CA3162281A1 - Heterocyclic compounds as delta-5 desaturase inhibitors and methods of use - Google Patents
Heterocyclic compounds as delta-5 desaturase inhibitors and methods of useInfo
- Publication number
- CA3162281A1 CA3162281A1 CA3162281A CA3162281A CA3162281A1 CA 3162281 A1 CA3162281 A1 CA 3162281A1 CA 3162281 A CA3162281 A CA 3162281A CA 3162281 A CA3162281 A CA 3162281A CA 3162281 A1 CA3162281 A1 CA 3162281A1
- Authority
- CA
- Canada
- Prior art keywords
- tautomer
- compound
- pyrazol
- trifluoromethyl
- alpyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 234
- 102100034542 Acyl-CoA (8-3)-desaturase Human genes 0.000 title abstract description 30
- 108010073542 Delta-5 Fatty Acid Desaturase Proteins 0.000 title abstract description 8
- 239000003112 inhibitor Substances 0.000 title description 6
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 582
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 56
- 230000002503 metabolic effect Effects 0.000 claims abstract description 13
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 12
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims description 211
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 199
- -1 2-hydroxy-2-methylpropyl Chemical group 0.000 claims description 158
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 140
- BDTRIDKONHOQQN-UHFFFAOYSA-N 4h-pyrimidin-5-one Chemical compound O=C1CN=CN=C1 BDTRIDKONHOQQN-UHFFFAOYSA-N 0.000 claims description 57
- 125000001424 substituent group Chemical group 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 54
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 39
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 18
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 18
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 16
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 230000037396 body weight Effects 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 208000008589 Obesity Diseases 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 9
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 6
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- DJSUEEHBHIPLDE-UHFFFAOYSA-N pyrimidine-2,5-dione Chemical compound O=C1C=NC(=O)N=C1 DJSUEEHBHIPLDE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 3
- 125000006413 ring segment Chemical group 0.000 claims description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- DMCLNIZKWQGPTM-UHFFFAOYSA-N 5-bromo-2-[(3-octoxyphenyl)methylsulfanyl]benzoic acid Chemical compound CCCCCCCCOC1=CC=CC(CSC=2C(=CC(Br)=CC=2)C(O)=O)=C1 DMCLNIZKWQGPTM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- UEZROEGYRDHMRV-UHFFFAOYSA-N [1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound O=C1C=CN=C2SC=CN12 UEZROEGYRDHMRV-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 288
- 239000000203 mixture Substances 0.000 abstract description 136
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 241
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 192
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 121
- 229910052681 coesite Inorganic materials 0.000 description 114
- 229910052906 cristobalite Inorganic materials 0.000 description 114
- 229910052682 stishovite Inorganic materials 0.000 description 114
- 229910052905 tridymite Inorganic materials 0.000 description 114
- 239000000377 silicon dioxide Substances 0.000 description 110
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 110
- 235000012239 silicon dioxide Nutrition 0.000 description 107
- 238000003818 flash chromatography Methods 0.000 description 81
- 230000002829 reductive effect Effects 0.000 description 81
- 239000000243 solution Substances 0.000 description 78
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 76
- 238000005160 1H NMR spectroscopy Methods 0.000 description 71
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 68
- 239000007832 Na2SO4 Substances 0.000 description 67
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 67
- 229910052938 sodium sulfate Inorganic materials 0.000 description 67
- 235000011152 sodium sulphate Nutrition 0.000 description 67
- 239000011541 reaction mixture Substances 0.000 description 57
- 235000019253 formic acid Nutrition 0.000 description 54
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 51
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 47
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 46
- 239000012074 organic phase Substances 0.000 description 45
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 43
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 40
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 239000013058 crude material Substances 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 36
- 238000001816 cooling Methods 0.000 description 34
- 230000004048 modification Effects 0.000 description 30
- 238000012986 modification Methods 0.000 description 30
- 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 29
- 229910000024 caesium carbonate Inorganic materials 0.000 description 29
- 101150041968 CDC13 gene Proteins 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 239000013543 active substance Substances 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
- 239000008280 blood Substances 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 210000004369 blood Anatomy 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 23
- 101710102367 Acyl-CoA (8-3)-desaturase Proteins 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 235000012000 cholesterol Nutrition 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 21
- 229910000029 sodium carbonate Inorganic materials 0.000 description 21
- 235000017550 sodium carbonate Nutrition 0.000 description 21
- 102000004877 Insulin Human genes 0.000 description 20
- 108090001061 Insulin Proteins 0.000 description 20
- 229940125396 insulin Drugs 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- 150000003626 triacylglycerols Chemical class 0.000 description 19
- 235000021342 arachidonic acid Nutrition 0.000 description 18
- 229940114079 arachidonic acid Drugs 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 235000019197 fats Nutrition 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 102000007330 LDL Lipoproteins Human genes 0.000 description 16
- 108010007622 LDL Lipoproteins Proteins 0.000 description 16
- HOBAELRKJCKHQD-UHFFFAOYSA-N (8Z,11Z,14Z)-8,11,14-eicosatrienoic acid Natural products CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 15
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 description 15
- DTMGIJFHGGCSLO-FIAQIACWSA-N ethyl (4z,7z,10z,13z,16z,19z)-docosa-4,7,10,13,16,19-hexaenoate;ethyl (5z,8z,11z,14z,17z)-icosa-5,8,11,14,17-pentaenoate Chemical class CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC.CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC DTMGIJFHGGCSLO-FIAQIACWSA-N 0.000 description 15
- 239000008103 glucose Substances 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- 235000012631 food intake Nutrition 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 235000011181 potassium carbonates Nutrition 0.000 description 14
- 125000004494 ethyl ester group Chemical group 0.000 description 13
- 230000037406 food intake Effects 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 230000036528 appetite Effects 0.000 description 12
- 235000019789 appetite Nutrition 0.000 description 12
- 150000002081 enamines Chemical class 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 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 10
- 241001465754 Metazoa Species 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 210000000593 adipose tissue white Anatomy 0.000 description 10
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000029936 alkylation Effects 0.000 description 9
- 238000005804 alkylation reaction Methods 0.000 description 9
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical group CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 9
- 229960002600 icosapent ethyl Drugs 0.000 description 9
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- QIQSYARFOIKJJR-LUTWCBITSA-N (4z,7z,10z,13z,16z,19z)-docosa-4,7,10,13,16,19-hexaenoic acid;(4z,7z,10z,13z,16z)-docosa-4,7,10,13,16-pentaenoic acid;(7z,10z,13z,16z,19z)-docosa-7,10,13,16,19-pentaenoic acid;(6z,9z,12z,15z,18z)-henicosa-6,9,12,15,18-pentaenoic acid;(5z,8z,11z,14z,17z)-i Chemical class CCCCC\C=C/C\C=C/CCCCCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O.CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/CCCCCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O QIQSYARFOIKJJR-LUTWCBITSA-N 0.000 description 8
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201962939821P | 2019-11-25 | 2019-11-25 | |
| US62/939,821 | 2019-11-25 | ||
| PCT/US2020/062020 WO2021108408A1 (en) | 2019-11-25 | 2020-11-24 | Heterocyclic compounds as delta-5 desaturase inhibitors and methods of use |
Publications (1)
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| CA3162281A1 true CA3162281A1 (en) | 2021-06-03 |
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| US11220510B2 (en) * | 2018-04-09 | 2022-01-11 | Incyte Corporation | Pyrrole tricyclic compounds as A2A / A2B inhibitors |
| PH12022551282A1 (en) * | 2019-11-25 | 2023-11-29 | Amgen Inc | Heterocyclic compounds as delta-5 desaturase inhibitors and methods of use |
| CN115557903A (zh) * | 2022-09-27 | 2023-01-03 | 山东潍坊润丰化工股份有限公司 | 一种特草定的制备方法 |
| TW202434254A (zh) | 2022-11-23 | 2024-09-01 | 美商安進公司 | 選擇用於fads1調節劑治療的患者之方法 |
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2020
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