
- GQZXYZIKUQUVKE-RFZPGFLSSA-N (2r,3r)-2-bromo-3-methylpentanoic acid Chemical compound CC[C@@H](C)[C@@H](Br)C(O)=O GQZXYZIKUQUVKE-RFZPGFLSSA-N 0.000 description 3
- GQZXYZIKUQUVKE-CRCLSJGQSA-N (2r,3s)-2-bromo-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@@H](Br)C(O)=O GQZXYZIKUQUVKE-CRCLSJGQSA-N 0.000 description 3
- GNTWJIXJCKRFJD-UHFFFAOYSA-N (4-fluoro-2,6-dimethylphenyl)boronic acid Chemical compound CC1=CC(F)=CC(C)=C1B(O)O GNTWJIXJCKRFJD-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 3
- ZPXCHEDAXFJYBZ-UHFFFAOYSA-N 2-bromo-1-methoxy-3-methylbenzene Chemical compound COC1=CC=CC(C)=C1Br ZPXCHEDAXFJYBZ-UHFFFAOYSA-N 0.000 description 3
- BPTDELCFYVYBRF-UHFFFAOYSA-N 2-bromo-3-cyclopropylpropanoic acid Chemical compound OC(=O)C(Br)CC1CC1 BPTDELCFYVYBRF-UHFFFAOYSA-N 0.000 description 3
- UTYYRLJAFLKUTL-UHFFFAOYSA-N 2-bromo-4-formylbenzonitrile Chemical compound BrC1=CC(C=O)=CC=C1C#N UTYYRLJAFLKUTL-UHFFFAOYSA-N 0.000 description 3
- XPJHOLSAXDMFTQ-UHFFFAOYSA-N 3-amino-3-(3-cyclobutyloxyphenyl)propanoic acid Chemical compound OC(=O)CC(N)C1=CC=CC(OC2CCC2)=C1 XPJHOLSAXDMFTQ-UHFFFAOYSA-N 0.000 description 3
- XULUNJJUXGJVIK-UHFFFAOYSA-N 3-amino-3-[4-cyano-3-(2-methylphenyl)phenyl]propanoic acid Chemical compound NC(CC(=O)O)C=1C=C(C(=CC=1)C#N)C1=C(C=CC=C1)C XULUNJJUXGJVIK-UHFFFAOYSA-N 0.000 description 3
- ATHGPVILYZYOBL-UHFFFAOYSA-N 3-amino-3-[4-cyclopropyl-3-(2-methylphenyl)phenyl]propanoic acid Chemical compound NC(CC(=O)O)C=1C=C(C(=CC=1)C1CC1)C1=C(C=CC=C1)C ATHGPVILYZYOBL-UHFFFAOYSA-N 0.000 description 3
- JUCSOBCVGZPJLT-UHFFFAOYSA-N 3-amino-3-[4-methoxy-3-(2-methylphenyl)phenyl]propanoic acid Chemical compound NC(CC(=O)O)C=1C=C(C(=CC=1)OC)C1=C(C=CC=C1)C JUCSOBCVGZPJLT-UHFFFAOYSA-N 0.000 description 3
- IKHLLNMSMFVTLP-UHFFFAOYSA-N 4-(trifluoromethyl)-1h-pyridin-2-one Chemical compound OC1=CC(C(F)(F)F)=CC=N1 IKHLLNMSMFVTLP-UHFFFAOYSA-N 0.000 description 3
- UJAROFFWJWGZPD-UHFFFAOYSA-N 4-[(dimethylamino)methyl]-1h-pyridin-2-one Chemical compound CN(C)CC1=CC=NC(O)=C1 UJAROFFWJWGZPD-UHFFFAOYSA-N 0.000 description 3
- POHQCHSXEDIZKX-UHFFFAOYSA-N 4-cyclopropyl-3-(2-methylphenyl)benzaldehyde Chemical compound C1(CC1)C1=CC=C(C=C1C1=C(C=CC=C1)C)C=O POHQCHSXEDIZKX-UHFFFAOYSA-N 0.000 description 3
- BSFRXLCFGBOOOC-UHFFFAOYSA-N 4-hydroxy-3-(2-methylphenyl)benzaldehyde Chemical compound CC1=CC=CC=C1C1=CC(C=O)=CC=C1O BSFRXLCFGBOOOC-UHFFFAOYSA-N 0.000 description 3
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 3
- NGUVGKAEOFPLDT-UHFFFAOYSA-N 5-bromopyridine-3-carbaldehyde Chemical compound BrC1=CN=CC(C=O)=C1 NGUVGKAEOFPLDT-UHFFFAOYSA-N 0.000 description 3
- BUMAFTGGYPBHHK-UHFFFAOYSA-N 6-oxo-1h-pyridine-3-carbaldehyde Chemical compound O=CC=1C=CC(=O)NC=1 BUMAFTGGYPBHHK-UHFFFAOYSA-N 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- ZRUJOJFAIXWDCE-UHFFFAOYSA-N [6-methyl-5-(2-methylphenyl)pyridin-3-yl]methanol Chemical compound CC1=C(C=C(C=N1)CO)C1=C(C=CC=C1)C ZRUJOJFAIXWDCE-UHFFFAOYSA-N 0.000 description 3
- WLHQGFDJAOXCAZ-VIFPVBQESA-N [6-methyl-5-[(3S)-3-methylmorpholin-4-yl]pyridin-3-yl]methanol Chemical compound CC1=C(C=C(C=N1)CO)N1[C@H](COCC1)C WLHQGFDJAOXCAZ-VIFPVBQESA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000012292 cell migration Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- AYYCGDYJGQKXIO-VIFPVBQESA-N methyl (3s)-3-amino-3-(3-bromophenyl)propanoate Chemical compound COC(=O)C[C@H](N)C1=CC=CC(Br)=C1 AYYCGDYJGQKXIO-VIFPVBQESA-N 0.000 description 3
- OGLVFDAJTRJFSV-UHFFFAOYSA-N methyl 3-amino-3-(3-bromo-4-methylphenyl)propanoate Chemical compound COC(=O)CC(N)c1ccc(C)c(Br)c1 OGLVFDAJTRJFSV-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 3
- SYNLANIZFUYFPJ-NSHDSACASA-N (2S)-2-(4,5-dimethyl-2-oxopyridin-1-yl)-4-methylpentanoic acid Chemical compound CC(C)C[C@H](N1C=C(C)C(C)=CC1=O)C(O)=O SYNLANIZFUYFPJ-NSHDSACASA-N 0.000 description 2
- WXBRLPRDVHDMJC-VIFPVBQESA-N (2S)-2-(4-methyl-2-oxopyridin-1-yl)pentanoic acid Chemical compound CCC[C@H](N1C=CC(C)=CC1=O)C(O)=O WXBRLPRDVHDMJC-VIFPVBQESA-N 0.000 description 2
- NIZSUIJTVCQNHJ-QMMMGPOBSA-N (2S)-4-methyl-2-(2-oxopyrazin-1-yl)pentanoic acid Chemical compound CC(C)C[C@H](N1C=CN=CC1=O)C(O)=O NIZSUIJTVCQNHJ-QMMMGPOBSA-N 0.000 description 2
- ZPJPHYOZYHODGO-VIFPVBQESA-N (2S)-4-methyl-2-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pentanoic acid Chemical compound CC(C[C@@H](C(=O)O)N1C(C=C(C=C1)C(F)(F)F)=O)C ZPJPHYOZYHODGO-VIFPVBQESA-N 0.000 description 2
- DHUMULLMWKLOKV-ONGXEEELSA-N (2S,3S)-3-methyl-2-(4-methyl-2-oxopyridin-1-yl)pentanoic acid Chemical compound CC[C@H](C)[C@H](N1C=CC(C)=CC1=O)C(O)=O DHUMULLMWKLOKV-ONGXEEELSA-N 0.000 description 2
- WMFATTFQNRPXBQ-SCSAIBSYSA-N (2r)-2-bromopentanoic acid Chemical compound CCC[C@@H](Br)C(O)=O WMFATTFQNRPXBQ-SCSAIBSYSA-N 0.000 description 2
- NNWUEBIEOFQMSS-LURJTMIESA-N (2s)-2-methylpiperidine Chemical compound C[C@H]1CCCCN1 NNWUEBIEOFQMSS-LURJTMIESA-N 0.000 description 2
- SFWWGMKXCYLZEG-YFKPBYRVSA-N (3s)-3-methylmorpholine Chemical compound C[C@H]1COCCN1 SFWWGMKXCYLZEG-YFKPBYRVSA-N 0.000 description 2
- HUZVSMBFTZNSPZ-MYWXAZLQSA-N (NE,R)-N-[(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide Chemical compound BrC1=NC=CC(=C1)\C=N\[S@](=O)C(C)(C)C HUZVSMBFTZNSPZ-MYWXAZLQSA-N 0.000 description 2
- XFDFDHCZSFEWRM-UHFFFAOYSA-N 2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanoic acid Chemical compound CC1(CCC(N(C1)C(C(=O)O)CC(C)C)=O)C XFDFDHCZSFEWRM-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JSXQDWGFTJCHHU-UHFFFAOYSA-N 2-[4-[(dimethylamino)methyl]-2-oxopyridin-1-yl]-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=CC(CN(C)C)=CC1=O)C(O)=O JSXQDWGFTJCHHU-UHFFFAOYSA-N 0.000 description 2
- ICCGOGITRBERQT-UHFFFAOYSA-N 2-[5-[(dimethylamino)methyl]-2-oxopyridin-1-yl]-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=C(CN(C)C)C=CC1=O)C(O)=O ICCGOGITRBERQT-UHFFFAOYSA-N 0.000 description 2
- NPVOAXNSRAKBBZ-KWCCSABGSA-N 2-[5-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]-2-oxopyridin-1-yl]-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=C(CN2CC[C@@H](F)C2)C=CC1=O)C(O)=O NPVOAXNSRAKBBZ-KWCCSABGSA-N 0.000 description 2
- RTWLIQFKXMWEJY-UHFFFAOYSA-N 2-bromopyridine-4-carbaldehyde Chemical compound BrC1=CC(C=O)=CC=N1 RTWLIQFKXMWEJY-UHFFFAOYSA-N 0.000 description 2
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 description 2
- REEFQHKNPLZFMZ-UHFFFAOYSA-N 3-(3-cyclobutyloxyphenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound C(C)(C)(C)OC(=O)NC(CC(=O)O)C1=CC(=CC=C1)OC1CCC1 REEFQHKNPLZFMZ-UHFFFAOYSA-N 0.000 description 2
- ZQVMOUBPZOTBLD-UHFFFAOYSA-N 3-(5-bromopyridin-3-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(CC(O)=O)C1=CN=CC(Br)=C1 ZQVMOUBPZOTBLD-UHFFFAOYSA-N 0.000 description 2
- HQORXMYDHTZZID-UHFFFAOYSA-N 3-amino-3-(3-bromo-4-methylphenyl)propanoic acid Chemical compound CC1=CC=C(C(N)CC(O)=O)C=C1Br HQORXMYDHTZZID-UHFFFAOYSA-N 0.000 description 2
- SNKDBJNZSTXOSR-UHFFFAOYSA-N 3-amino-3-(3-tert-butylphenyl)propanoic acid Chemical compound NC(CC(=O)O)C1=CC(=CC=C1)C(C)(C)C SNKDBJNZSTXOSR-UHFFFAOYSA-N 0.000 description 2
- HZFKWSBFNQKERT-UHFFFAOYSA-N 3-amino-3-[6-methyl-5-(2-methylphenyl)pyridin-3-yl]propanoic acid Chemical compound NC(CC(=O)O)C=1C=NC(=C(C=1)C1=C(C=CC=C1)C)C HZFKWSBFNQKERT-UHFFFAOYSA-N 0.000 description 2
- DOHHGYXZPWMNKT-UHFFFAOYSA-N 3-azaniumyl-3-(3-phenoxyphenyl)propanoate Chemical compound [O-]C(=O)CC([NH3+])C1=CC=CC(OC=2C=CC=CC=2)=C1 DOHHGYXZPWMNKT-UHFFFAOYSA-N 0.000 description 2
- UOTMHAOCAJROQF-UHFFFAOYSA-N 3-bromo-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1Br UOTMHAOCAJROQF-UHFFFAOYSA-N 0.000 description 2
- HRACUCMBNAHOJO-UHFFFAOYSA-N 3-cyclobutyloxybenzaldehyde Chemical compound O=CC1=CC=CC(OC2CCC2)=C1 HRACUCMBNAHOJO-UHFFFAOYSA-N 0.000 description 2
- UPGOSSRACUWPOQ-UHFFFAOYSA-N 3-methoxy-2-(4-methyl-2-oxopyridin-1-yl)propanoic acid Chemical compound COCC(N1C=CC(C)=CC1=O)C(O)=O UPGOSSRACUWPOQ-UHFFFAOYSA-N 0.000 description 2
- YRLFXLAHSCLCGF-UHFFFAOYSA-N 3-methyl-2-(4-methyl-2-oxopyridin-1-yl)butanoic acid Chemical compound CC(C)C(C(O)=O)N1C=CC(C)=CC1=O YRLFXLAHSCLCGF-UHFFFAOYSA-N 0.000 description 2
- AZLXKTGBKZWNGA-UHFFFAOYSA-N 4,4,4-trifluoro-2-(2-oxopyridin-1-yl)butanoic acid Chemical compound OC(=O)C(CC(F)(F)F)N1C=CC=CC1=O AZLXKTGBKZWNGA-UHFFFAOYSA-N 0.000 description 2
- FLKBNILXXMIRFX-UHFFFAOYSA-N 4,5-dimethyl-1h-pyridin-2-one Chemical compound CC1=CNC(=O)C=C1C FLKBNILXXMIRFX-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- GHHWRQWLHFZCIB-UHFFFAOYSA-N 4-formyl-2-(2-methylphenyl)benzonitrile Chemical compound CC1=CC=CC=C1C1=CC(C=O)=CC=C1C#N GHHWRQWLHFZCIB-UHFFFAOYSA-N 0.000 description 2
- IIPZTFBGQFWCID-UHFFFAOYSA-N 4-methoxy-3-(2-methylphenyl)benzaldehyde Chemical compound COC1=CC=C(C=O)C=C1C1=CC=CC=C1C IIPZTFBGQFWCID-UHFFFAOYSA-N 0.000 description 2
- FBKXGYIYIKDCSB-UHFFFAOYSA-N 4-methyl-2-(3-oxo-1h-isoindol-2-yl)pentanoic acid Chemical compound C1=CC=C2C(=O)N(C(CC(C)C)C(O)=O)CC2=C1 FBKXGYIYIKDCSB-UHFFFAOYSA-N 0.000 description 2
- BOXKVZTZXZQWII-UHFFFAOYSA-N 5-[(3,3-difluoroazetidin-1-yl)methyl]-1H-pyridin-2-one Chemical compound FC1(CN(C1)CC=1C=CC(NC=1)=O)F BOXKVZTZXZQWII-UHFFFAOYSA-N 0.000 description 2
- UMMSHHUYOHBQNU-UHFFFAOYSA-N 5-[(dimethylamino)methyl]-1h-pyridin-2-one Chemical compound CN(C)CC1=CC=C(O)N=C1 UMMSHHUYOHBQNU-UHFFFAOYSA-N 0.000 description 2
- MWOKAOUMDPBQHI-UHFFFAOYSA-N 5-[2-(azetidin-1-yl)ethyl]-1H-pyridin-2-one Chemical compound N1(CCC1)CCC=1C=CC(NC=1)=O MWOKAOUMDPBQHI-UHFFFAOYSA-N 0.000 description 2
- SOHMZGMHXUQHGE-UHFFFAOYSA-N 5-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(O)N=C1 SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 description 2
- UFYDFUJHDFDSHS-VIFPVBQESA-N 6-methyl-5-[(3S)-3-methylmorpholin-4-yl]pyridine-3-carbaldehyde Chemical compound CC1=NC=C(C=O)C=C1N1[C@H](COCC1)C UFYDFUJHDFDSHS-VIFPVBQESA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- RKBIJQNLTJFSDP-UHFFFAOYSA-N ethyl 2-[4-(2-aminoethyl)-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=CC(CCN)=CC1=O RKBIJQNLTJFSDP-UHFFFAOYSA-N 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910001867 inorganic solvent Inorganic materials 0.000 description 2
- 239000003049 inorganic solvent Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- AOSWEDIDPYRZRA-UHFFFAOYSA-N methyl 5-bromo-6-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(C)C(Br)=C1 AOSWEDIDPYRZRA-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- YYFIGOPUHPDIBO-UHFFFAOYSA-N propanoic acid;hydrochloride Chemical compound Cl.CCC(O)=O YYFIGOPUHPDIBO-UHFFFAOYSA-N 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- DBZAICSEFBVFHL-UHFFFAOYSA-N (2,6-difluorophenyl)boronic acid Chemical compound OB(O)C1=C(F)C=CC=C1F DBZAICSEFBVFHL-UHFFFAOYSA-N 0.000 description 1
- NPLZNDDFVCGRAG-UHFFFAOYSA-N (2-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C#N NPLZNDDFVCGRAG-UHFFFAOYSA-N 0.000 description 1
- XOVMDVZAWWQSDC-UHFFFAOYSA-N (2-fluoro-6-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(F)=C1B(O)O XOVMDVZAWWQSDC-UHFFFAOYSA-N 0.000 description 1
- DHUMULLMWKLOKV-KOLCDFICSA-N (2S,3R)-3-methyl-2-(4-methyl-2-oxopyridin-1-yl)pentanoic acid Chemical compound CC[C@@H](C)[C@H](N1C=CC(C)=CC1=O)C(O)=O DHUMULLMWKLOKV-KOLCDFICSA-N 0.000 description 1
- LGAJYTCRJPCZRJ-RXMQYKEDSA-N (2r)-2-bromopentane Chemical compound CCC[C@@H](C)Br LGAJYTCRJPCZRJ-RXMQYKEDSA-N 0.000 description 1
- LENYOXXELREKGZ-PGMHMLKASA-N (3r)-3-fluoropyrrolidine;hydrochloride Chemical compound Cl.F[C@@H]1CCNC1 LENYOXXELREKGZ-PGMHMLKASA-N 0.000 description 1
- HUZVSMBFTZNSPZ-COSNYCCFSA-N (NE,S)-N-[(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide Chemical compound BrC1=NC=CC(=C1)\C=N\[S@@](=O)C(C)(C)C HUZVSMBFTZNSPZ-COSNYCCFSA-N 0.000 description 1
- LVRFTAZAXQPQHI-RXMQYKEDSA-N (R)-2-hydroxy-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](O)C(O)=O LVRFTAZAXQPQHI-RXMQYKEDSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- BBYWOYAFBUOUFP-JOCHJYFZSA-N 1-stearoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OCCN BBYWOYAFBUOUFP-JOCHJYFZSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 description 1
- UFLFSJVTFSZTKX-UHFFFAOYSA-N 2,2-dimethylmorpholine Chemical compound CC1(C)CNCCO1 UFLFSJVTFSZTKX-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- ULCXUINXWBDFBU-UHFFFAOYSA-N 2-(5-fluoro-4-methyl-2-oxopyridin-1-yl)-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=C(F)C(C)=CC1=O)C(O)=O ULCXUINXWBDFBU-UHFFFAOYSA-N 0.000 description 1
- AXXPIFNHLXRSKW-UHFFFAOYSA-N 2-(6-oxo-1H-pyridin-3-yl)propanal Chemical compound CC(C=O)C1=CNC(C=C1)=O AXXPIFNHLXRSKW-UHFFFAOYSA-N 0.000 description 1
- LTHJLBMECJFTON-UHFFFAOYSA-N 2-(6-oxo-1h-pyridin-3-yl)acetaldehyde Chemical compound O=CCC=1C=CC(=O)NC=1 LTHJLBMECJFTON-UHFFFAOYSA-N 0.000 description 1
- ZBTUTYMFICPYPW-UHFFFAOYSA-N 2-[4-[2-(dimethylamino)ethyl]-2-oxopyridin-1-yl]-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=CC(CCN(C)C)=CC1=O)C(O)=O ZBTUTYMFICPYPW-UHFFFAOYSA-N 0.000 description 1
- XYNYBKOIPCIBOG-UHFFFAOYSA-N 2-[5-[(3,3-difluoroazetidin-1-yl)methyl]-2-oxopyridin-1-yl]-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=C(CN2CC(F)(F)C2)C=CC1=O)C(O)=O XYNYBKOIPCIBOG-UHFFFAOYSA-N 0.000 description 1
- XEHUSRLLUPHKGE-UHFFFAOYSA-N 2-[5-[2-(dimethylamino)ethyl]-2-oxopyridin-1-yl]-4-methylpentanoic acid Chemical compound CC(C)CC(N1C=C(CCN(C)C)C=CC1=O)C(O)=O XEHUSRLLUPHKGE-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- XGUXJMWPVJQIHI-UHFFFAOYSA-N 2-azaniumyl-3-cyclopropylpropanoate Chemical compound OC(=O)C(N)CC1CC1 XGUXJMWPVJQIHI-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- VKLVRTHTYBBACJ-UHFFFAOYSA-N 2-bromo-1-chloro-3,4-dimethylbenzene Chemical compound CC1=CC=C(Cl)C(Br)=C1C VKLVRTHTYBBACJ-UHFFFAOYSA-N 0.000 description 1
- FNIBRUOFKCBDGB-UHFFFAOYSA-N 2-bromo-2-phenylpropanoic acid Chemical compound OC(=O)C(Br)(C)C1=CC=CC=C1 FNIBRUOFKCBDGB-UHFFFAOYSA-N 0.000 description 1
- HUGNLEZLTOVJLD-UHFFFAOYSA-N 2-bromo-3-methylphenol Chemical compound CC1=CC=CC(O)=C1Br HUGNLEZLTOVJLD-UHFFFAOYSA-N 0.000 description 1
- YAQLSKVCTLCIIE-UHFFFAOYSA-N 2-bromobutyric acid Chemical compound CCC(Br)C(O)=O YAQLSKVCTLCIIE-UHFFFAOYSA-N 0.000 description 1
- LVRFTAZAXQPQHI-UHFFFAOYSA-M 2-hydroxy-4-methylvalerate Chemical compound CC(C)CC(O)C([O-])=O LVRFTAZAXQPQHI-UHFFFAOYSA-M 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- KPWZMXSALQACPB-UHFFFAOYSA-N 2-oxo-3h-pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC(=O)C1 KPWZMXSALQACPB-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- CDBAEFXTCRKJPZ-UHFFFAOYSA-N 3,3-difluoroazetidine;hydron;chloride Chemical compound Cl.FC1(F)CNC1 CDBAEFXTCRKJPZ-UHFFFAOYSA-N 0.000 description 1
- YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 description 1
- YVPNYPQBNGOMCO-UHFFFAOYSA-N 3-(2-methoxyethenyl)pyridine Chemical compound COC=CC1=CC=CN=C1 YVPNYPQBNGOMCO-UHFFFAOYSA-N 0.000 description 1
- NJEQTWBJPJNKRT-QHGLUPRGSA-N 3-amino-3-[6-methyl-5-[(3S)-3-methylmorpholin-4-yl]pyridin-3-yl]propanoic acid Chemical compound NC(CC(=O)O)C=1C=NC(=C(C=1)N1[C@H](COCC1)C)C NJEQTWBJPJNKRT-QHGLUPRGSA-N 0.000 description 1
- YDUGVOUXNSWQSW-UHFFFAOYSA-N 3-bromo-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1Br YDUGVOUXNSWQSW-UHFFFAOYSA-N 0.000 description 1
- QMPNFQLVIGPNEI-UHFFFAOYSA-N 3-bromo-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1Br QMPNFQLVIGPNEI-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- KVPZLCXFXOTPLZ-UHFFFAOYSA-N 3-cyclopropyl-2-(2-oxopyridin-1-yl)propanoic acid Chemical compound OC(=O)C(CC1CC1)N1C=CC=CC1=O KVPZLCXFXOTPLZ-UHFFFAOYSA-N 0.000 description 1
- PXFUWRWCKSLCLS-UHFFFAOYSA-N 3-fluoroazetidine;hydron;chloride Chemical compound Cl.FC1CNC1 PXFUWRWCKSLCLS-UHFFFAOYSA-N 0.000 description 1
- MRLGCTNJRREZHZ-UHFFFAOYSA-N 3-phenoxybenzaldehyde Chemical compound O=CC1=CC=CC(OC=2C=CC=CC=2)=C1 MRLGCTNJRREZHZ-UHFFFAOYSA-N 0.000 description 1
- HKEQMVXZDQLSDY-UHFFFAOYSA-N 3-tert-butylbenzaldehyde Chemical compound CC(C)(C)C1=CC=CC(C=O)=C1 HKEQMVXZDQLSDY-UHFFFAOYSA-N 0.000 description 1
- RISOHYOEPYWKOB-UHFFFAOYSA-N 4-bromo-3,5-dimethyl-1h-pyrazole Chemical compound CC1=NNC(C)=C1Br RISOHYOEPYWKOB-UHFFFAOYSA-N 0.000 description 1
- HYZVAVYBDNKXDG-UHFFFAOYSA-N 4-bromo-3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1Br HYZVAVYBDNKXDG-UHFFFAOYSA-N 0.000 description 1
- MOOCQPRYCNJSSA-UHFFFAOYSA-N 4-methyl-2-(2-oxo-3,4-dihydroquinolin-1-yl)pentanoic acid Chemical compound CC(C)CC(N1C(=O)CCC2=C1C=CC=C2)C(O)=O MOOCQPRYCNJSSA-UHFFFAOYSA-N 0.000 description 1
- QPUATBDOZGZNNK-UHFFFAOYSA-N 4-methyl-2-(2-oxopyridin-1-yl)pentanoic acid Chemical compound CC(C)CC(C(O)=O)N1C=CC=CC1=O QPUATBDOZGZNNK-UHFFFAOYSA-N 0.000 description 1
- BFWBPJITBXTHLT-UHFFFAOYSA-N 4-methyl-2-[5-(morpholin-4-ylmethyl)-2-oxopyridin-1-yl]pentanoic acid Chemical compound CC(C)CC(N1C=C(CN2CCOCC2)C=CC1=O)C(O)=O BFWBPJITBXTHLT-UHFFFAOYSA-N 0.000 description 1
- PTSGHGGLRADEFP-UHFFFAOYSA-N 4-methylpiperidin-2-one Chemical compound CC1CCNC(=O)C1 PTSGHGGLRADEFP-UHFFFAOYSA-N 0.000 description 1
- LZDUSDGRALPEID-UHFFFAOYSA-N 5,5-dimethylpiperidin-2-one Chemical compound CC1(C)CCC(=O)NC1 LZDUSDGRALPEID-UHFFFAOYSA-N 0.000 description 1
- SIZWUJZYEYQXPN-UHFFFAOYSA-N 5-(2-methoxyethenyl)-1H-pyridin-2-one Chemical compound COC=CC=1C=CC(NC=1)=O SIZWUJZYEYQXPN-UHFFFAOYSA-N 0.000 description 1
- OUKTYJJHPALZHT-UHFFFAOYSA-N 5-(morpholin-4-ylmethyl)-1H-pyridin-2-one Chemical compound O1CCN(CC1)CC=1C=CC(=NC=1)O OUKTYJJHPALZHT-UHFFFAOYSA-N 0.000 description 1
- ASOUUUWTFMQDIS-UHFFFAOYSA-N 5-[2-(dimethylamino)ethyl]-1H-pyridin-2-one Chemical compound CN(CCC=1C=CC(NC=1)=O)C ASOUUUWTFMQDIS-UHFFFAOYSA-N 0.000 description 1
- NSRPFJGOCZUUHE-UHFFFAOYSA-N 5-methylpiperidin-2-one Chemical compound CC1CCC(=O)NC1 NSRPFJGOCZUUHE-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- VFEBXDUMVXOMJN-UHFFFAOYSA-N 6-methyl-5-(2-methylphenyl)pyridine-3-carbaldehyde Chemical compound CC1=NC=C(C=O)C=C1C1=C(C=CC=C1)C VFEBXDUMVXOMJN-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- LDWRUBXKZFSBOZ-UHFFFAOYSA-N CCC(OC1=CC=CC(C2=C(C)C=CC=C2)=C1)=O Chemical compound CCC(OC1=CC=CC(C2=C(C)C=CC=C2)=C1)=O LDWRUBXKZFSBOZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 229940123150 Chelating agent Drugs 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- SNDPXSYFESPGGJ-SCSAIBSYSA-N D-2-aminopentanoic acid Chemical compound CCC[C@@H](N)C(O)=O SNDPXSYFESPGGJ-SCSAIBSYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-Isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- AGPKZVBTJJNPAG-CRCLSJGQSA-N D-allo-isoleucine Chemical compound CC[C@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-CRCLSJGQSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229930182845 D-isoleucine Natural products 0.000 description 1
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- FVIGODVHAVLZOO-UHFFFAOYSA-N Dixanthogen Chemical compound CCOC(=S)SSC(=S)OCC FVIGODVHAVLZOO-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 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
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010056764 Eptifibatide Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 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 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- GQLSEYOOXBRDFZ-UHFFFAOYSA-N N-formylnornicotine Natural products O=CN1CCCC1C1=CC=CN=C1 GQLSEYOOXBRDFZ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000013544 Platelet disease Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- MUBGEKQUCSEECZ-UHFFFAOYSA-N [4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]boronic acid Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(B(O)O)C=C1 MUBGEKQUCSEECZ-UHFFFAOYSA-N 0.000 description 1
- XVDAJTSEMFGUGD-UHFFFAOYSA-N [4-formyl-2-(2-methylphenyl)phenyl] trifluoromethanesulfonate Chemical compound FC(S(=O)(=O)OC1=C(C=C(C=C1)C=O)C1=C(C=CC=C1)C)(F)F XVDAJTSEMFGUGD-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940000279 aggrastat Drugs 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- LVRFTAZAXQPQHI-UHFFFAOYSA-N alpha-hydroxyisocaproic acid Natural products CC(C)CC(O)C(O)=O LVRFTAZAXQPQHI-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 208000037979 autoimmune inflammatory disease Diseases 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000002511 behenyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 102000008395 cell adhesion mediator activity proteins Human genes 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CZKPOZZJODAYPZ-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CNC2=CC=CC=C12 CZKPOZZJODAYPZ-LROMGURASA-N 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- NSUKHOPQKVCFSF-UHFFFAOYSA-N ethyl 2-(3-bromo-2-oxopyridin-1-yl)-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=CC=C(Br)C1=O NSUKHOPQKVCFSF-UHFFFAOYSA-N 0.000 description 1
- BIVVIYZAJSJTPA-UHFFFAOYSA-N ethyl 2-(4-bromo-5-fluoro-2-oxopyridin-1-yl)-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=C(F)C(Br)=CC1=O BIVVIYZAJSJTPA-UHFFFAOYSA-N 0.000 description 1
- ZHNVKUUKVWLPLP-UHFFFAOYSA-N ethyl 2-[3-(2-aminoethyl)-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound NCCC=1C(N(C=CC=1)C(C(=O)OCC)CC(C)C)=O ZHNVKUUKVWLPLP-UHFFFAOYSA-N 0.000 description 1
- SZBIYLGCPKPLOE-UHFFFAOYSA-N ethyl 2-[3-[2-(dimethylamino)ethyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CN(CCC=1C(N(C=CC=1)C(C(=O)OCC)CC(C)C)=O)C SZBIYLGCPKPLOE-UHFFFAOYSA-N 0.000 description 1
- TYMOFJMNRBAWPF-UHFFFAOYSA-N ethyl 2-[4-[(dimethylamino)methyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=CC(CN(C)C)=CC1=O TYMOFJMNRBAWPF-UHFFFAOYSA-N 0.000 description 1
- VONRIPRMUCQQDQ-UHFFFAOYSA-N ethyl 2-[4-[2-(dimethylamino)ethyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=CC(CCN(C)C)=CC1=O VONRIPRMUCQQDQ-UHFFFAOYSA-N 0.000 description 1
- BJSXEXLCSIQREM-UHFFFAOYSA-N ethyl 2-[5-[(3-fluoroazetidin-1-yl)methyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=C(CN2CC(F)C2)C=CC1=O BJSXEXLCSIQREM-UHFFFAOYSA-N 0.000 description 1
- PNFUGHMKCSUVOY-UHFFFAOYSA-N ethyl 2-[5-[(dimethylamino)methyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=C(CN(C)C)C=CC1=O PNFUGHMKCSUVOY-UHFFFAOYSA-N 0.000 description 1
- KHKVXBKZZIPGIX-UHFFFAOYSA-N ethyl 2-[5-[2-(dimethylamino)ethyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=C(CCN(C)C)C=CC1=O KHKVXBKZZIPGIX-UHFFFAOYSA-N 0.000 description 1
- XHIFLJVIDVFEKS-AAFJCEBUSA-N ethyl 2-[5-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]-2-oxopyridin-1-yl]-4-methylpentanoate Chemical compound CCOC(=O)C(CC(C)C)N1C=C(CN2CC[C@@H](F)C2)C=CC1=O XHIFLJVIDVFEKS-AAFJCEBUSA-N 0.000 description 1
- WNFUWONOILPKNX-UHFFFAOYSA-N ethyl 2-bromo-3-methylbutanoate Chemical compound CCOC(=O)C(Br)C(C)C WNFUWONOILPKNX-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 210000004837 gut-associated lymphoid tissue Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002977 hyperthermial effect Effects 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940056984 integrilin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- CBEQRNSPHCCXSH-UHFFFAOYSA-N iodine monobromide Chemical compound IBr CBEQRNSPHCCXSH-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000002463 lignoceryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000005210 lymphoid organ Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- DODCBMODXGJOKD-RGMNGODLSA-N methyl (2s)-2-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(C)C DODCBMODXGJOKD-RGMNGODLSA-N 0.000 description 1
- NVBLRKGCQVZDMQ-UHFFFAOYSA-N methyl 2-bromo-3-methoxypropanoate Chemical compound COCC(Br)C(=O)OC NVBLRKGCQVZDMQ-UHFFFAOYSA-N 0.000 description 1
- WNPDQEDHQZXSOT-UHFFFAOYSA-N methyl 5-bromo-6-iodopyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(I)C(Br)=C1 WNPDQEDHQZXSOT-UHFFFAOYSA-N 0.000 description 1
- FQEUZKCLJVCGCQ-UHFFFAOYSA-N methyl 6-methyl-5-(2-methylphenyl)pyridine-3-carboxylate Chemical compound CC1=NC=C(C(=O)OC)C=C1C1=C(C=CC=C1)C FQEUZKCLJVCGCQ-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- HKKDKUMUWRTAIA-UHFFFAOYSA-N nitridooxidocarbon(.) Chemical compound [O]C#N HKKDKUMUWRTAIA-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000005064 octadecenyl group Chemical group C(=CCCCCCCCCCCCCCCCC)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940107685 reopro Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000007970 thio esters Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical group 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
Abstract
Description
本出願は、2018年4月12日に出願された米国仮特許出願第62/656,742号の優先権の利益を主張する。
R1が、H、アルキル、アルキレン−シクロアルキル、ヘテロシクリル、アルキレン−O−アルキル、アリール、ヘテロアリール、またはアルキレン−CF3であり、
R2が、ヘテロシクリルであり、
R3が、
R4が、H、または(C1−C6)−アルキルであり、
Raが、H、アルキル、シクロアルキル、CN、または−O−アルキルであり、
Rbが、H、アリール、ヘテロシクリル、−O−シクロアルキル、−O−アリール、または−O−ヘテロシクリルであり、
Rcが、H、アルキル、シクロアルキル、ヘテロシクリル、またはアルキレン−CF3であり、
Rdが、アリール、ヘテロアリール、ヘテロシクリル、−O−シクロアルキル、−O−アリール、または−O−ヘテロシクリルであり、
Reが、アリール、ヘテロアリール、またはヘテロシクリルである、
化合物、またはその薬学的に許容される塩に関する。
便宜上、本発明をさらに説明する前に、本明細書、実施例、及び添付の特許請求の範囲で使用される特定の用語をここに集める。これらの定義は、本開示の残りの部分を考慮して読まれ、当業者によって理解されるべきである。別途定義されない限り、本明細書で使用されるすべての技術用語及び科学用語は、当業者によって一般に理解されるのと同じ意味を有する。
特定の実施形態では、本発明は、式Iの化合物であって、
R1が、H、アルキル、アルキレン−シクロアルキル、ヘテロシクリル、アルキレン−O−アルキル、アリール、ヘテロアリール、またはアルキレン−CF3であり、
R2が、ヘテロシクリルであり、
R3が、
R4が、H、または(C1−C6)−アルキルであり、
Raが、H、アルキル、シクロアルキル、CN、または−O−アルキルであり、
Rbが、H、アルキル、アリール、ヘテロアリール、ヘテロシクリル、−O−シクロアルキル、−O−アリール、または−O−ヘテロシクリルであり、
Rcが、H、アルキル、シクロアルキル、ヘテロシクリル、またはアルキレン−CF3であり、
Rdが、アリール、ヘテロアリール、ヘテロシクリル、−O−シクロアルキル、−O−アリール、または−O−ヘテロシクリルであり、及び
Reが、アリール、ヘテロアリール、またはヘテロシクリルである、
化合物、またはその薬学的に許容される塩に関する。
特定の実施形態では、本発明は、前述の化合物のうちのいずれか1つ及び薬学的に許容される担体を含む薬学的組成物に関する。
特定の実施形態では、本発明は、炎症性腸疾患、回腸肛門吻合、好酸球性食道炎、膵炎、インスリン依存型糖尿病、乳房炎、胆嚢炎、胆管炎、胆管周囲炎、慢性気管支炎、慢性副鼻腔炎、喘息、移植片対宿主病、肺の慢性炎症性疾患、HIV、及び血液腫瘍からなる群から選択される、疾患または状態を治療する方法であって、それを必要とする対象に、治療有効量の前述の化合物のうちのいずれか1つを投与するステップを含む、方法に関する。
一般的な手順
鈴木カップリング
LCMS分析法
最終化合物を、214nm及び254nmでモニタリングするUV検出器、及びESI+イオン化モードで110〜800amuをスキャンする質量分析を用いてLC/MS条件を使用して分析した。
LC/MS C:カラム:XBridge C18、4.6×50mm、3.5μm、移動相:A 水(10mM炭酸水素アンモニウム)、B CH3CN、勾配:5%〜95%Bで1.5分、その後1.5分保持、流速:1.8mL/分、オーブン温度50℃。
粗試料をMeOHに溶解し、検出波長214nmで、Gilson 215機器を使用して分取HPLCで精製した。
ラセミ及び/またはジアステレオマー生成物を、検出波長214nmで、SFC−80(Thar、Waters)機器を使用して分取キラルSFCにより、個々のエナンチオマーに分離した。
移動相:CO2/メタノール(0.2%メタノールアンモニア)=60/40、流量:80g/分、背圧:100バール。
移動相:CO2/メタノール(0.2%メタノールアンモニア)=60/40、流量:80g/分、背圧:100バール。
移動相:CO2/メタノール(0.2%メタノールアンモニア)=60/40、流量:80g/分、背圧:100バール。
移動相:CO2/メタノール(0.2%メタノールアンモニア)=60/40、流量:80g/分、背圧:100バール。
キラル生成物を、検出波長214nmで、SFC−80(Thar、Waters)機器を使用してキラルSFCで分析した。
移動相:CO2/メタノール(0.2%メタノールアンモニア)、テキストの定組成溶離、流量:4g/分、背圧:120バール。
移動相:CO2/メタノール(0.2%メタノールアンモニア)、テキストの定組成溶離、流量:4g/分、背圧:120バール。
(R)−2−ブロモ−4−メチルペンタン酸
ステップ1:メチル2−(5−メチル−2−オキソピリジン−1(2H)−イル)−2−フェニル酢酸
化合物A21H NMR δ 5.58(d、J=4.0Hz、1H)、8.49(d、J=4.0Hz、1H)、7.79(d、J=4.0Hz、1H)、5.70(s、1H)、5.11(s、1H)、3.66(s、3H)、2.87(d、J=8.0Hz、2H)、1.43(s、9H)。
ステップ1:(S)−メチル3−アミノ−3−(3−ブロモフェニル)プロパノエート
((3S)−3−(3’,5’−ジメチル−[3,4’−ビピリジン]−5−イル)−3−(4−メチル−2−(4−メチル−2−オキソピリジン−1(2H)−イル)ペンタナミド)プロパン酸(化合物1−D1及び化合物1−D2)の調整
化合物C2LC/MS B:100%純度、UV=214nm、Rt=1.98分、ESI530(M+H)+。1H−NMR(500MHz、MeOD)δ 8.55(d、J=2.0Hz、1H)、8.17(d、J=1.8Hz、1H)、7.95(d、J=7.3Hz、1H)、7.59(s、1H)、7.19(t、J=7.5Hz、1H)、7.16−7.12(m、2H)、6.71(s、1H)、6.53(dd、J=7.3、2.0Hz、1H)、5.72(dd、J=9.2、6.9Hz、1H)、5.41(t、J=7.0Hz、1H)、2.85(t、J=15.6Hz、2H)、2.04−1.92(m、5H)、1.85(s、3H)、1.55−1.42(m、1H)、0.98−0.86(m、6H)。キラルSFC A(15%MeOH):ee 98%、Rt=3.59分
ステップ1:(3S)−メチル3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)−3−(4−メチル−2−(2−オキソ−4−(トリフルオロメチル)ピリジン−1(2H)−イル)ペンタアミド)プロパノエート
ステップ1:(3S)−メチル3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)−3−((2S)−4−メチル−2−(2−オキソ−4−(トリフルオロメチル)ピペリジン−1−イル)ペンタアミド)プロパノエート
ステップ1:(3S)−メチル3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)−3−(2−(5−メチル−2−オキソピリジン−1(2H)−イル)−2−フェニルアセトアミド)プロパノエート
ステップ1:(3S)−3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)−3−((2S)−2−(5−メチル−2−オキソピペリジン−1−イル)−2−フェニルアセトアミド)プロパン酸
ステップ1:メチル3−(2’,6’−ジメチルビフェニル−3−イル)−3−(3−メトキシ−2−(4−メチル−2−オキソピリジン−1(2H)−イル)プロパンアミド)プロパノエート
ステップ1:(S)−メチル3−((S)−4−メチル−2−(4−オキソキナゾリン−3(4H)−イル)ペンタアミド)−3−(2’−メチルビフェニル−3−イル)プロパノエート
ステップ1:(S)−メチル3−((R)−2−ヒドロキシ−4−メチルペンタアミド)−3−(2’−メチルビフェニル−3−イル)プロパノエート
化合物J1b:(100%純度、UV=254nm、ESI461.1(M+H)+)。
ステップ4:化合物J1
ステップ1:(S)−メチル3−(2’,6’−ジフルオロビフェニル−3−イル)−3−((S)−4−メチル−2−(4−オキソキナゾリン−3(4H)−イル)ペンタアミド)プロパノエート
ステップ1:(S)−メチル3−(3−ブロモフェニル)−3−((S)−4−メチル−2−(4−オキソキナゾリン−3(4H)−イル)ペンタアミド)プロパノエート
ステップ1:(S)−メチル3−(2’−フルオロ−6’−メトキシビフェニル−3−イル)−3−((S)−4−メチル−2−(4−オキソキナゾリン−3(4H)−イル))ペンタナミド)プロパノエート
ステップ1:(S)−メチル3−(3−ブロモフェニル)−3−(tert−ブトキシカルボニルアミノ)プロパノエート
ステップ41:メチル3−(tert−ブトキシカルボニルアミノ)−3−(2−o−トリルピリジン−4−イル)プロパノエート
化合物M2(50mg)を、白色の固体として分取キラルSFC EでM2a(6mg)及びM2b(12mg)に分離した。
ステップ1:3−シクロブトキシベンズアルデヒド
(360mg、1.07mmol)、BnBr(183mg、1.07mmol)、及びK2CO3(298mg、2.14mmol)の溶液を、室温で一晩撹拌した。混合物をDCM(18mL)及び水(5mL)で希釈した。有機層を分離し、Na2SO4で乾燥させた。混合物を濾過し、濾液を濃縮して褐色の油を得、これをシリカゲルフラッシュ(石油エーテル中5%〜10%EtOAc)で精製し、所望の生成物ベンジル3−(tert−ブトキシカルボニルアミノ)−3−(3−シクロブトキシフェニル)プロパノエートを無色の油(386mg)として得た。収率85%(91%純度、UV=214nm、ESI326(MH−Boc)+)。
1H−NMR(500MHz、MeOD)δ 7.74(dd、J=7.0、1.5Hz、1H)、7.54−7.51(m、1H)、7.23(t、J=7.5 Hz、1H)、6.91(s、1H)、6.83(s、1H)、6.74(dd、J=8.0、1.5Hz、1H)、6.68(d、J=9.0Hz、1H)、6.41−6.39(m、1H)、5.76(m、1H)、5.28(t,J=8.0Hz,1H)、4.69(t、J=7.0Hz、1H)、2.78(m、2H)、2.50−2.45(m、2H)、2.15−2.11(m、2H)、1.88−1.84(m、3H)、1.76−1.74(m、H)、1.36−1.34(m、1H)、1.03−0.96(m、6H)。
ステップ1:(S)−メチル3−(tert−ブトキシカルボニルアミノ)−3−(3−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル)プロパノエート
ステップ1:6−ヒドロキシ−2’−メチルビフェニル−3−カルバルデヒド
化合物P2 LC/MS A:100%純度、UV=214nm、Rt=1.69分、ESI487.2(M+H)+。
ステップ1:3−アミノ−3−(3−ブロモ−4−メチルフェニル)プロパン酸
ステップ1:3−アミノ−3−(3−tert−ブチルフェニル)プロパン酸
ステップ1:3−アミノ−3−(3−フェノキシフェニル)プロパン酸
ステップ1:3 3−アミノ−3−(5−ブロモピリジン−3−イル)プロパン酸
T2混合物を、分取キラルSFC Dでさらに分離し、ジアステレオマー化合物T2a(8mg)及びT2b(7.5mg)を白色固体として得た。
ステップ1:2−ブロモ−4,4,4−トリフルオロブタン酸
ステップ1:2−ブロモ−3−シクロプロピルプロパン酸
ステップ1:メチル3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)−3−(4−メチル−2−(4−メチル−2−オキソピリジン−1(2H)−イル)ペンタアミド)プロパノエート
ステップ1:メチル(S)−3−((tert−ブトキシカルボニル)アミノ)−3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)プロパノエート
ステップ1:(R)−メチル3−(tert−ブトキシカルボニルアミノ)−3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)プロパノエート
ステップ1:メチル3−(5−ブロモピリジン−3−イル)−3−(tert−ブトキシカルボニルアミノ)プロパノエート
ステップ1:4,5−ジメチルピリジン−2−オール
ステップ1:メチル(S)−メチル3−(tert−ブトキシカルボニルアミノ)−3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)プロパノエート
ステップ1:エチル4−メチル−2−(1−オキソイソインドリン−2−イル)ペンタノエート
ステップ1:2−ブロモ−4−ホルミルベンゾニトリル
ステップ1:6−メトキシ−2’−メチルビフェニル−3−カルバルデヒド
ステップ1:メチル3−(3−ブロモ−4−メチルフェニル)−3−((tert−ブトキシカルボニル)アミノ)プロパノエート
ステップ1:メチル6−メチル−5−o−トリルニコチネート
ステップ1:メチル5−ブロモ−6−ヨードニコチネート
ステップ1:(S)−メチル3−(5−ブロモピリジン−3−イル)−3−(tert−ブトキシカルボニルアミノ)プロパノエート
ステップ1:(R)−メチル3−(5−ブロモピリジン−3−イル)−3−(tert−ブトキシカルボニルアミノ)プロパノエート
ステップ1:(R)−ベンジル3−アミノ−3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)プロパノエート塩酸塩
ステップ1:3−アミノ−3−(5−ブロモピリジン−3−イル)プロパン酸
ステップ1:(R)−2−ブロモペンタン酸
ステップ1:(3S)−3−(5−(2,6−ジメチルフェニル)ピリジン−3−イル)−3−((2R)−4−メチル−2−(4−メチル−2−オキソピペリジン−1−イル)ペンタアミド)プロパン酸
ステップ1:(S)−メチル3−(tert−ブトキシカルボニルアミノ)−3−(5−(2,2−ジメチルモルホリノ)ピリジン−3−イル)プロパノエート
ステップ1:2−(5,5−ジメチル−2−オキソピペリジン−1−イル)−4−メチルペンタン酸
ステップ1:4−メチル−2−(メチルスルホニルオキシ)ペンタノエート
ステップ1:(S)−5−(1−(tert−ブトキシカルボニルアミノ)−3−メトキシ−3−オキソプロピル)ピリジン−3−イルボロン酸
ステップ4:(3S)−メチル3−(5−(2−クロロ−6−メチルフェニル)ピリジン−3−イル)−3−(4−メチル−2−(4−メチル−2−オキソピリジン−1(2H)−イル)ペンタナミド)プロパノエート
化合物AN1 LC/MS 100%純度、UV=214nm、Rt=1.77分、ESI496.3(M+H)+。
ステップ1:(4−フルオロ−2,6−ジメチルフェニル)ボロン酸
化合物AO1LC/MS C:99%純度、UV=214nm、Rt=1.58分、ESI494.0(M+H)+。
ステップ1:2−ブロモ−1−メトキシ−3−メチルベンゼン
化合物AP2:LC/MS 100%純度、UV=214nm、Rt=1.59分、ESI492.3(M+H)+。
ステップ1:(R)−エチル3−(tert−ブトキシカルボニルアミノ)−3−(2−(2,6−ジメチルフェニル)ピリジン−4−イル)プロパノエート
化合物AQ1b LC/MS A:100%純度、UV=214nm、Rt=1.56分、ESI476(M+H)+。
ステップ1:エチル(S)−3−((tert−ブトキシカルボニル)アミノ)−3−(2−(2,6−ジメチルフェニル)ピリジン−4−イル)プロパノエート
ステップ1:エチル2−(4−ブロモ−5−フルオロ−2−オキソピリジン−1(2H)−イル)−4−メチルペンタノエート
ステップ1:エチル3−メチル−2−(4−メチル−2−オキソピリジン−1(2H)−イル)ブタノエート
ステップ1:(2R,3S)−2−ブロモ−3−メチルペンタン酸
ステップ1:(2R,3R)−2−ブロモ−3−メチルペンタン酸
AT2b LC/MS A:100%純度、UV=214nm、Rt=1.72分、ESI476(M+H)+。
ステップ1:5−((ジメチルアミノ)メチル)ピリジン−2(1H)−オン
ステップ1:2−オキソ−2,3−ジヒドロピリジン−4−カルバルデヒド
ステップ1:5−(2−メトキシビニル)ピリジン−2(1H)−オン
ステップ1:エチル2−(4−ブロモ−2−オキソピリジン−1(2H)−イル)−4−メチルペンタノエート
ステップ1:メチル(3S)−3−(2’,6’−ジメチル−[1,1’−ビフェニル]−3−イル)−3−(2−(5−((ジメチルアミノ)メチル)−2−オキソピリジン−1(2H)−イル)−4−メチルペンタナミド)プロパノエート
ステップ1:エチル2−(5−ホルミル−2−オキソピリジン−1(2H)−イル)−4−メチルペンタノエート
ステップ1:エチル2−(3−ブロモ−2−オキソピリジン−1(2H)−イル)−4−メチルペンタノエート
化合物BE1 ESI532.3(M+H)+。
ステップ1:エチル4−メチル−2−(5−(モルホリノメチル)−2−オキソピリジン−1(2H)−イル)ペンタノエート
化合物BF1 ESI561.0(M+H)+。
ステップ1:エチル2−(5−(((R)−3−フルオロピロリジン−1−イル)メチル)−2−オキソピリジン−1(2H)−イル)−4−メチルペンタノエート
ステップ1:(3S)−メチル3−(2’,6’−ジメチルビフェニル−3−イル)−3−(2−(5−(((R)−3−フルオロピロリジン−1−イル)メチル)−2−オキソピリジン−1(2H)−イル)−4−メチルペンタアミド)プロパノエート
ステップ1:(3S)−エチル3−(2−(4−(2−(ジメチルアミノ)エチル)−2−オキソピリジン−1(2H)−イル)−4−メチルペンタアミド)−3−(2’,6’−ジメチルビフェニル−3−イル)プロパノエート
ステップ1:エチル(3S)−エチル3−(2’,6’−ジメチルビフェニル−3−イル)−3−(2−(5−((3−フルオロアゼチジン−1−イル)メチル)−2−オキソピリジン−1(2H)−イル)−4−メチルペンタナミド)プロパノエート
ステップ1:メチル(3S)−3−(2’,6’−ジメチル−[1,1’−ビフェニル]−3−イル)−3−(2−(5−(2−(ジメチルアミノ)エチル)−2−オキソピリジン−1(2H)−イル)−4−メチルペンタナミド)プロパノエート
ステップ1:5−(2−(アゼチジン−1−イル)エチル)ピリジン−2(1H)−オン
ステップ1:(E)−2−メトキシ−5−(2−メトキシビニル)−4−メチルピリジン
ステップ1:5−(2−(3−フルオロアゼチジン−1−イル)エチル)ピリジン−2(1H)−オン
2(M+H)+)。
ステップ1:(E)−2−メトキシ−5−(2−メトキシビニル)−4−(トリフルオロメチル)ピリジン
ステップ1:6−ヒドロキシ−4−メチルニコチンアルデヒド
ステップ1:5−ブロモ−3−(ジフルオロメチル)−2−メトキシピリジン
蛍光偏光(FP)アッセイを使用して、フルオレセイン標識ペプチドCRSDTLCGE{Lys(FITC)}との結合競合を通じて化合物の活性を測定した。アッセイでは、6.5nMのインテグリンa4b7を、2mMの塩化マンガン、0.1mMの塩化カルシウム、20mMのHEPES緩衝剤(pH7.3)、150mMの塩化ナトリウム、0.01%のTritonX−100、2%のDMSO、及び3nMのフルオレセイン標識ペプチド中で試験化合物とインキュベートした。384ウェルプレートでアッセイを実行し、フルオレセイン標識ペプチドを添加する前に、インテグリンタンパク質を試験化合物と22℃で15分間プレインキュベートした。フルオレセイン標識ペプチドを添加した後、アッセイを22℃で1時間インキュベートし、蛍光偏光を測定した。IC50値を、非線形回帰、4パラメーター曲線フィッティングによって決定した。
本明細書で引用されるすべての米国特許ならびに米国及びPCT特許出願公開は、参照により本明細書に組み込まれる。
当業者は、日常的な実験のみを使用して、本明細書に記載の本発明の特定の実施形態に対する多くの等価物を認識するか、または確認することができるであろう。そのような等価物は、以下の特許請求の範囲によって網羅されることが意図される。
Claims (104)
- 式(I)によって表される化合物であって、
R1が、H、アルキル、アルキレン−シクロアルキル、ヘテロシクリル、アルキレン−O−アルキル、アリール、ヘテロアリール、またはアルキレン−CF3であり、
R2が、ヘテロシクリルであり、
R3が、
R4が、H、または(C1−C6)−アルキルであり、
Raが、H、アルキル、シクロアルキル、CN、または−O−アルキルであり、
Rbが、H、アルキル、アリール、ヘテロアリール、ヘテロシクリル、−O−シクロアルキル、−O−アリール、または−O−ヘテロシクリルであり、
Rcが、H、アルキル、シクロアルキル、ヘテロシクリル、またはアルキレン−CF3であり、
Rdが、アリール、ヘテロアリール、ヘテロシクリル、−O−シクロアルキル、−O−アリール、または−O−ヘテロシクリルであり、及び
Reが、アリール、ヘテロアリール、またはヘテロシクリルである、
前記化合物、またはその薬学的に許容される塩。 - R1が、アルキルである、請求項1に記載の化合物。
- アルキルが、メチル、エチル、イソプロピル、n−プロピル、i−ブチル、n−ブチル、またはt−ブチルである、請求項2に記載の化合物。
- R1が、アルキレン−シクロアルキルである、請求項1に記載の化合物。
- アルキレン−シクロアルキルが、メチレン−シクロプロピルである、請求項4に記載の化合物。
- R1が、ヘテロシクリルである、請求項1に記載の化合物。
- ヘテロシクリルが、Nを含むヘテロシクリルである、請求項6に記載の化合物。
- ヘテロシクリルが、置換ヘテロシクリルである、請求項6または7に記載の化合物。
- R1が、アルキレン−O−アルキルである、請求項1に記載の化合物。
- −アルキレン−O−アルキルが、−メチレン−O−メチルである、請求項9に記載の化合物。
- R1が、アリールである、請求項1に記載の化合物。
- アリールが、フェニルである、請求項11に記載の化合物。
- フェニルが、非置換フェニルである、請求項12に記載の化合物。
- フェニルが、置換フェニルである、請求項12に記載の化合物。
- 置換フェニルが、アルキル及びハロゲンから選択される1つ以上の置換基で置換される、請求項14に記載の化合物。
- R1が、アルキレン−CF3である、請求項1に記載の化合物。
- アルキレン−CF3が、メチレン−CF3である、請求項16に記載の化合物。
- R2が、ヘテロシクリルである、請求項1〜17のいずれか1項に記載の化合物。
- ヘテロシクリルが、置換ヘテロシクリルである、請求項18に記載の化合物。
- ヘテロシクリルが、N含有ヘテロシクリルである、請求項18または19に記載の化合物。
- 前記N含有ヘテロシクリルが、6員〜12員のヘテロシクリルである、請求項20に記載の化合物。
- R2が、アミノ、アルキル、及びアルコキシから選択される1つ以上の置換基で置換され、アルキルまたはアルコキシが、モルフィリノ、環状アミノ、または非環状アミノで置換され、ならびに前記アルキル、アルコキシ、モルホリノ、環状アミノ、または非環状アミノ部分が、1つ以上のアルコキシルまたはフッ素で任意に置換される、請求項19〜21のいずれか1項に記載の化合物。
- R2が、非置換ピリジノニルである、請求項21に記載の化合物。
- R2が、置換ピリジノニルである、請求項21に記載の化合物。
- 置換ピリジノニルが、アルキル、シクロアルキル、ヘテロシクロアルキル、ハロゲン、アリール、ヘテロアリール、及びCF3から選択される1つ以上の置換基で置換される、請求項24に記載の化合物。
- Raが、メチル、シクロプロピル、CN、または−OMeである、請求項28に記載の化合物。
- Rbが、アルキル、アリール、ヘテロシクリル、ヘテロアリール、−O−シクロアルキル、−O−アリール、または−O−ヘテロアリールである、請求項1〜29のいずれか1項に記載の化合物。
- Rbが、アルキルである、請求項30に記載の化合物。
- アルキルが、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、i−ブチル、またはt−ブチルである、請求項31に記載の化合物。
- アルキルが、t−ブチルである、請求項32記載の化合物。
- Rbが、アリールまたはヘテロアリールである、請求項30に記載の化合物。
- Rbが、置換アリールである、請求項34に記載の化合物。
- Rbが、置換ヘテロアリールである、請求項34に記載の化合物。
- 置換アリールまたは置換ヘテロアリールが、アルキル、ハロゲン、OH、−O−アルキル、CN、シクロアルキル、及びヘテロシクロアルキルから選択される1つ以上の置換基で置換される、請求項35または36に記載の化合物。
- Rb が、ヘテロシクリルである、請求項30に記載の化合物。
- ヘテロシクリルが、置換ヘテロシクリルである、請求項39記載の化合物。
- 置換ヘテロシクリルが、アルキル、シクロアルキル、OH、及び−O−アルキルから選択される1つ以上の置換基で置換される、請求項40に記載の化合物。
- Rbが、−O−シクロアルキルである、請求項30に記載の化合物。
- −O−シクロアルキルが、−O−シクロブチルである、請求項44に記載の化合物。
- Rbが、−O−アリールである、請求項30に記載の化合物。
- −O−アリールが、−O−フェニルである、請求項46に記載の化合物。
- Rcが、アルキル、シクロアルキル、(ヘテロシクリル)アルキル、ハロゲン、またはCF3である、請求項48に記載の化合物。
- アルキルが、メチルまたはエチルである、請求項49に記載の化合物。
- Rcが、CF3である、請求項49に記載の化合物。
- Rdが、アリール、ヘテロアリール、またはヘテロシクリルである、請求項48〜52のいずれか1項に記載の化合物。
- Rdが、アリールである、請求項53に記載の化合物。
- アリールが、置換アリールである、請求項54に記載の化合物。
- 置換アリールが、アルキル、シクロアルキル、(ヘテロシクリル)アルキル、ハロゲン、OH、OMe、CF3、及びCNから選択される1つ以上の置換基で置換される、請求項55に記載の化合物。
- Rdが、ヘテロシクリルである、請求項53に記載の化合物。
- ヘテロシクリルが、置換ヘテロシクリルである、請求項58に記載の化合物。
- Rdが、ヘテロアリールである、請求項53に記載の化合物。
- ヘテロアリールが、置換ヘテロアリールである、請求項60に記載の化合物。
- 置換ヘテロシクリルまたは置換ヘテロアリールが、アルキル及びシクロアルキルから選択される1つ以上の置換基で置換される、請求項59または61に記載の化合物。
- Reが、アリールである、請求項65に記載の化合物。
- アリールが、フェニルである、請求項66に記載の化合物。
- フェニルが、置換フェニルである、請求項67に記載の化合物。
- 置換フェニルが、アルキル置換フェニルである、請求項68に記載の化合物。
- Reが、ヘテロシクリルである、請求項65に記載の化合物。
- ヘテロシクリルが、置換ピロリジニルである、請求項71に記載の化合物。
- 置換ピロリジニルが、アルキル置換ピロリジニルである、請求項72に記載の化合物。
- R4が、Hである、請求項1〜74のいずれか1項に記載の化合物。
- R4が、(C1−C6)−アルキルである、請求項1〜74のいずれか1項に記載の化合物。
- R4が、メチル、エチル、イソ−プロピル、n−プロピル、イソ−ブチル、n−ブチル、またはtert−ブチルである、請求項76に記載の化合物。
- 請求項1〜90のいずれか1項に記載の化合物と、薬学的に許容される賦形剤と、を含む、薬学的組成物。
- 炎症性腸疾患、回腸肛門吻合、好酸球性食道炎、膵炎、インスリン依存型糖尿病、乳房炎、胆嚢炎、胆管炎、胆管周囲炎、慢性気管支炎、慢性副鼻腔炎、喘息、移植片対宿主病、肺の慢性炎症性疾患、HIV、及び血液腫瘍からなる群から選択される、疾患または状態を治療する方法であって、それを必要とする対象に、治療有効量の請求項1〜90のいずれか1項に記載の化合物を投与することを含む、前記方法。
- 前記疾患または状態が、炎症性腸疾患である、請求項92記載の方法。
- 前記炎症性腸疾患が、大腸炎、クローン病、回腸炎、セリアック病、非熱帯性スプルー、血清陰性関節症に関連する腸症、胃腸炎、または嚢炎である、請求項93に記載の方法。
- 前記疾患または状態が、大腸炎であり、前記大腸炎が、潰瘍性大腸炎、顕微鏡的大腸炎、または膠原性大腸炎である、請求項94に記載の方法。
- 前記疾患または状態が、嚢炎であり、前記嚢炎が、直腸結腸切除術から生じる、請求項94に記載の方法。
- 前記疾患または状態が、胃腸炎である、請求項92に記載の方法。
- 胃腸炎が、好酸球性胃腸炎である、請求項97に記載の方法。
- 前記疾患または状態が、好酸球性食道炎である、請求項92に記載の方法。
- 前記疾患または状態が、肺の慢性炎症性疾患である、請求項92記載の方法。
- 前記肺の慢性炎症性疾患が、間質性線維症である、請求項100に記載の方法。
- 前記間質性線維症が、過敏性肺炎、膠原病、またはサルコイドーシスである、請求項101に記載の方法。
- 前記疾患または状態が、血液腫瘍である、請求項92に記載の方法。
- 前記血液腫瘍が、急性リンパ性白血病、急性骨髄性白血病、慢性リンパ性白血病、慢性骨髄性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、及び多発性骨髄腫からなる群から選択される、請求項103に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023174330A JP2024001201A (ja) | 2018-04-12 | 2023-10-06 | ヒトインテグリンα4β7のアンタゴニスト |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862656742P | 2018-04-12 | 2018-04-12 | |
US62/656,742 | 2018-04-12 | ||
PCT/US2019/027141 WO2019200202A1 (en) | 2018-04-12 | 2019-04-12 | Antagonists of human integrin (alpha4)(beta7) |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023174330A Division JP2024001201A (ja) | 2018-04-12 | 2023-10-06 | ヒトインテグリンα4β7のアンタゴニスト |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2021531234A true JP2021531234A (ja) | 2021-11-18 |
JPWO2019200202A5 JPWO2019200202A5 (ja) | 2022-04-20 |
JP7365358B2 JP7365358B2 (ja) | 2023-10-19 |
Family
ID=68161020
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020555323A Active JP7365358B2 (ja) | 2018-04-12 | 2019-04-12 | ヒトインテグリンα4β7のアンタゴニスト |
JP2023174330A Pending JP2024001201A (ja) | 2018-04-12 | 2023-10-06 | ヒトインテグリンα4β7のアンタゴニスト |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023174330A Pending JP2024001201A (ja) | 2018-04-12 | 2023-10-06 | ヒトインテグリンα4β7のアンタゴニスト |
Country Status (8)
Country | Link |
---|---|
US (3) | US10759756B2 (ja) |
EP (1) | EP3773573A4 (ja) |
JP (2) | JP7365358B2 (ja) |
CN (1) | CN112312910A (ja) |
AR (1) | AR114489A1 (ja) |
MA (1) | MA52249A (ja) |
TW (1) | TW202003466A (ja) |
WO (1) | WO2019200202A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022542184A (ja) * | 2019-10-16 | 2022-09-29 | 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 | ヒトインテグリン(アルファ-4)(ベータ-7)の阻害 |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112312910A (zh) * | 2018-04-12 | 2021-02-02 | 莫菲克医疗股份有限公司 | 人整合素α4β7拮抗剂 |
CA3115820A1 (en) | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Compounds for inhibition of .alpha.4.beta.7 integrin |
BR112021007213A2 (pt) | 2018-10-30 | 2021-08-10 | Gilead Sciences, Inc. | derivados de quinolina como inibidores de integrina alfa4beta7 |
CA3114240C (en) | 2018-10-30 | 2023-09-05 | Gilead Sciences, Inc. | Imidazopyridine derivatives as alpha4beta7 integrin inhibitors |
CN112969504B (zh) | 2018-10-30 | 2024-04-09 | 吉利德科学公司 | 用于抑制α4β7整合素的化合物 |
AU2020329207B2 (en) | 2019-08-14 | 2024-02-29 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4 beta 7 integrin |
WO2023125182A1 (zh) * | 2021-12-27 | 2023-07-06 | 海思科医药集团股份有限公司 | 一种丙酸衍生物及其在医药上的应用 |
WO2024051819A1 (zh) * | 2022-09-09 | 2024-03-14 | 西藏海思科制药有限公司 | 一种丙酸衍生物及其在医药上的应用 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08508732A (ja) * | 1993-03-31 | 1996-09-17 | ジー.ディー.サール アンド カンパニー | 血小板凝集阻害剤としての1−アミジノフェニル−ピロリドンピペリジノンアゼチノン |
JPH09505062A (ja) * | 1993-11-15 | 1997-05-20 | ヘキスト・アクチェンゲゼルシャフト | 置換された5環状ヘテロ環類、その製造方法及びその使用方法 |
JPH09505590A (ja) * | 1993-11-24 | 1997-06-03 | ザ・デュポン・メルク・ファーマシュウティカル・カンパニー | 新規なイソオキサゾリンおよびイソオキサゾールフィブリノーゲン受容体拮抗剤 |
JPH1059948A (ja) * | 1996-06-05 | 1998-03-03 | Hoechst Ag | 3−(2−(4−(4−(アミノ− イミノ− メチル)− フエニル)− 4− メチル− 2,5− ジオキソ− イミダゾリジン− 1− イル)− アセチルアミノ)− 3 − フエニル− プロピオン酸− エチルエステルの塩 |
JPH11246531A (ja) * | 1997-11-19 | 1999-09-14 | Hoechst Marion Roussel Deutsche Gmbh | 置換されたイミダゾリジン誘導体、その製法および使用ならびにそれを含有する医薬製剤 |
WO2000000481A1 (en) * | 1998-06-29 | 2000-01-06 | Du Pont Pharmaceuticals Company | Cyclic carbamates and isoxazolidines as iib/iiia antagonists |
JP2002515509A (ja) * | 1998-05-14 | 2002-05-28 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | イミダゾリジン誘導体、その製造方法、その使用およびそれを含有する製剤 |
JP2002531439A (ja) * | 1998-11-30 | 2002-09-24 | セルテック セラピューティックス リミテッド | α4インテグリン阻害剤としてのβ−アラニン誘導体 |
JP2002544187A (ja) * | 1999-05-07 | 2002-12-24 | テキサス・バイオテクノロジー・コーポレイシヨン | インテグリンのその受容体への結合を阻害するプロパン酸誘導体 |
JP2004519491A (ja) * | 2001-03-10 | 2004-07-02 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 医薬活性成分のための中間体としてのビス(トリフルオロメチル)ヒダントイン |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US5849736A (en) * | 1993-11-24 | 1998-12-15 | The Dupont Merck Pharmaceutical Company | Isoxazoline and isoxazole fibrinogen receptor antagonists |
US5981546A (en) * | 1996-08-29 | 1999-11-09 | Merck & Co., Inc. | Integrin antagonists |
CA2268270A1 (en) | 1996-10-11 | 1998-04-23 | Cor Therapeutics, Inc. | Heterocyclic derivatives as factor xa inhibitors |
WO1998016547A1 (en) | 1996-10-11 | 1998-04-23 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
US6645939B1 (en) | 1997-11-24 | 2003-11-11 | Merck & Co., Inc. | Substituted β-alanine derivatives as cell adhesion inhibitors |
MY153569A (en) | 1998-01-20 | 2015-02-27 | Mitsubishi Tanabe Pharma Corp | Inhibitors of ?4 mediated cell adhesion |
US6972296B2 (en) | 1999-05-07 | 2005-12-06 | Encysive Pharmaceuticals Inc. | Carboxylic acid derivatives that inhibit the binding of integrins to their receptors |
US6723711B2 (en) * | 1999-05-07 | 2004-04-20 | Texas Biotechnology Corporation | Propanoic acid derivatives that inhibit the binding of integrins to their receptors |
ES2288871T3 (es) | 1999-09-24 | 2008-02-01 | Genentech, Inc. | Derivados de tirosina. |
DE10041423A1 (de) | 2000-08-23 | 2002-03-07 | Merck Patent Gmbh | Biphenylderivate |
DE10154280A1 (de) | 2001-11-05 | 2003-05-15 | Wilex Ag | Antagonisten für alpha¶4¶-Integrine |
MY157727A (en) | 2002-02-25 | 2016-07-15 | Biogen Idec Inc | Administration of agents for the treatment of inflamation |
PT2990422T (pt) | 2004-09-03 | 2018-10-18 | Genentech Inc | Antagonistas humanizados anti-beta7 e suas utilizações |
EP1863940B1 (en) | 2005-03-03 | 2012-06-06 | Seedlings Life Science Ventures, LLC. | Method of risk management for patients undergoing natalizumab treatment |
WO2006126529A1 (ja) | 2005-05-25 | 2006-11-30 | Shionogi & Co., Ltd. | 6,7-不飽和-7-カルバモイル置換モルヒナン誘導体 |
KR20080021085A (ko) | 2005-06-09 | 2008-03-06 | 유씨비 파마, 에스.에이. | 2,6 퀴놀리닐 유도체, 이들을 제조하는 방법 및 이들의약제로서의 용도 |
SI2676967T1 (sl) | 2006-02-28 | 2020-01-31 | Biogen Ma Inc. | Metode zdravljenja vnetne in avtoimunske bolezni z natalizumabom |
US20100272680A1 (en) | 2009-02-09 | 2010-10-28 | Subramanian Baskaran | Piperidinyl Cyclic Amido Antiviral Agents |
CN114642731A (zh) | 2011-03-31 | 2022-06-21 | 豪夫迈·罗氏有限公司 | 施用β7整联蛋白拮抗剂的方法 |
CN104870056A (zh) | 2012-10-05 | 2015-08-26 | 弗·哈夫曼-拉罗切有限公司 | 用于诊断和治疗炎性肠病的方法 |
SG11201607938UA (en) | 2014-03-27 | 2016-10-28 | Genentech Inc | Methods for diagnosing and treating inflammatory bowel disease |
WO2016011940A1 (zh) | 2014-07-25 | 2016-01-28 | 江苏恒瑞医药股份有限公司 | 氮茚-酰胺类衍生物、其制备方法及其在医药上的应用 |
EP3978530A1 (en) | 2015-02-26 | 2022-04-06 | F. Hoffmann-La Roche AG | Integrin beta7 antagonists and methods of treating crohn's disease |
US10246451B2 (en) | 2017-04-26 | 2019-04-02 | Aviara Pharmaceuticals, Inc. | Propionic acid derivatives and methods of use thereof |
CN112312910A (zh) | 2018-04-12 | 2021-02-02 | 莫菲克医疗股份有限公司 | 人整合素α4β7拮抗剂 |
BR112021007213A2 (pt) | 2018-10-30 | 2021-08-10 | Gilead Sciences, Inc. | derivados de quinolina como inibidores de integrina alfa4beta7 |
CA3114240C (en) | 2018-10-30 | 2023-09-05 | Gilead Sciences, Inc. | Imidazopyridine derivatives as alpha4beta7 integrin inhibitors |
CA3115820A1 (en) | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Compounds for inhibition of .alpha.4.beta.7 integrin |
CN112969504B (zh) | 2018-10-30 | 2024-04-09 | 吉利德科学公司 | 用于抑制α4β7整合素的化合物 |
UY38926A (es) | 2019-10-16 | 2021-05-31 | Morphic Therapeutic Inc | INHIBICIÓN DE INTEGRINA alfa4beta7 HUMANA |
-
2019
- 2019-04-12 CN CN201980033206.5A patent/CN112312910A/zh active Pending
- 2019-04-12 MA MA052249A patent/MA52249A/fr unknown
- 2019-04-12 US US16/382,512 patent/US10759756B2/en active Active
- 2019-04-12 EP EP19785592.7A patent/EP3773573A4/en active Pending
- 2019-04-12 TW TW108112877A patent/TW202003466A/zh unknown
- 2019-04-12 WO PCT/US2019/027141 patent/WO2019200202A1/en unknown
- 2019-04-12 JP JP2020555323A patent/JP7365358B2/ja active Active
- 2019-04-12 AR ARP190100980A patent/AR114489A1/es unknown
-
2020
- 2020-07-27 US US16/939,812 patent/US11174228B2/en active Active
-
2021
- 2021-11-12 US US17/525,479 patent/US20220340529A1/en not_active Abandoned
-
2023
- 2023-10-06 JP JP2023174330A patent/JP2024001201A/ja active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08508732A (ja) * | 1993-03-31 | 1996-09-17 | ジー.ディー.サール アンド カンパニー | 血小板凝集阻害剤としての1−アミジノフェニル−ピロリドンピペリジノンアゼチノン |
JPH09505062A (ja) * | 1993-11-15 | 1997-05-20 | ヘキスト・アクチェンゲゼルシャフト | 置換された5環状ヘテロ環類、その製造方法及びその使用方法 |
JPH09505590A (ja) * | 1993-11-24 | 1997-06-03 | ザ・デュポン・メルク・ファーマシュウティカル・カンパニー | 新規なイソオキサゾリンおよびイソオキサゾールフィブリノーゲン受容体拮抗剤 |
JPH1059948A (ja) * | 1996-06-05 | 1998-03-03 | Hoechst Ag | 3−(2−(4−(4−(アミノ− イミノ− メチル)− フエニル)− 4− メチル− 2,5− ジオキソ− イミダゾリジン− 1− イル)− アセチルアミノ)− 3 − フエニル− プロピオン酸− エチルエステルの塩 |
JPH11246531A (ja) * | 1997-11-19 | 1999-09-14 | Hoechst Marion Roussel Deutsche Gmbh | 置換されたイミダゾリジン誘導体、その製法および使用ならびにそれを含有する医薬製剤 |
JP2002515509A (ja) * | 1998-05-14 | 2002-05-28 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | イミダゾリジン誘導体、その製造方法、その使用およびそれを含有する製剤 |
WO2000000481A1 (en) * | 1998-06-29 | 2000-01-06 | Du Pont Pharmaceuticals Company | Cyclic carbamates and isoxazolidines as iib/iiia antagonists |
JP2002531439A (ja) * | 1998-11-30 | 2002-09-24 | セルテック セラピューティックス リミテッド | α4インテグリン阻害剤としてのβ−アラニン誘導体 |
JP2002544187A (ja) * | 1999-05-07 | 2002-12-24 | テキサス・バイオテクノロジー・コーポレイシヨン | インテグリンのその受容体への結合を阻害するプロパン酸誘導体 |
JP2004519491A (ja) * | 2001-03-10 | 2004-07-02 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 医薬活性成分のための中間体としてのビス(トリフルオロメチル)ヒダントイン |
Non-Patent Citations (2)
Title |
---|
HANS ULRICH STILZ ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 39(11), JPN6023011841, 1996, pages 2118 - 2122, ISSN: 0005022064 * |
RESISTRY(STN)[ONLINE], JPN7023001186, ISSN: 0005022065 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022542184A (ja) * | 2019-10-16 | 2022-09-29 | 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 | ヒトインテグリン(アルファ-4)(ベータ-7)の阻害 |
JP2023500437A (ja) * | 2019-10-16 | 2023-01-06 | 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 | ヒトインテグリンα4β7の阻害 |
JP7437490B2 (ja) | 2019-10-16 | 2024-02-22 | 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 | ヒトインテグリン(アルファ-4)(ベータ-7)の阻害 |
JP7437495B2 (ja) | 2019-10-16 | 2024-02-22 | 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 | ヒトインテグリンα4β7の阻害 |
Also Published As
Publication number | Publication date |
---|---|
EP3773573A4 (en) | 2022-04-06 |
CN112312910A (zh) | 2021-02-02 |
TW202003466A (zh) | 2020-01-16 |
EP3773573A1 (en) | 2021-02-17 |
US20190315692A1 (en) | 2019-10-17 |
JP7365358B2 (ja) | 2023-10-19 |
US20220340529A1 (en) | 2022-10-27 |
US11174228B2 (en) | 2021-11-16 |
MA52249A (fr) | 2021-05-05 |
JP2024001201A (ja) | 2024-01-09 |
AR114489A1 (es) | 2020-09-09 |
US10759756B2 (en) | 2020-09-01 |
US20200385352A1 (en) | 2020-12-10 |
WO2019200202A1 (en) | 2019-10-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7365358B2 (ja) | ヒトインテグリンα4β7のアンタゴニスト | |
TWI716458B (zh) | γ-羥基丁酸的前藥及其組合物和用途 | |
TWI312779B (ja) | ||
CN107266416B (zh) | 作为mgat2抑制剂的芳基二氢吡啶酮及哌啶酮 | |
KR20190005838A (ko) | 이중 lsd1/hdac 억제제로서 사이클로프로필-아마이드 화합물 | |
KR102291444B1 (ko) | 디히드로피리디논 mgat2 억제제 | |
CN111433207B (zh) | 作为αV整合素抑制剂的吡咯并吡嗪衍生物 | |
KR20050071472A (ko) | 퀴놀린 항생 물질 중간체의 제조 방법 | |
CN115942972A (zh) | Lpa受体拮抗剂及其用途 | |
JPWO2003029218A1 (ja) | 新規含窒素化合物及びその用途 | |
US8088920B2 (en) | 3-trifluoromethyl-pyrazine-2-carboxylic acid amide derivatives as HDL-cholesterol raising agents | |
WO1998021185A1 (fr) | Arylurees ou derives d'arylmethylcarbamyle | |
TW202102493A (zh) | 作為rsv抑制劑的苯并二氮呯衍生物 | |
CN113698390B (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
WO2017008681A1 (zh) | 酰胺类衍生物、其制备方法及其在医药上的用途 | |
TWI838747B (zh) | Lpa受體拮抗劑及其用途 | |
CN111233661A (zh) | 靶向泛素化降解ERRα蛋白的化合物及其药用组合物和应用 | |
EP2755952B1 (en) | 5-cycloalkyl- or 5-heterocyclyl-nicotinamides | |
TW202300486A (zh) | Lpa受體拮抗劑及其用途 | |
JPH0441143B2 (ja) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20210512 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20210512 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220412 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220412 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230316 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230328 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230627 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230808 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230901 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231006 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7365358 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |