CA2920415A1 - Dihydropyrimidine compounds and their application in pharmaceuticals - Google Patents
Dihydropyrimidine compounds and their application in pharmaceuticals Download PDFInfo
- Publication number
- CA2920415A1 CA2920415A1 CA2920415A CA2920415A CA2920415A1 CA 2920415 A1 CA2920415 A1 CA 2920415A1 CA 2920415 A CA2920415 A CA 2920415A CA 2920415 A CA2920415 A CA 2920415A CA 2920415 A1 CA2920415 A1 CA 2920415A1
- Authority
- CA
- Canada
- Prior art keywords
- cr10r10a
- alkyl
- compound
- mmol
- independently
- 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.)
- Abandoned
Links
- 239000003814 drug Substances 0.000 title claims description 45
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 565
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 108
- 201000010099 disease Diseases 0.000 claims abstract description 104
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 239000012453 solvate Substances 0.000 claims abstract description 17
- -1 alkyl-S(=O)q- Chemical group 0.000 claims description 167
- 238000000034 method Methods 0.000 claims description 161
- 125000000217 alkyl group Chemical group 0.000 claims description 83
- 229910052739 hydrogen Inorganic materials 0.000 claims description 78
- 239000001257 hydrogen Substances 0.000 claims description 77
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 66
- 125000001072 heteroaryl group Chemical group 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 40
- 230000003612 virological effect Effects 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims description 34
- 208000002672 hepatitis B Diseases 0.000 claims description 34
- 108010050904 Interferons Proteins 0.000 claims description 32
- 102000014150 Interferons Human genes 0.000 claims description 32
- 229940079322 interferon Drugs 0.000 claims description 32
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000001425 triazolyl group Chemical group 0.000 claims description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 125000000335 thiazolyl group Chemical group 0.000 claims description 22
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
- 239000000651 prodrug Substances 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 125000001153 fluoro group Chemical group F* 0.000 claims description 19
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 18
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 125000002720 diazolyl group Chemical group 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000002883 imidazolyl group Chemical group 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 13
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 13
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 13
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 13
- 125000004306 triazinyl group Chemical group 0.000 claims description 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 12
- 206010016654 Fibrosis Diseases 0.000 claims description 12
- 230000007882 cirrhosis Effects 0.000 claims description 12
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 12
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 12
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 150000001204 N-oxides Chemical class 0.000 claims description 10
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229960001627 lamivudine Drugs 0.000 claims description 7
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- UQZPGHOJMQTOHB-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)-n-ethylethanamine Chemical compound ClCCN(CC)CCCl UQZPGHOJMQTOHB-UHFFFAOYSA-N 0.000 claims description 6
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 6
- WAEDMQMDOHQPFL-UHFFFAOYSA-N n,n-bis(2-chloroethyl)propan-2-amine Chemical compound ClCCN(C(C)C)CCCl WAEDMQMDOHQPFL-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 239000003981 vehicle Substances 0.000 claims description 5
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 claims description 4
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 108010019182 Alloferon Proteins 0.000 claims description 4
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 4
- 108700024845 Hepatitis B virus P Proteins 0.000 claims description 4
- 102000000588 Interleukin-2 Human genes 0.000 claims description 4
- 108010002350 Interleukin-2 Proteins 0.000 claims description 4
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 4
- 229920000519 Sizofiran Polymers 0.000 claims description 4
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 claims description 4
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 4
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 4
- 229950001357 celmoleukin Drugs 0.000 claims description 4
- 229960005338 clevudine Drugs 0.000 claims description 4
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 claims description 4
- 239000013256 coordination polymer Substances 0.000 claims description 4
- 229960000366 emtricitabine Drugs 0.000 claims description 4
- 229960000980 entecavir Drugs 0.000 claims description 4
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims description 4
- 229960004396 famciclovir Drugs 0.000 claims description 4
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002955 immunomodulating agent Substances 0.000 claims description 4
- 229940121354 immunomodulator Drugs 0.000 claims description 4
- 230000002584 immunomodulator Effects 0.000 claims description 4
- WOUUWUGULFOVHG-UHFFFAOYSA-N mivotilate Chemical compound S1CSC1=C(C(=O)OC(C)C)C(=O)NC1=NC(C)=CS1 WOUUWUGULFOVHG-UHFFFAOYSA-N 0.000 claims description 4
- 229950008403 mivotilate Drugs 0.000 claims description 4
- 229960002480 nitazoxanide Drugs 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 108010092853 peginterferon alfa-2a Proteins 0.000 claims description 4
- 229960003930 peginterferon alfa-2a Drugs 0.000 claims description 4
- 229960000329 ribavirin Drugs 0.000 claims description 4
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 4
- 229950001403 sizofiran Drugs 0.000 claims description 4
- 229960005311 telbivudine Drugs 0.000 claims description 4
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims description 4
- 229960004556 tenofovir Drugs 0.000 claims description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
- 108010078049 Interferon alpha-2 Proteins 0.000 claims description 3
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 claims description 3
- 229960003205 adefovir dipivoxil Drugs 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 108010050151 hepatitis B hyperimmune globulin Proteins 0.000 claims description 3
- SPSXSWRZQFPVTJ-ZQQKUFEYSA-N hepatitis b vaccine Chemical compound C([C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC1N=CN=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)OC(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@@H](N)CCCNC(N)=N)C1=CC=CC=C1 SPSXSWRZQFPVTJ-ZQQKUFEYSA-N 0.000 claims description 3
- 229960001614 levamisole Drugs 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- XEABSBMNTNXEJM-UHFFFAOYSA-N propagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 claims 1
- 229950002828 propagermanium Drugs 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 138
- 238000004611 spectroscopical analysis Methods 0.000 description 128
- 150000002500 ions Chemical class 0.000 description 119
- 239000000203 mixture Substances 0.000 description 117
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 113
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 90
- 239000007787 solid Substances 0.000 description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 55
- 239000000243 solution Substances 0.000 description 55
- 235000019441 ethanol Nutrition 0.000 description 54
- 239000003921 oil Substances 0.000 description 54
- 235000019198 oils Nutrition 0.000 description 54
- 239000000460 chlorine Substances 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 48
- 229910000027 potassium carbonate Inorganic materials 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- 150000002431 hydrogen Chemical group 0.000 description 42
- 239000002253 acid Substances 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- 235000011181 potassium carbonates Nutrition 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 27
- 230000000670 limiting effect Effects 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 19
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 150000001721 carbon Chemical group 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 18
- 208000015181 infectious disease Diseases 0.000 description 18
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 18
- 235000019260 propionic acid Nutrition 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- 239000004698 Polyethylene Substances 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 101150041968 CDC13 gene Proteins 0.000 description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 15
- 229910052731 fluorine Inorganic materials 0.000 description 15
- 229940124597 therapeutic agent Drugs 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 13
- 239000001301 oxygen Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000007832 Na2SO4 Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 12
- 230000001684 chronic effect Effects 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- 239000011593 sulfur Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 235000015320 potassium carbonate Nutrition 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 238000010348 incorporation Methods 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
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- WARYEJDBHKIWSK-VIFPVBQESA-N tert-butyl (2S)-4,4-difluoro-2-(3-hydroxypropyl)pyrrolidine-1-carboxylate Chemical compound FC1(C[C@@H](N(C1)C(=O)OC(C)(C)C)CCCO)F WARYEJDBHKIWSK-VIFPVBQESA-N 0.000 description 1
- LLAVVIOANPDDEK-VIFPVBQESA-N tert-butyl (2S)-4,4-difluoro-2-(3-oxopropyl)pyrrolidine-1-carboxylate Chemical compound FC1(C[C@@H](N(C1)C(=O)OC(C)(C)C)CCC=O)F LLAVVIOANPDDEK-VIFPVBQESA-N 0.000 description 1
- NWCZKENXBRNRMY-QMMMGPOBSA-N tert-butyl (2S)-5,5-difluoro-2-(hydroxymethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(F)(F)CC[C@H]1CO NWCZKENXBRNRMY-QMMMGPOBSA-N 0.000 description 1
- RLYJVDHFVHSBHS-UHFFFAOYSA-N tert-butyl 4,4-difluoro-2-(2-oxoethyl)pyrrolidine-1-carboxylate Chemical compound FC1(CC(N(C1)C(=O)OC(C)(C)C)CC=O)F RLYJVDHFVHSBHS-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
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- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- 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
- 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
- C07D417/06—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 carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D417/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
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- Public Health (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310590683.6 | 2013-11-19 | ||
| CN201310590683 | 2013-11-19 | ||
| CN201410108925 | 2014-03-23 | ||
| CN201410108925.8 | 2014-03-23 | ||
| PCT/CN2014/091444 WO2015074546A1 (en) | 2013-11-19 | 2014-11-18 | Dihydropyrimidine compounds and their application in pharmaceuticals |
Publications (1)
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| CA2920415A1 true CA2920415A1 (en) | 2015-05-28 |
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| KR20160133563A (ko) | 2014-03-28 | 2016-11-22 | 선샤인 레이크 파르마 컴퍼니 리미티드 | 다이하이드로피리미딘 화합물 및 이의 약제학적 용도 |
| CN105859708B (zh) | 2015-02-07 | 2020-01-21 | 广东东阳光药业有限公司 | 二氢嘧啶衍生物的盐及其在药物中的应用 |
| US10021567B2 (en) | 2015-03-23 | 2018-07-10 | Qualcomm Incorporated | Schedule selection and connection setup between devices participating in a NAN data link |
| WO2016161268A1 (en) | 2015-04-01 | 2016-10-06 | Enanta Pharmaceuticals, Inc. | Hepatitis b antviral agents |
| US10738035B2 (en) | 2015-05-13 | 2020-08-11 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| WO2017011552A1 (en) * | 2015-07-13 | 2017-01-19 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| US10301255B2 (en) | 2015-07-22 | 2019-05-28 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| HK1255463A1 (zh) | 2015-11-03 | 2019-08-16 | F. Hoffmann-La Roche Ag | Hbv衣壳组装抑制剂和干扰素的组合疗法 |
| WO2017136403A1 (en) | 2016-02-02 | 2017-08-10 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| EP3411359B1 (en) | 2016-02-04 | 2021-10-13 | Merck Sharp & Dohme Corp. | Methods of preparing hydroxylamine derivatives useful in the preparation of anti-infective agents |
| CN109069488B (zh) | 2016-03-07 | 2021-09-07 | 英安塔制药有限公司 | 乙型肝炎抗病毒剂 |
| KR20190027814A (ko) * | 2016-06-10 | 2019-03-15 | 이난타 파마슈티칼스, 인코포레이티드 | B형 간염 항바이러스제 |
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| CN109790145B (zh) * | 2016-11-18 | 2020-09-22 | 四川科伦博泰生物医药股份有限公司 | 二氢嘧啶类化合物及其制备方法和用途 |
| US11166954B2 (en) | 2016-11-18 | 2021-11-09 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Dihydropyrimidine compound and preparation method and use thereof |
| WO2019001396A1 (en) * | 2017-06-26 | 2019-01-03 | Sunshine Lake Pharma Co., Ltd. | DIHYDROPYRIMIDINE COMPOUNDS AND USES THEREOF IN MEDICINE |
| JP2020525490A (ja) | 2017-06-27 | 2020-08-27 | ヤンセン ファーマシューティカ エヌ．ベー． | ヘテロアリールジヒドロピリミジン誘導体及びｂ型肝炎感染を治療する方法 |
| TWI811236B (zh) | 2017-08-28 | 2023-08-11 | 美商因那塔製藥公司 | B型肝炎抗病毒試劑 |
| US11261190B2 (en) * | 2017-10-18 | 2022-03-01 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and uses thereof in medicine |
| TW201927789A (zh) | 2017-12-06 | 2019-07-16 | 美商因那塔製藥公司 | B型肝炎抗病毒試劑 |
| WO2019113175A1 (en) | 2017-12-06 | 2019-06-13 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| WO2019143902A2 (en) | 2018-01-22 | 2019-07-25 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
| WO2019191166A1 (en) | 2018-03-29 | 2019-10-03 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| CN108329308B (zh) | 2018-05-16 | 2022-11-01 | 四川科伦博泰生物医药股份有限公司 | 一种二氢嘧啶类化合物的固体形式及其制备方法 |
| US11053235B2 (en) | 2018-08-09 | 2021-07-06 | Janssen Sciences Ireland Unlimited Company | Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases |
| US10865211B2 (en) | 2018-09-21 | 2020-12-15 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| AU2019373090B2 (en) | 2018-10-31 | 2023-05-25 | The University Of Sydney | Compositions and methods for treating viral infections |
| US11198693B2 (en) | 2018-11-21 | 2021-12-14 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| US11236111B2 (en) | 2019-06-03 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| US11472808B2 (en) | 2019-06-04 | 2022-10-18 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents |
| WO2020247561A1 (en) | 2019-06-04 | 2020-12-10 | Enanta Pharmaceuticals, Inc, | Hepatitis b antiviral agents |
| US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
| US11236108B2 (en) | 2019-09-17 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| US11802125B2 (en) | 2020-03-16 | 2023-10-31 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
| CN113831359A (zh) * | 2020-06-24 | 2021-12-24 | 广东东阳光药业有限公司 | 二氢嘧啶类化合物及其在药物中的应用 |
| CN118955353A (zh) * | 2024-10-14 | 2024-11-15 | 南京恒远科技开发有限公司 | 一种(s)-4,4-二氟-1-甘氨酰吡咯烷-2-氰基的合成方法 |
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| JPS61271278A (ja) | 1985-05-20 | 1986-12-01 | イ− ア−ル スクイブ アンド サンズ インコ−ポレ−テツド | ２−置換チオまたはオキソ−４−アリ−ルまたはヘテロシクロ−５−カルボキシ−１，４−ジヒドロピリミジン |
| GB8906168D0 (en) | 1989-03-17 | 1989-05-04 | Pfizer Ltd | Therapeutic agents |
| SE9702564D0 (sv) | 1997-07-02 | 1997-07-02 | Astra Ab | New compounds |
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| DE19817262A1 (de) | 1998-04-18 | 1999-10-21 | Bayer Ag | Neue 2-heterocyclisch substituierte Dihydropyrimidine |
| DE19817264A1 (de) | 1998-04-18 | 1999-10-21 | Bayer Ag | Neue Dihydropyrimidine |
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| WO2000058302A1 (de) | 1999-03-25 | 2000-10-05 | Bayer Aktiengesellschaft | Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b |
| DE10012549A1 (de) | 2000-03-15 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
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| AU2014356984B2 (en) * | 2013-11-27 | 2018-01-04 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
-
2014
- 2014-11-18 JP JP2016530248A patent/JP6524081B2/ja active Active
- 2014-11-18 EP EP14863769.7A patent/EP3071564B1/en active Active
- 2014-11-18 AU AU2014352404A patent/AU2014352404B2/en active Active
- 2014-11-18 RU RU2016122908A patent/RU2678990C1/ru active
- 2014-11-18 US US15/022,562 patent/US9498479B2/en active Active
- 2014-11-18 CA CA2920415A patent/CA2920415A1/en not_active Abandoned
- 2014-11-18 KR KR1020167008618A patent/KR20160077050A/ko not_active Withdrawn
- 2014-11-18 WO PCT/CN2014/091444 patent/WO2015074546A1/en not_active Ceased
- 2014-11-18 MX MX2016006564A patent/MX2016006564A/es unknown
- 2014-11-18 CN CN201410657898.XA patent/CN104650068B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016537358A (ja) | 2016-12-01 |
| RU2016122908A (ru) | 2017-12-25 |
| EP3071564B1 (en) | 2020-08-05 |
| CN104650068A (zh) | 2015-05-27 |
| JP6524081B2 (ja) | 2019-06-05 |
| WO2015074546A1 (en) | 2015-05-28 |
| EP3071564A4 (en) | 2017-04-26 |
| KR20160077050A (ko) | 2016-07-01 |
| EP3071564A1 (en) | 2016-09-28 |
| MX2016006564A (es) | 2017-09-12 |
| AU2014352404A1 (en) | 2016-02-18 |
| RU2678990C1 (ru) | 2019-02-05 |
| US9498479B2 (en) | 2016-11-22 |
| US20160206616A1 (en) | 2016-07-21 |
| CN104650068B (zh) | 2018-08-10 |
| HK1224286A1 (en) | 2017-08-18 |
| AU2014352404B2 (en) | 2018-07-19 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |
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