KR20160077050A - 다이하이드로피리미딘 화합물 및 이의 약제학적 용도 - Google Patents

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Publication number

KR20160077050A

KR20160077050A KR1020167008618A KR20167008618A KR20160077050A KR 20160077050 A KR20160077050 A KR 20160077050A KR 1020167008618 A KR1020167008618 A KR 1020167008618A KR 20167008618 A KR20167008618 A KR 20167008618A KR 20160077050 A KR20160077050 A KR 20160077050A

Authority

KR

South Korea

Prior art keywords

alkyl

compound

independently

methyl

mmol

Prior art date

2013-11-19

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.)

Withdrawn

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• 239000003814 drug Substances 0.000 title claims description 37
• WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 title abstract description 7
• 150000001875 compounds Chemical class 0.000 claims abstract description 555
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 110
• 201000010099 disease Diseases 0.000 claims abstract description 105
• 150000003839 salts Chemical class 0.000 claims abstract description 39
• 239000012453 solvate Substances 0.000 claims abstract description 16
• 230000002265 prevention Effects 0.000 claims abstract description 12
• -1 -S (= O) q - Chemical group 0.000 claims description 328
• 238000000034 method Methods 0.000 claims description 164
• 125000000217 alkyl group Chemical group 0.000 claims description 118
• 239000000203 mixture Substances 0.000 claims description 96
• 241000700721 Hepatitis B virus Species 0.000 claims description 94
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 94
• 229910052739 hydrogen Inorganic materials 0.000 claims description 77
• 239000001257 hydrogen Substances 0.000 claims description 76
• 125000001072 heteroaryl group Chemical group 0.000 claims description 68
• 125000000623 heterocyclic group Chemical group 0.000 claims description 65
• 150000002431 hydrogen Chemical class 0.000 claims description 62
• 125000003118 aryl group Chemical group 0.000 claims description 56
• 125000004432 carbon atom Chemical group C* 0.000 claims description 51
• 208000015181 infectious disease Diseases 0.000 claims description 48
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 41
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
• 230000003612 virological effect Effects 0.000 claims description 40
• 239000008194 pharmaceutical composition Substances 0.000 claims description 38
• 125000000335 thiazolyl group Chemical group 0.000 claims description 36
• 125000003545 alkoxy group Chemical group 0.000 claims description 33
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 33
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 31
• 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 29
• 125000001424 substituent group Chemical group 0.000 claims description 27
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
• 208000002672 hepatitis B Diseases 0.000 claims description 23
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 21
• 125000001425 triazolyl group Chemical group 0.000 claims description 21
• 238000004519 manufacturing process Methods 0.000 claims description 20
• 239000000651 prodrug Substances 0.000 claims description 20
• 229940002612 prodrug Drugs 0.000 claims description 20
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
• 239000003795 chemical substances by application Substances 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
• 229910052799 carbon Inorganic materials 0.000 claims description 16
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 15
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 15
• 206010016654 Fibrosis Diseases 0.000 claims description 14
• 230000007882 cirrhosis Effects 0.000 claims description 14
• 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 14
• 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
• 125000004076 pyridyl group Chemical group 0.000 claims description 13
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
• 125000002541 furyl group Chemical group 0.000 claims description 12
• 125000002883 imidazolyl group Chemical group 0.000 claims description 12
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 12
• 108010050904 Interferons Proteins 0.000 claims description 11
• 102000014150 Interferons Human genes 0.000 claims description 11
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 11
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
• 229940079322 interferon Drugs 0.000 claims description 10
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 10
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 10
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 125000002971 oxazolyl group Chemical group 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
• 102100040018 Interferon alpha-2 Human genes 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 150000002367 halogens Chemical class 0.000 claims description 8
• 125000001624 naphthyl group Chemical group 0.000 claims description 8
• 150000001204 N-oxides Chemical class 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001786 isothiazolyl group Chemical group 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
• 125000004306 triazinyl group Chemical group 0.000 claims description 7
• 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 6
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 6
• 108010078049 Interferon alpha-2 Proteins 0.000 claims description 6
• 239000002671 adjuvant Substances 0.000 claims description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims description 6
• 125000001188 haloalkyl group Chemical group 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
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 239000003981 vehicle Substances 0.000 claims description 6
• 108010079944 Interferon-alpha2b Proteins 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
• 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
• 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 claims description 4
• 102100040019 Interferon alpha-1/13 Human genes 0.000 claims description 4
• 108010002350 Interleukin-2 Proteins 0.000 claims description 4
• 102000000588 Interleukin-2 Human genes 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
• 125000003282 alkyl amino group Chemical group 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
• 125000002720 diazolyl group Chemical group 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
• 239000002955 immunomodulating agent Substances 0.000 claims description 4
• 229940121354 immunomodulator Drugs 0.000 claims description 4
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 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 class FC(F)(F)S(*)(=O)=O 0.000 claims description 4
• 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 3
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
• 108010019182 Alloferon Proteins 0.000 claims description 3
• 108010005716 Interferon beta-1a Proteins 0.000 claims description 3
• 108010047761 Interferon-alpha Proteins 0.000 claims description 3
• 102000006992 Interferon-alpha Human genes 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
• 229940123066 Polymerase inhibitor Drugs 0.000 claims description 3
• 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 3
• 229920000519 Sizofiran Polymers 0.000 claims description 3
• 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 3
• 229960003205 adefovir dipivoxil Drugs 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 229950001357 celmoleukin Drugs 0.000 claims description 3
• 229960005338 clevudine Drugs 0.000 claims description 3
• 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 3
• 239000013256 coordination polymer Substances 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
• 229960004396 famciclovir Drugs 0.000 claims description 3
• 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 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
• 230000002584 immunomodulator Effects 0.000 claims description 3
• 229960004461 interferon beta-1a Drugs 0.000 claims description 3
• 229960001614 levamisole Drugs 0.000 claims description 3
• 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 3
• 229950008403 mivotilate Drugs 0.000 claims description 3
• 229960002480 nitazoxanide Drugs 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 229960000329 ribavirin Drugs 0.000 claims description 3
• 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 3
• 229950001403 sizofiran Drugs 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000003107 substituted aryl group Chemical class 0.000 claims description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 140
• 238000004611 spectroscopical analysis Methods 0.000 description 129
• 150000002500 ions Chemical class 0.000 description 118
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
• 238000005481 NMR spectroscopy Methods 0.000 description 69
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 66
• 239000007787 solid Substances 0.000 description 64
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
• 239000000243 solution Substances 0.000 description 59
• 238000006243 chemical reaction Methods 0.000 description 55
• 235000019441 ethanol Nutrition 0.000 description 55
• 235000019439 ethyl acetate Nutrition 0.000 description 47
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 44
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 44
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 44
• 239000003921 oil Substances 0.000 description 42
• 235000019198 oils Nutrition 0.000 description 42
• 238000002360 preparation method Methods 0.000 description 35
• 229910000027 potassium carbonate Inorganic materials 0.000 description 33
• 0 CCCC(C)N1CC(*)(*)CC*(CC*C)C1 Chemical compound CCCC(C)N1CC(*)(*)CC*(CC*C)C1 0.000 description 31
• 125000005997 bromomethyl group Chemical group 0.000 description 29
• 230000000670 limiting effect Effects 0.000 description 28
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
• 238000004440 column chromatography Methods 0.000 description 27
• 239000000377 silicon dioxide Substances 0.000 description 27
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 26
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 25
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
• 235000019260 propionic acid Nutrition 0.000 description 25
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
• 230000015572 biosynthetic process Effects 0.000 description 24
• 239000012230 colorless oil Substances 0.000 description 24
• 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 24
• 238000003786 synthesis reaction Methods 0.000 description 24
• 229910052757 nitrogen Inorganic materials 0.000 description 22
• 239000000126 substance Substances 0.000 description 20
• 239000011541 reaction mixture Substances 0.000 description 18
• 239000011734 sodium Substances 0.000 description 18
• 239000004698 Polyethylene Substances 0.000 description 17
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 17
• 239000012074 organic phase Substances 0.000 description 17
• IJVLVRYLIMQVDD-UHFFFAOYSA-N 1,3-thiazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CS1 IJVLVRYLIMQVDD-UHFFFAOYSA-N 0.000 description 16
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
• 229910052805 deuterium Inorganic materials 0.000 description 14
• 125000006239 protecting group Chemical group 0.000 description 14
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 13
• 230000001684 chronic effect Effects 0.000 description 13
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• 239000000706 filtrate Substances 0.000 description 12
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• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
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• 229940124597 therapeutic agent Drugs 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• 238000004458 analytical method Methods 0.000 description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
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• 239000003153 chemical reaction reagent Substances 0.000 description 8
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• 230000002401 inhibitory effect Effects 0.000 description 8
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• PPAKHTONXJJHHK-UHFFFAOYSA-N 1,1-dioxo-1,4-thiazinane-3-carboxylic acid Chemical compound OC(=O)C1CS(=O)(=O)CCN1 PPAKHTONXJJHHK-UHFFFAOYSA-N 0.000 description 7
• WMRYWMDQRKGTOB-QFWZMSBNSA-N 3-[(2R)-4,4-difluoropyrrolidin-2-yl]-2-methylpropanoic acid hydrochloride Chemical compound Cl.FC1(C[C@H](NC1)CC(C(=O)O)C)F WMRYWMDQRKGTOB-QFWZMSBNSA-N 0.000 description 7
• 230000001154 acute effect Effects 0.000 description 7
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
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• 150000002148 esters Chemical class 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
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