JP5815874B2 - Hdlコレステロール上昇剤としての3−ピリジンカルボン酸ヒドラジド - Google Patents
Hdlコレステロール上昇剤としての3−ピリジンカルボン酸ヒドラジド Download PDFInfo
- Publication number
- JP5815874B2 JP5815874B2 JP2014530158A JP2014530158A JP5815874B2 JP 5815874 B2 JP5815874 B2 JP 5815874B2 JP 2014530158 A JP2014530158 A JP 2014530158A JP 2014530158 A JP2014530158 A JP 2014530158A JP 5815874 B2 JP5815874 B2 JP 5815874B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- phenyl
- halogen
- trifluoroethoxy
- methyl
- 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.)
- Expired - Fee Related
Links
- 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 title description 47
- 235000012000 cholesterol Nutrition 0.000 title description 20
- 235000010855 food raising agent Nutrition 0.000 title description 6
- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 232
- 238000002360 preparation method Methods 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 48
- -1 pyridin-4-ylmethyl Chemical group 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 31
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 201000001386 familial hypercholesterolemia Diseases 0.000 claims description 18
- 201000001320 Atherosclerosis Diseases 0.000 claims description 17
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 15
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 15
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 230000008878 coupling Effects 0.000 claims description 14
- 238000010168 coupling process Methods 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- YXMIQJXMAJAQFD-UHFFFAOYSA-N 5-cyclopropyl-6-(cyclopropylmethoxy)-n'-(4-fluorophenyl)-n'-methylpyridine-3-carbohydrazide Chemical compound C=1C=C(F)C=CC=1N(C)NC(=O)C(C=C1C2CC2)=CN=C1OCC1CC1 YXMIQJXMAJAQFD-UHFFFAOYSA-N 0.000 claims description 10
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 10
- 206010021024 Hypolipidaemia Diseases 0.000 claims description 10
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 10
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 10
- 208000029498 hypoalphalipoproteinemia Diseases 0.000 claims description 10
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 206010002383 Angina Pectoris Diseases 0.000 claims description 8
- 208000037487 Endotoxemia Diseases 0.000 claims description 8
- 206010010164 Hypertension complications Diseases 0.000 claims description 8
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 claims description 8
- 208000008589 Obesity Diseases 0.000 claims description 8
- 206010063837 Reperfusion injury Diseases 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 8
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 claims description 8
- 238000002399 angioplasty Methods 0.000 claims description 8
- ICCBZGUDUOMNOF-UHFFFAOYSA-N azidoamine Chemical group NN=[N+]=[N-] ICCBZGUDUOMNOF-UHFFFAOYSA-N 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 8
- 230000005494 condensation Effects 0.000 claims description 8
- 201000009101 diabetic angiopathy Diseases 0.000 claims description 8
- 230000002641 glycemic effect Effects 0.000 claims description 8
- 208000028867 ischemia Diseases 0.000 claims description 8
- 208000010125 myocardial infarction Diseases 0.000 claims description 8
- 208000031225 myocardial ischemia Diseases 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 208000037803 restenosis Diseases 0.000 claims description 8
- CUQZGBSEDZOUEI-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-cyclobutyloxy-n-(4-hydroxypiperidin-1-yl)pyridine-3-carboxamide Chemical compound C1CC(O)CCN1NC(=O)C(C=C1C=2C=CC(Cl)=CC=2)=CN=C1OC1CCC1 CUQZGBSEDZOUEI-UHFFFAOYSA-N 0.000 claims description 7
- KDFZCAGDYKHHJJ-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-[4-(2-hydroxyethyl)piperidin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CC(CCO)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 KDFZCAGDYKHHJJ-UHFFFAOYSA-N 0.000 claims description 7
- BLXKBXAIPYKIMF-UHFFFAOYSA-N 5-cyclohexyl-n-(4-hydroxypiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CC(O)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCCC2)=C1 BLXKBXAIPYKIMF-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- ZRHUKEFBCXAQJZ-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-(4-hydroxypiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CC(O)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 ZRHUKEFBCXAQJZ-UHFFFAOYSA-N 0.000 claims description 6
- VWXJKJDXJWFBFE-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-[4-(2-hydroxyethyl)piperazin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CN(CCO)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 VWXJKJDXJWFBFE-UHFFFAOYSA-N 0.000 claims description 6
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 6
- ONEZQSDDZYQSQQ-UHFFFAOYSA-N 5-(3-fluorophenyl)-n'-methyl-n'-phenyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1=CC=CC(F)=C1 ONEZQSDDZYQSQQ-UHFFFAOYSA-N 0.000 claims description 5
- PBJQDCWJKCGOCR-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-n-(4-hydroxypiperidin-1-yl)pyridine-3-carboxamide Chemical compound C1CC(O)CCN1NC(=O)C(C=C1C=2C=CC(Cl)=CC=2)=CN=C1OCC1CC1 PBJQDCWJKCGOCR-UHFFFAOYSA-N 0.000 claims description 5
- XKZATUGERUGCIC-UHFFFAOYSA-N 5-(4-chlorophenyl)-n'-(3-hydroxypropyl)-n'-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound OCCCN(C)NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 XKZATUGERUGCIC-UHFFFAOYSA-N 0.000 claims description 5
- JSNCWUPMKZBYFO-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-(3-hydroxyazetidin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1C(O)CN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 JSNCWUPMKZBYFO-UHFFFAOYSA-N 0.000 claims description 5
- PWVQODNMXRBSMV-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-(4-methyl-3-oxopiperazin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1C(=O)N(C)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 PWVQODNMXRBSMV-UHFFFAOYSA-N 0.000 claims description 5
- KQBUYLPQSJXMMW-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-(4-methylsulfonylpiperazin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 KQBUYLPQSJXMMW-UHFFFAOYSA-N 0.000 claims description 5
- RQHVKGJMPBAXHH-UHFFFAOYSA-N 5-(4-cyanophenyl)-n-(4-hydroxypiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CC(O)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(=CC=2)C#N)=C1 RQHVKGJMPBAXHH-UHFFFAOYSA-N 0.000 claims description 5
- WCSBZEBNZICNHZ-UHFFFAOYSA-N 5-cyclohexyl-n'-methyl-n'-phenyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CCCCC1 WCSBZEBNZICNHZ-UHFFFAOYSA-N 0.000 claims description 5
- VUWPBFVPAGTLTH-UHFFFAOYSA-N 5-cyclopentyl-n'-methyl-n'-phenyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CCCC1 VUWPBFVPAGTLTH-UHFFFAOYSA-N 0.000 claims description 5
- DSXUTKFDZSIMEL-HNNXBMFYSA-N 5-cyclopentyl-n-[(2s)-2-(methoxymethyl)pyrrolidin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound COC[C@@H]1CCCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCC2)=C1 DSXUTKFDZSIMEL-HNNXBMFYSA-N 0.000 claims description 5
- UWSOZBSWZBRYOH-UHFFFAOYSA-N 5-cyclopentyl-n-morpholin-4-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCOCC2)C=C1C1CCCC1 UWSOZBSWZBRYOH-UHFFFAOYSA-N 0.000 claims description 5
- YABHUHBMGUTQCM-UHFFFAOYSA-N 5-cyclopropyl-n'-(pyridin-4-ylmethyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NNCC=2C=CN=CC=2)C=C1C1CC1 YABHUHBMGUTQCM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
- JTLHGRNMWSAMTC-UHFFFAOYSA-N 6-cyclobutyloxy-5-cyclopropyl-n'-(4-fluorophenyl)-n'-methylpyridine-3-carbohydrazide Chemical compound C=1C=C(F)C=CC=1N(C)NC(=O)C(C=C1C2CC2)=CN=C1OC1CCC1 JTLHGRNMWSAMTC-UHFFFAOYSA-N 0.000 claims description 5
- SZLGXOWVURPREO-UHFFFAOYSA-N 6-cyclobutyloxy-n'-(4-fluorophenyl)-5-(furan-2-yl)pyridine-3-carbohydrazide Chemical compound C1=CC(F)=CC=C1NNC(=O)C(C=C1C=2OC=CC=2)=CN=C1OC1CCC1 SZLGXOWVURPREO-UHFFFAOYSA-N 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- KUKFGZZXWRFQRY-UHFFFAOYSA-N n'-(4-cyanophenyl)-6-cyclobutyloxy-5-cyclopropyl-n'-methylpyridine-3-carbohydrazide Chemical compound C=1C=C(C#N)C=CC=1N(C)NC(=O)C(C=C1C2CC2)=CN=C1OC1CCC1 KUKFGZZXWRFQRY-UHFFFAOYSA-N 0.000 claims description 5
- GPTWGBOORMMVAV-UHFFFAOYSA-N n'-(6-chloropyridazin-3-yl)-5-cyclopentyl-n'-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=C(Cl)N=NC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CCCC1 GPTWGBOORMMVAV-UHFFFAOYSA-N 0.000 claims description 5
- WBPULFKJXCKTKX-UHFFFAOYSA-N n'-methyl-5-(oxan-4-yl)-n'-phenyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CCOCC1 WBPULFKJXCKTKX-UHFFFAOYSA-N 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- MFIYRECNFTZQJQ-UHFFFAOYSA-N 5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=C(F)C(Cl)=CC=2)=C1 MFIYRECNFTZQJQ-UHFFFAOYSA-N 0.000 claims description 4
- QZKDUCQXKHTJHW-UHFFFAOYSA-N 5-(4-chlorophenyl)-n'-(6-chloropyridazin-3-yl)-n'-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=C(Cl)N=NC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1=CC=C(Cl)C=C1 QZKDUCQXKHTJHW-UHFFFAOYSA-N 0.000 claims description 4
- RKVTXARFCMZBNX-UHFFFAOYSA-N 5-(4-chlorophenyl)-n'-methyl-n'-phenyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1=CC=C(Cl)C=C1 RKVTXARFCMZBNX-UHFFFAOYSA-N 0.000 claims description 4
- RGGUURMMKQGAMX-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-[4-(hydroxymethyl)piperidin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CC(CO)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 RGGUURMMKQGAMX-UHFFFAOYSA-N 0.000 claims description 4
- WUAQPWNIVUPPBN-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-[5-(morpholin-4-ylmethyl)-2-oxo-1,3-oxazolidin-3-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2C(OC(CN3CCOCC3)C2)=O)C=C1C1=CC=C(Cl)C=C1 WUAQPWNIVUPPBN-UHFFFAOYSA-N 0.000 claims description 4
- ZQSLHUCGSTXSGC-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-morpholin-4-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCOCC2)C=C1C1=CC=C(Cl)C=C1 ZQSLHUCGSTXSGC-UHFFFAOYSA-N 0.000 claims description 4
- VSMIVMIUBIZUMS-UHFFFAOYSA-N 5-(4-cyanophenyl)-n-[4-(2-hydroxyethyl)piperidin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1CC(CCO)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(=CC=2)C#N)=C1 VSMIVMIUBIZUMS-UHFFFAOYSA-N 0.000 claims description 4
- XNPOSEFXTNYHKW-UHFFFAOYSA-N 5-(4-cyanophenyl)-n-morpholin-4-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCOCC2)C=C1C1=CC=C(C#N)C=C1 XNPOSEFXTNYHKW-UHFFFAOYSA-N 0.000 claims description 4
- ZALMXDAKFFZMCI-INIZCTEOSA-N 5-cyclohexyl-n-[(2s)-2-(methoxymethyl)pyrrolidin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound COC[C@@H]1CCCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCCC2)=C1 ZALMXDAKFFZMCI-INIZCTEOSA-N 0.000 claims description 4
- DDOOXPDNFMCJNZ-UHFFFAOYSA-N 5-cyclohexyl-n-morpholin-4-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCOCC2)C=C1C1CCCCC1 DDOOXPDNFMCJNZ-UHFFFAOYSA-N 0.000 claims description 4
- QVVKRBFVBWDLBL-UHFFFAOYSA-N 5-cyclohexyl-n-pyrrolidin-1-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCCC2)C=C1C1CCCCC1 QVVKRBFVBWDLBL-UHFFFAOYSA-N 0.000 claims description 4
- UVYIWCZDIVRFQF-UHFFFAOYSA-N 5-cyclopentyl-n-(2-oxopyrrolidin-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2C(CCC2)=O)C=C1C1CCCC1 UVYIWCZDIVRFQF-UHFFFAOYSA-N 0.000 claims description 4
- LKGYXBQDHRJESU-UHFFFAOYSA-N 5-cyclopropyl-6-(cyclopropylmethoxy)-n'-methyl-n'-phenylpyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=C1C2CC2)=CN=C1OCC1CC1 LKGYXBQDHRJESU-UHFFFAOYSA-N 0.000 claims description 4
- CQMOXRGXEVTVCI-BETUJISGSA-N 5-cyclopropyl-6-(cyclopropylmethoxy)-n-[(2s,6r)-2,6-dimethylmorpholin-4-yl]pyridine-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1NC(=O)C(C=C1C2CC2)=CN=C1OCC1CC1 CQMOXRGXEVTVCI-BETUJISGSA-N 0.000 claims description 4
- ITAAGHOHRLAODU-UHFFFAOYSA-N 5-cyclopropyl-n'-methyl-n'-phenyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=CC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CC1 ITAAGHOHRLAODU-UHFFFAOYSA-N 0.000 claims description 4
- GEOLQBPUAKXKRQ-UHFFFAOYSA-N 5-cyclopropyl-n'-methyl-n'-pyridin-4-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=NC=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CC1 GEOLQBPUAKXKRQ-UHFFFAOYSA-N 0.000 claims description 4
- VLTMUNQVHNTUQN-UHFFFAOYSA-N 5-cyclopropyl-n-(1,1-dioxo-1,4-thiazinan-4-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCS(=O)(=O)CC2)C=C1C1CC1 VLTMUNQVHNTUQN-UHFFFAOYSA-N 0.000 claims description 4
- PSSRMWWAGFEYGQ-ZDUSSCGKSA-N 5-cyclopropyl-n-[(2s)-2-(methoxymethyl)pyrrolidin-1-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound COC[C@@H]1CCCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C2CC2)=C1 PSSRMWWAGFEYGQ-ZDUSSCGKSA-N 0.000 claims description 4
- QLXCBGDEQUSBOG-PHIMTYICSA-N 5-cyclopropyl-n-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C2CC2)=C1 QLXCBGDEQUSBOG-PHIMTYICSA-N 0.000 claims description 4
- QZSMJBJHLYUNDY-UHFFFAOYSA-N 5-cyclopropyl-n-morpholin-4-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide Chemical compound FC(F)(F)COC1=NC=C(C(=O)NN2CCOCC2)C=C1C1CC1 QZSMJBJHLYUNDY-UHFFFAOYSA-N 0.000 claims description 4
- SLAFDRWXQPXEMT-UHFFFAOYSA-N 6-cyclobutyloxy-5-(furan-2-yl)-n'-methyl-n'-pyridin-4-ylpyridine-3-carbohydrazide Chemical compound C=1C=NC=CC=1N(C)NC(=O)C(C=C1C=2OC=CC=2)=CN=C1OC1CCC1 SLAFDRWXQPXEMT-UHFFFAOYSA-N 0.000 claims description 4
- SGIHGWCVRXCTFR-UHFFFAOYSA-N 6-cyclobutyloxy-5-(furan-2-yl)-n-(4-hydroxypiperidin-1-yl)pyridine-3-carboxamide Chemical compound C1CC(O)CCN1NC(=O)C(C=C1C=2OC=CC=2)=CN=C1OC1CCC1 SGIHGWCVRXCTFR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- NGTYUKJMTNLCTG-UHFFFAOYSA-N n'-(4-cyanophenyl)-5-cyclopropyl-6-(cyclopropylmethoxy)-n'-methylpyridine-3-carbohydrazide Chemical compound C=1C=C(C#N)C=CC=1N(C)NC(=O)C(C=C1C2CC2)=CN=C1OCC1CC1 NGTYUKJMTNLCTG-UHFFFAOYSA-N 0.000 claims description 4
- UPRNRDVKBNBQEY-UHFFFAOYSA-N n'-(4-cyanophenyl)-5-cyclopropyl-n'-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=C(C#N)C=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CC1 UPRNRDVKBNBQEY-UHFFFAOYSA-N 0.000 claims description 4
- NYZJLBCMOOGDDL-UHFFFAOYSA-N n'-(6-chloropyridazin-3-yl)-5-cyclohexyl-n'-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=C(Cl)N=NC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CCCCC1 NYZJLBCMOOGDDL-UHFFFAOYSA-N 0.000 claims description 4
- KRCRHEWULMKEHU-UHFFFAOYSA-N n'-(6-chloropyridazin-3-yl)-6-cyclobutyloxy-5-(furan-2-yl)-n'-methylpyridine-3-carbohydrazide Chemical compound C=1C=C(Cl)N=NC=1N(C)NC(=O)C(C=C1C=2OC=CC=2)=CN=C1OC1CCC1 KRCRHEWULMKEHU-UHFFFAOYSA-N 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- DDOKGZLQKHJNOU-UHFFFAOYSA-N tert-butyl 2-[5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl]pyrazolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCN1C(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 DDOKGZLQKHJNOU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- ZEVMYALVVREGBZ-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-n'-(2,2,2-trifluoroethyl)pyridine-3-carbohydrazide Chemical compound FC(F)(F)CNNC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 ZEVMYALVVREGBZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- YJCUIPKVUVRWHL-UHFFFAOYSA-N tert-butyl 4-[5-[[4-(2-hydroxyethyl)piperidin-1-yl]carbamoyl]-2-(2,2,2-trifluoroethoxy)pyridin-3-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC(C(=O)NN2CCC(CCO)CC2)=CN=C1OCC(F)(F)F YJCUIPKVUVRWHL-UHFFFAOYSA-N 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 83
- 239000011541 reaction mixture Substances 0.000 description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
- 239000000243 solution Substances 0.000 description 65
- 239000007787 solid Substances 0.000 description 55
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 239000007858 starting material Substances 0.000 description 41
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 108010010234 HDL Lipoproteins Proteins 0.000 description 26
- 102000015779 HDL Lipoproteins Human genes 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 239000003112 inhibitor Substances 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 150000002632 lipids Chemical class 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012442 inert solvent Substances 0.000 description 15
- 239000012317 TBTU Substances 0.000 description 14
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- YACPBZACSFEVIY-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 YACPBZACSFEVIY-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 13
- 239000011664 nicotinic acid Substances 0.000 description 13
- 229960003512 nicotinic acid Drugs 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- FWXFKNMQSPQETB-UHFFFAOYSA-N 5-cyclohexyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCCC2)=C1 FWXFKNMQSPQETB-UHFFFAOYSA-N 0.000 description 11
- CRZXMNLPARUNSU-UHFFFAOYSA-N 5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(OCC(F)(F)F)C(C2CC2)=C1 CRZXMNLPARUNSU-UHFFFAOYSA-N 0.000 description 11
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 11
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 235000001968 nicotinic acid Nutrition 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 10
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 10
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 10
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 description 10
- 239000003613 bile acid Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000012876 carrier material Substances 0.000 description 10
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 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 9
- KWOYMTABCJRVMM-UHFFFAOYSA-N 5-cyclopentyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCC2)=C1 KWOYMTABCJRVMM-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000012980 RPMI-1640 medium Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- MKQLBNJQQZRQJU-UHFFFAOYSA-N morpholin-4-amine Chemical compound NN1CCOCC1 MKQLBNJQQZRQJU-UHFFFAOYSA-N 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 150000003626 triacylglycerols Chemical class 0.000 description 9
- 238000010626 work up procedure Methods 0.000 description 9
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 8
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 8
- 241000699800 Cricetinae Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 229940011051 isopropyl acetate Drugs 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- MWOODERJGVWYJE-UHFFFAOYSA-N 1-methyl-1-phenylhydrazine Chemical compound CN(N)C1=CC=CC=C1 MWOODERJGVWYJE-UHFFFAOYSA-N 0.000 description 7
- 102000004895 Lipoproteins Human genes 0.000 description 7
- 108090001030 Lipoproteins Proteins 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 125000001153 fluoro group Chemical group F* 0.000 description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 7
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 6
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 108010023302 HDL Cholesterol Proteins 0.000 description 6
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 6
- 238000008214 LDL Cholesterol Methods 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 230000006806 disease prevention Effects 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 229940125753 fibrate Drugs 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000003456 ion exchange resin Substances 0.000 description 6
- 229920003303 ion-exchange polymer Polymers 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- ACXPNVRTMHEHMQ-UHFFFAOYSA-N tert-butyl 3-(4-cyanophenyl)oxaziridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1OC1C1=CC=C(C#N)C=C1 ACXPNVRTMHEHMQ-UHFFFAOYSA-N 0.000 description 6
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 6
- KEHRVXCBFSPWOH-UHFFFAOYSA-N 1-aminopiperidin-4-ol Chemical compound NN1CCC(O)CC1 KEHRVXCBFSPWOH-UHFFFAOYSA-N 0.000 description 5
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 5
- UKSJFPJNCLXWSY-UHFFFAOYSA-N 5-cyclopropyl-n'-(4-fluorophenyl)-n'-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbohydrazide Chemical compound C=1C=C(F)C=CC=1N(C)NC(=O)C(C=1)=CN=C(OCC(F)(F)F)C=1C1CC1 UKSJFPJNCLXWSY-UHFFFAOYSA-N 0.000 description 5
- 102000055510 ATP Binding Cassette Transporter 1 Human genes 0.000 description 5
- 108700005241 ATP Binding Cassette Transporter 1 Proteins 0.000 description 5
- 102000018616 Apolipoproteins B Human genes 0.000 description 5
- 108010027006 Apolipoproteins B Proteins 0.000 description 5
- 239000004131 EU approved raising agent Substances 0.000 description 5
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 5
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 229940125890 compound Ia Drugs 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- CMLMZYWFGJUBLU-UHFFFAOYSA-N methyl 5-bromo-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(Br)=C1 CMLMZYWFGJUBLU-UHFFFAOYSA-N 0.000 description 5
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 5
- 125000002098 pyridazinyl group Chemical group 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 108010028554 LDL Cholesterol Proteins 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001952 enzyme assay Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
- LERMECNLIVEERL-OLQVQODUSA-N (2r,6s)-2,6-dimethylmorpholin-4-amine Chemical compound C[C@H]1CN(N)C[C@@H](C)O1 LERMECNLIVEERL-OLQVQODUSA-N 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- GAJJFWCERZCSQH-UHFFFAOYSA-N 4-[amino(methyl)amino]benzonitrile Chemical compound CN(N)C1=CC=C(C#N)C=C1 GAJJFWCERZCSQH-UHFFFAOYSA-N 0.000 description 3
- PAQXUYLVOLOQMM-UHFFFAOYSA-N 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC(C(O)=O)=CN=C1OCC(F)(F)F PAQXUYLVOLOQMM-UHFFFAOYSA-N 0.000 description 3
- NDDUCEMRFZUCTI-UHFFFAOYSA-N 5-bromo-6-(cyclopropylmethoxy)pyridine-3-carboxylic acid Chemical compound BrC1=CC(C(=O)O)=CN=C1OCC1CC1 NDDUCEMRFZUCTI-UHFFFAOYSA-N 0.000 description 3
- OIBWFFRRQNGCFL-UHFFFAOYSA-N 5-bromo-6-cyclobutyloxypyridine-3-carboxylic acid Chemical compound BrC1=CC(C(=O)O)=CN=C1OC1CCC1 OIBWFFRRQNGCFL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 229940127328 Cholesterol Synthesis Inhibitors Drugs 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 108010022164 acetyl-LDL Proteins 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000001906 cholesterol absorption Effects 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
- 230000002596 correlated effect Effects 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- CZJKDHSZCAAJGU-UHFFFAOYSA-N methyl 5-(cyclopenten-1-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(C=2CCCC=2)=C1 CZJKDHSZCAAJGU-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- CMJQIHGBUKZEHP-UHFFFAOYSA-N (4-chloro-3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C(F)=C1 CMJQIHGBUKZEHP-UHFFFAOYSA-N 0.000 description 2
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 2
- ZXBMIRYQUFQQNX-UHFFFAOYSA-N (4-fluorophenyl)hydrazine Chemical compound NNC1=CC=C(F)C=C1 ZXBMIRYQUFQQNX-UHFFFAOYSA-N 0.000 description 2
- FMHXXJNNWLWDLN-UHFFFAOYSA-N 1-(4-fluorophenyl)-1-methylhydrazine;hydrochloride Chemical compound Cl.CN(N)C1=CC=C(F)C=C1 FMHXXJNNWLWDLN-UHFFFAOYSA-N 0.000 description 2
- XWEFKJNJSVXMOD-UHFFFAOYSA-N 1-methyl-1-pyridin-4-ylhydrazine Chemical compound CN(N)C1=CC=NC=C1 XWEFKJNJSVXMOD-UHFFFAOYSA-N 0.000 description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- QNZFUMVTUFOLRT-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CCCCC1 QNZFUMVTUFOLRT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LDSQQXKSEFZAPE-UHFFFAOYSA-N 2-piperidin-4-ylethanol Chemical compound OCCC1CCNCC1 LDSQQXKSEFZAPE-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- LRKKVPOVHKOENQ-UHFFFAOYSA-N 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-1-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(C)(C)[Si](C)(C)OCCC1CCN(N)CC1 LRKKVPOVHKOENQ-UHFFFAOYSA-N 0.000 description 2
- LKUZTPMHQQCNTL-UHFFFAOYSA-N 5-(4-chlorophenyl)-n-piperazin-1-yl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.FC(F)(F)COC1=NC=C(C(=O)NN2CCNCC2)C=C1C1=CC=C(Cl)C=C1 LKUZTPMHQQCNTL-UHFFFAOYSA-N 0.000 description 2
- KRDMLWXBTGQOCF-UHFFFAOYSA-N 5-(4-cyanophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(=CC=2)C#N)=C1 KRDMLWXBTGQOCF-UHFFFAOYSA-N 0.000 description 2
- WXDLWNNDDDWZLT-UHFFFAOYSA-N 5-(oxan-4-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCOCC2)=C1 WXDLWNNDDDWZLT-UHFFFAOYSA-N 0.000 description 2
- DXEUARPQHJXMII-UHFFFAOYSA-N 5-bromo-6-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C(Br)=C1 DXEUARPQHJXMII-UHFFFAOYSA-N 0.000 description 2
- 101150092476 ABCA1 gene Proteins 0.000 description 2
- 239000012114 Alexa Fluor 647 Substances 0.000 description 2
- 239000012099 Alexa Fluor family Substances 0.000 description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 2
- 229940123239 Cholesterol synthesis inhibitor Drugs 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000710961 Semliki Forest virus Species 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-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001543 aryl boronic acids Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- KTHXBEHDVMTNOH-UHFFFAOYSA-N cyclobutanol Chemical compound OC1CCC1 KTHXBEHDVMTNOH-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 150000002429 hydrazines Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000006140 methanolysis reaction Methods 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- HXVIBKLKNORIEN-UHFFFAOYSA-N methyl 5-(4-cyanophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(=CC=2)C#N)=C1 HXVIBKLKNORIEN-UHFFFAOYSA-N 0.000 description 2
- BSSINYIZABOCJK-UHFFFAOYSA-N methyl 5-(oxan-4-yl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCOCC2)=C1 BSSINYIZABOCJK-UHFFFAOYSA-N 0.000 description 2
- QUTMGEBHVBDEDX-UHFFFAOYSA-N methyl 5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(C2CC2)=C1 QUTMGEBHVBDEDX-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- YXLHEYVCMFJDOV-UHFFFAOYSA-N pyridin-4-ylmethylhydrazine Chemical compound NNCC1=CC=NC=C1 YXLHEYVCMFJDOV-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 238000003345 scintillation counting Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- NHGBXSBAIAMLEX-UHFFFAOYSA-N tert-butyl 4-[[5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl]amino]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 NHGBXSBAIAMLEX-UHFFFAOYSA-N 0.000 description 2
- PADGJNOHLWFTLG-UHFFFAOYSA-N tert-butyl n-(4-methyl-3-oxopiperazin-1-yl)carbamate Chemical compound CN1CCN(NC(=O)OC(C)(C)C)CC1=O PADGJNOHLWFTLG-UHFFFAOYSA-N 0.000 description 2
- VDPMTTONBRNUGH-UHFFFAOYSA-N tert-butyl n-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]carbamate Chemical compound CC(C)(C)OC(=O)NN1CC(O[Si](C)(C)C(C)(C)C)C1 VDPMTTONBRNUGH-UHFFFAOYSA-N 0.000 description 2
- DNOCVONHYLPTTP-UHFFFAOYSA-N tert-butyl n-[3-[tert-butyl(dimethyl)silyl]oxypropyl-methylamino]carbamate Chemical compound CC(C)(C)OC(=O)NN(C)CCCO[Si](C)(C)C(C)(C)C DNOCVONHYLPTTP-UHFFFAOYSA-N 0.000 description 2
- HBGFARJLOOVHPQ-UHFFFAOYSA-N tert-butyl n-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-1-yl]carbamate Chemical compound CC(C)(C)OC(=O)NN1CCC(CCO[Si](C)(C)C(C)(C)C)CC1 HBGFARJLOOVHPQ-UHFFFAOYSA-N 0.000 description 2
- XYDJKXOUFKUIRJ-UHFFFAOYSA-N tert-butyl-dimethyl-(2-piperidin-4-ylethoxy)silane;hydrochloride Chemical compound Cl.CC(C)(C)[Si](C)(C)OCCC1CCNCC1 XYDJKXOUFKUIRJ-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 description 1
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- 0 *c(cc(cn1)C(N(*)N(*)*)=O)c1O* Chemical compound *c(cc(cn1)C(N(*)N(*)*)=O)c1O* 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RCYFNBYVHAIWKG-UHFFFAOYSA-N 1-(4-fluorophenyl)-1-methylhydrazine Chemical compound CN(N)C1=CC=C(F)C=C1 RCYFNBYVHAIWKG-UHFFFAOYSA-N 0.000 description 1
- RPBZJGTXXMJLGI-UHFFFAOYSA-N 1-(6-chloropyridazin-3-yl)-1-methylhydrazine Chemical compound CN(N)C1=CC=C(Cl)N=N1 RPBZJGTXXMJLGI-UHFFFAOYSA-N 0.000 description 1
- FXWVDWHCKMFDIG-UHFFFAOYSA-N 1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-1-methylhydrazine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CN(N)CCCO[Si](C)(C)C(C)(C)C FXWVDWHCKMFDIG-UHFFFAOYSA-N 0.000 description 1
- LSROBYZLBGODRN-UHFFFAOYSA-N 1-aminopyrrolidin-2-one Chemical compound NN1CCCC1=O LSROBYZLBGODRN-UHFFFAOYSA-N 0.000 description 1
- SCNLSIHPABOZQF-UHFFFAOYSA-N 1-methyl-1-pyridazin-3-ylhydrazine Chemical compound CN(N)C=1N=NC=CC1 SCNLSIHPABOZQF-UHFFFAOYSA-N 0.000 description 1
- KMRWHESBJZFGFH-UHFFFAOYSA-N 1-methylpiperazin-2-one;hydrochloride Chemical compound Cl.CN1CCNCC1=O KMRWHESBJZFGFH-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- OPMFFAOEPFATTG-UHFFFAOYSA-N 2,2,2-trifluoroethylhydrazine Chemical compound NNCC(F)(F)F OPMFFAOEPFATTG-UHFFFAOYSA-N 0.000 description 1
- GVYVZISYQXLXIZ-UHFFFAOYSA-N 2-(1-aminopiperidin-4-yl)ethanol Chemical compound NN1CCC(CCO)CC1 GVYVZISYQXLXIZ-UHFFFAOYSA-N 0.000 description 1
- AHZQTMTWYRXVDE-UHFFFAOYSA-N 2-(cyclopropylmethoxy)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1OCC1CC1 AHZQTMTWYRXVDE-UHFFFAOYSA-N 0.000 description 1
- FQOJETOYFYDGIU-UHFFFAOYSA-N 2-[4-[[5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl]amino]piperazin-1-yl]ethyl acetate Chemical compound C1CN(CCOC(=O)C)CCN1NC(=O)C1=CN=C(OCC(F)(F)F)C(C=2C=CC(Cl)=CC=2)=C1 FQOJETOYFYDGIU-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- RLTFGHBYCOGAJY-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxy-n-methylpropan-1-amine;hydrochloride Chemical compound Cl.CNCCCO[Si](C)(C)C(C)(C)C RLTFGHBYCOGAJY-UHFFFAOYSA-N 0.000 description 1
- MZZPSGLZJUSERX-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(C)(C)[Si](C)(C)OC1CN(N)C1 MZZPSGLZJUSERX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- CXQKAEAIDWERLK-UHFFFAOYSA-N 4-(2-tert-butylsilyloxypropan-2-yl)piperidin-1-amine 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.C(C)(C)(C)[SiH2]OC(C1CCN(CC1)N)(C)C CXQKAEAIDWERLK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NNYVTMPQVMDXLP-UHFFFAOYSA-N 4-amino-1-methylpiperazin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CN1CCN(N)CC1=O NNYVTMPQVMDXLP-UHFFFAOYSA-N 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- JTRNQTFTRDPITG-UHFFFAOYSA-N 4-iodooxane Chemical compound IC1CCOCC1 JTRNQTFTRDPITG-UHFFFAOYSA-N 0.000 description 1
- RJWLLQWLBMJCFD-UHFFFAOYSA-N 4-methylpiperazin-1-amine Chemical compound CN1CCN(N)CC1 RJWLLQWLBMJCFD-UHFFFAOYSA-N 0.000 description 1
- ZKONHSIXYGSHNI-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)pyridine-3-carboxylic acid Chemical compound C=1C=C(Cl)C=CC=1C1=CC(C(=O)O)=CN=C1OCC1CC1 ZKONHSIXYGSHNI-UHFFFAOYSA-N 0.000 description 1
- GGCICZHFWINFFY-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-cyclobutyloxypyridine-3-carboxylic acid Chemical compound C=1C=C(Cl)C=CC=1C1=CC(C(=O)O)=CN=C1OC1CCC1 GGCICZHFWINFFY-UHFFFAOYSA-N 0.000 description 1
- OETMNCHRWZTBNO-UHFFFAOYSA-N 5-(morpholin-4-ylmethyl)-1,3-oxazolidin-2-one Chemical compound O1C(=O)NCC1CN1CCOCC1 OETMNCHRWZTBNO-UHFFFAOYSA-N 0.000 description 1
- SXODTTHCORPAOJ-UHFFFAOYSA-N 5-cyclopropyl-6-(cyclopropylmethoxy)pyridine-3-carboxylic acid Chemical compound C1CC1C1=CC(C(=O)O)=CN=C1OCC1CC1 SXODTTHCORPAOJ-UHFFFAOYSA-N 0.000 description 1
- LPRUZRPAFIALRF-UHFFFAOYSA-N 6-cyclobutyloxy-5-(furan-2-yl)pyridine-3-carboxylic acid Chemical compound C=1C=COC=1C1=CC(C(=O)O)=CN=C1OC1CCC1 LPRUZRPAFIALRF-UHFFFAOYSA-N 0.000 description 1
- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WSNYLDPNKJLDQW-UHFFFAOYSA-N C1CCC(CC1)C2=C(C=CC(=N2)OCC(F)(F)F)C(=O)O Chemical compound C1CCC(CC1)C2=C(C=CC(=N2)OCC(F)(F)F)C(=O)O WSNYLDPNKJLDQW-UHFFFAOYSA-N 0.000 description 1
- IUIZTWMWKZODLY-UHFFFAOYSA-N CC(C)(C)OC(NN(C)CCCO[SiH-](C)(C)C(C)(C)C)=O Chemical compound CC(C)(C)OC(NN(C)CCCO[SiH-](C)(C)C(C)(C)C)=O IUIZTWMWKZODLY-UHFFFAOYSA-N 0.000 description 1
- MFJACRBXZZMAAT-UHFFFAOYSA-N CC(C)(C)[SiH-](C)(C)OCCC(CC1)CCN1N Chemical compound CC(C)(C)[SiH-](C)(C)OCCC(CC1)CCN1N MFJACRBXZZMAAT-UHFFFAOYSA-N 0.000 description 1
- VMBJKTULOCKQMJ-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)OCCC1CCNCC1 Chemical compound CC(C)(C)[Si](C)(C)OCCC1CCNCC1 VMBJKTULOCKQMJ-UHFFFAOYSA-N 0.000 description 1
- KKZFHAYFEIPTHF-UHFFFAOYSA-N COCNN1CCCC1 Chemical compound COCNN1CCCC1 KKZFHAYFEIPTHF-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 101000875075 Homo sapiens Cannabinoid receptor 2 Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 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 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 238000006411 Negishi coupling reaction Methods 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 108010069201 VLDL Cholesterol Proteins 0.000 description 1
- COERJHDMQUPDCV-UHFFFAOYSA-N [K].FB(F)F Chemical compound [K].FB(F)F COERJHDMQUPDCV-UHFFFAOYSA-N 0.000 description 1
- PDKXJKWLFFZPPF-UHFFFAOYSA-N [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(C(N(C)C)=[N+](C)C)N=[N+]([O-])C2=N1 PDKXJKWLFFZPPF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- ULMHPBVREZOAQD-UHFFFAOYSA-N azetidin-3-yloxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1CNC1 ULMHPBVREZOAQD-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 125000004651 chloromethoxy group Chemical group ClCO* 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001258 dyslipidemic effect Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 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
- 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
- 102000056693 human CNR2 Human genes 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- KJMHFARMACEBBD-UHFFFAOYSA-N methyl 5-cyclohexyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCCC2)=C1 KJMHFARMACEBBD-UHFFFAOYSA-N 0.000 description 1
- TYUKMLGFHNLQRT-UHFFFAOYSA-N methyl 5-cyclopentyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OCC(F)(F)F)C(C2CCCC2)=C1 TYUKMLGFHNLQRT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229920001223 polyethylene glycol Chemical class 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 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 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YFWQFKUQVJNPKP-UHFFFAOYSA-N tert-butyl 4-iodopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(I)CC1 YFWQFKUQVJNPKP-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
- C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11180929 | 2011-09-12 | ||
| EP11180929.9 | 2011-09-12 | ||
| PCT/EP2012/067469 WO2013037703A1 (en) | 2011-09-12 | 2012-09-07 | 3 -pyridine carboxylic acid hydrazides as hdl-cholesterol raising agents |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2014527073A JP2014527073A (ja) | 2014-10-09 |
| JP2014527073A5 JP2014527073A5 (OSRAM) | 2015-07-16 |
| JP5815874B2 true JP5815874B2 (ja) | 2015-11-17 |
Family
ID=46796631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014530158A Expired - Fee Related JP5815874B2 (ja) | 2011-09-12 | 2012-09-07 | Hdlコレステロール上昇剤としての3−ピリジンカルボン酸ヒドラジド |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US8648099B2 (OSRAM) |
| EP (1) | EP2755953A1 (OSRAM) |
| JP (1) | JP5815874B2 (OSRAM) |
| KR (1) | KR20140057652A (OSRAM) |
| CN (1) | CN103781765A (OSRAM) |
| BR (1) | BR112014005634A2 (OSRAM) |
| CA (1) | CA2844865A1 (OSRAM) |
| MX (1) | MX2014001860A (OSRAM) |
| RU (1) | RU2014111321A (OSRAM) |
| WO (1) | WO2013037703A1 (OSRAM) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056749A (zh) * | 2015-03-12 | 2017-08-18 | 佛山市赛维斯医药科技有限公司 | 一类含烟酸酰胺和哌啶结构ptp1b抑制剂及其用途 |
| US20200085810A1 (en) | 2018-07-26 | 2020-03-19 | Hoffmann-La Roche Inc. | Compounds for use in treating kidney disorders |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2479744A1 (en) * | 2002-03-28 | 2003-10-09 | Paul E. Finke | Substituted 2,3-diphenyl pyridines |
| MX2007012213A (es) * | 2005-04-06 | 2007-12-10 | Hoffmann La Roche | Derivados de piridin-3-carboxamida como agonistas inversos de canabinoides. |
| WO2007011760A2 (en) * | 2005-07-15 | 2007-01-25 | Kalypsys, Inc. | Inhibitors of mitotic kinesin |
| US7629346B2 (en) * | 2006-06-19 | 2009-12-08 | Hoffmann-La Roche Inc. | Pyrazinecarboxamide derivatives as CB1 antagonists |
| MX2009003222A (es) * | 2006-10-04 | 2009-04-06 | Hoffmann La Roche | Derivados de 3-piridinocarboxamida y 2-pirazinocarboxamida como agentes elevadores de colesterol de lipoproteina de alta densidad. |
| TW200940537A (en) * | 2008-02-26 | 2009-10-01 | Astrazeneca Ab | Heterocyclic urea derivatives and methods of use thereof |
-
2012
- 2012-09-07 CA CA2844865A patent/CA2844865A1/en not_active Abandoned
- 2012-09-07 JP JP2014530158A patent/JP5815874B2/ja not_active Expired - Fee Related
- 2012-09-07 EP EP12754017.7A patent/EP2755953A1/en not_active Withdrawn
- 2012-09-07 BR BR112014005634A patent/BR112014005634A2/pt not_active IP Right Cessation
- 2012-09-07 CN CN201280044104.1A patent/CN103781765A/zh active Pending
- 2012-09-07 MX MX2014001860A patent/MX2014001860A/es unknown
- 2012-09-07 WO PCT/EP2012/067469 patent/WO2013037703A1/en not_active Ceased
- 2012-09-07 RU RU2014111321/04A patent/RU2014111321A/ru not_active Application Discontinuation
- 2012-09-07 KR KR1020147008882A patent/KR20140057652A/ko not_active Ceased
- 2012-09-11 US US13/609,429 patent/US8648099B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2014527073A (ja) | 2014-10-09 |
| WO2013037703A1 (en) | 2013-03-21 |
| US20130065876A1 (en) | 2013-03-14 |
| RU2014111321A (ru) | 2015-10-20 |
| MX2014001860A (es) | 2014-05-30 |
| KR20140057652A (ko) | 2014-05-13 |
| US8648099B2 (en) | 2014-02-11 |
| BR112014005634A2 (pt) | 2017-03-28 |
| CA2844865A1 (en) | 2013-03-21 |
| EP2755953A1 (en) | 2014-07-23 |
| CN103781765A (zh) | 2014-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5646082B2 (ja) | Hdlコレステロール上昇剤としてのオキシム化合物 | |
| KR101546595B1 (ko) | 헤테로아릴메틸 아마이드 | |
| KR20140049026A (ko) | 바닐로이드 수용체 리간드로서의 치환된 헤테로방향족 피라졸―함유 카복스아미드 및 우레아 유도체 | |
| JP2014521618A (ja) | 置換複素環アザ誘導体 | |
| JP5815876B2 (ja) | 5−シクロアルキル−又は5−ヘテロシクリル−ニコチンアミド類 | |
| JP5243596B2 (ja) | Hdl−コレステロール上昇剤としての3−トリフルオロメチル−ピラジン−2−カルボン酸アミド誘導体 | |
| JP5815874B2 (ja) | Hdlコレステロール上昇剤としての3−ピリジンカルボン酸ヒドラジド | |
| JP5762548B2 (ja) | N−ピリジン−3−イル又はn−ピラジン−2−イルカルボキサミド類 | |
| JP5815875B2 (ja) | N−(5−シクロアルキル−又は5−ヘテロシクリル)−ピリジン−3−イルカルボキサミド | |
| HK1193597A (en) | 3-pyridine carboxylic acid hydrazides as hdl-cholesterol raising agents | |
| HK1181759B (en) | N-pyridin-3-yl or n-pyrazin-2-yl carboxamides | |
| HK1193599B (en) | N-(5-cycloalkyl- or 5-heterocyclyl-)-pyridin-3-yl carboxamides | |
| HK1193598A (en) | 5-cycloalkyl-or 5-heterocyclyl-nicotinamides | |
| HK1181655B (zh) | 杂芳基甲酰胺 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140509 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150127 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20150310 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20150424 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150525 |
|
| A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20150525 |
|
| 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: 20150915 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150924 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5815874 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |