JP2008508319A

JP2008508319A - 新規ヌクレオシド誘導体

新規ヌクレオシド誘導体 Download PDF

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Publication number: JP2008508319A
Authority: JP; Japan
Prior art keywords: alkyl; group; aryl; substituted; optionally substituted
Prior art date: 2004-07-29
Legal status : Withdrawn

Application number

JP2007523879A

Other languages

English (en)

Japanese (ja)

Other versions

JP2008508319A5 (enExample

Inventor

ケイ・ラジャ・レディ

マーク・ディ・エライオン

Current Assignee

Metabasis Therapeutics Inc

Original Assignee

Metabasis Therapeutics Inc

Priority date

2004-07-29

Filing date

2005-07-29

Publication date

2008-03-21

2004-07-29 Priority claimed from US10/903,215 external-priority patent/US20050182252A1/en

2005-07-29 Application filed by Metabasis Therapeutics Inc filed Critical Metabasis Therapeutics Inc

2008-03-21 Publication of JP2008508319A publication Critical patent/JP2008508319A/ja

2008-09-11 Publication of JP2008508319A5 publication Critical patent/JP2008508319A5/ja

Status Withdrawn legal-status Critical Current

Links

150000003833 nucleoside derivatives Chemical class 0.000 title description 52
150000001875 compounds Chemical class 0.000 claims abstract description 182
239000000651 prodrug Substances 0.000 claims abstract description 126
229940002612 prodrug Drugs 0.000 claims abstract description 126
150000003839 salts Chemical class 0.000 claims abstract description 31
206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
206010028980 Neoplasm Diseases 0.000 claims abstract description 9
201000011510 cancer Diseases 0.000 claims abstract description 9
125000000217 alkyl group Chemical group 0.000 claims description 209
-1 hydrate Substances 0.000 claims description 197
125000003118 aryl group Chemical group 0.000 claims description 138
238000000034 method Methods 0.000 claims description 100
229910052721 tungsten Inorganic materials 0.000 claims description 83
229910052799 carbon Inorganic materials 0.000 claims description 76
125000004429 atom Chemical group 0.000 claims description 69
125000004122 cyclic group Chemical group 0.000 claims description 59
125000001424 substituent group Chemical group 0.000 claims description 52
125000003710 aryl alkyl group Chemical group 0.000 claims description 51
229910052717 sulfur Inorganic materials 0.000 claims description 49
125000005842 heteroatom Chemical group 0.000 claims description 48
239000003814 drug Substances 0.000 claims description 46
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
229910052739 hydrogen Inorganic materials 0.000 claims description 44
229910052736 halogen Inorganic materials 0.000 claims description 43
150000002367 halogens Chemical class 0.000 claims description 43
229910052760 oxygen Inorganic materials 0.000 claims description 43
229940079593 drug Drugs 0.000 claims description 42
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 40
125000000753 cycloalkyl group Chemical group 0.000 claims description 39
125000003545 alkoxy group Chemical group 0.000 claims description 34
125000000304 alkynyl group Chemical group 0.000 claims description 33
125000003342 alkenyl group Chemical group 0.000 claims description 32
150000002148 esters Chemical class 0.000 claims description 32
125000001309 chloro group Chemical group Cl* 0.000 claims description 31
125000004093 cyano group Chemical group *C#N 0.000 claims description 31
125000001072 heteroaryl group Chemical group 0.000 claims description 31
125000002252 acyl group Chemical group 0.000 claims description 30
229910052731 fluorine Inorganic materials 0.000 claims description 30
229910052757 nitrogen Inorganic materials 0.000 claims description 30
125000001246 bromo group Chemical group Br* 0.000 claims description 28
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
229910052698 phosphorus Inorganic materials 0.000 claims description 27
230000009385 viral infection Effects 0.000 claims description 27
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 22
208000036142 Viral infection Diseases 0.000 claims description 22
239000012453 solvate Substances 0.000 claims description 22
229910052720 vanadium Inorganic materials 0.000 claims description 22
125000003282 alkyl amino group Chemical group 0.000 claims description 20
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 19
239000011574 phosphorus Substances 0.000 claims description 19
125000002877 alkyl aryl group Chemical group 0.000 claims description 17
125000004432 carbon atom Chemical group C* 0.000 claims description 17
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
239000003795 chemical substances by application Substances 0.000 claims description 16
125000004663 dialkyl amino group Chemical group 0.000 claims description 16
125000001153 fluoro group Chemical group F* 0.000 claims description 16
125000003107 substituted aryl group Chemical group 0.000 claims description 16
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
208000015181 infectious disease Diseases 0.000 claims description 13
125000004076 pyridyl group Chemical group 0.000 claims description 13
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 12
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 11
125000004414 alkyl thio group Chemical group 0.000 claims description 11
239000003112 inhibitor Substances 0.000 claims description 11
239000008194 pharmaceutical composition Substances 0.000 claims description 11
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
125000004423 acyloxy group Chemical group 0.000 claims description 10
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
125000000547 substituted alkyl group Chemical group 0.000 claims description 10
125000001544 thienyl group Chemical group 0.000 claims description 10
IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group 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 9
125000002993 cycloalkylene group Chemical group 0.000 claims description 9
125000002541 furyl group Chemical group 0.000 claims description 9
230000002401 inhibitory effect Effects 0.000 claims description 9
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 9
229960000329 ribavirin Drugs 0.000 claims description 9
150000001540 azides Chemical class 0.000 claims description 8
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
125000006310 cycloalkyl amino group Chemical group 0.000 claims description 8
230000029812 viral genome replication Effects 0.000 claims description 8
IWUCXVSUMQZMFG-RGDLXGNYSA-N 1-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide Chemical compound N1=C(C(=O)N)N=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 IWUCXVSUMQZMFG-RGDLXGNYSA-N 0.000 claims description 7
108010047761 Interferon-alpha Proteins 0.000 claims description 7
102000006992 Interferon-alpha Human genes 0.000 claims description 7
125000005041 acyloxyalkyl group Chemical group 0.000 claims description 7
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 7
150000001721 carbon Chemical group 0.000 claims description 7
230000001419 dependent effect Effects 0.000 claims description 7
239000000546 pharmaceutical excipient Substances 0.000 claims description 7
125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 6
230000010076 replication Effects 0.000 claims description 6
102000009346 Adenosine receptors Human genes 0.000 claims description 5
108050000203 Adenosine receptors Proteins 0.000 claims description 5
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
206010061218 Inflammation Diseases 0.000 claims description 5
108010050904 Interferons Proteins 0.000 claims description 5
102000014150 Interferons Human genes 0.000 claims description 5
125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 5
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
230000004054 inflammatory process Effects 0.000 claims description 5
229940079322 interferon Drugs 0.000 claims description 5
NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 claims description 5
229910052727 yttrium Inorganic materials 0.000 claims description 5
208000024172 Cardiovascular disease Diseases 0.000 claims description 4
150000003838 adenosines Chemical class 0.000 claims description 4
125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 claims description 4
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 4
208000015114 central nervous system disease Diseases 0.000 claims description 4
208000019425 cirrhosis of liver Diseases 0.000 claims description 4
239000002464 receptor antagonist Substances 0.000 claims description 4
229940044551 receptor antagonist Drugs 0.000 claims description 4
229950006081 taribavirin Drugs 0.000 claims description 4
208000031226 Hyperlipidaemia Diseases 0.000 claims description 3
208000008589 Obesity Diseases 0.000 claims description 3
208000013544 Platelet disease Diseases 0.000 claims description 3
102000012479 Serine Proteases Human genes 0.000 claims description 3
108010022999 Serine Proteases Proteins 0.000 claims description 3
125000004419 alkynylene group Chemical group 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
235000019000 fluorine Nutrition 0.000 claims description 3
125000002950 monocyclic group Chemical group 0.000 claims description 3
208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 3
206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 3
235000020824 obesity Nutrition 0.000 claims description 3
125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 3
229910052711 selenium Inorganic materials 0.000 claims description 3
MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 claims description 2
101710088194 Dehydrogenase Proteins 0.000 claims description 2
108090000467 Interferon-beta Proteins 0.000 claims description 2
102000003996 Interferon-beta Human genes 0.000 claims description 2
108010078233 Thymalfasin Proteins 0.000 claims description 2
102400000800 Thymosin alpha-1 Human genes 0.000 claims description 2
229960001388 interferon-beta Drugs 0.000 claims description 2
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 claims description 2
229960004231 thymalfasin Drugs 0.000 claims description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
HAEJPQIATWHALX-KQYNXXCUSA-N ITP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(N=CNC2=O)=C2N=C1 HAEJPQIATWHALX-KQYNXXCUSA-N 0.000 claims 1
125000005189 alkyl hydroxy group Chemical group 0.000 claims 1
125000005724 cycloalkenylene group Chemical group 0.000 claims 1
125000005750 substituted cyclic group Chemical group 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 32
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 19
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OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 240
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239000000243 solution Substances 0.000 description 116
239000002777 nucleoside Substances 0.000 description 104
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
235000019439 ethyl acetate Nutrition 0.000 description 90
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238000000921 elemental analysis Methods 0.000 description 82
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238000002844 melting Methods 0.000 description 60
230000008018 melting Effects 0.000 description 60
125000003835 nucleoside group Chemical group 0.000 description 54
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229910019142 PO4 Inorganic materials 0.000 description 47
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IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
238000003756 stirring Methods 0.000 description 35
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
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238000006317 isomerization reaction Methods 0.000 description 26
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241000711549 Hepacivirus C Species 0.000 description 25
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239000000543 intermediate Substances 0.000 description 21
210000004185 liver Anatomy 0.000 description 21
150000004649 carbonic acid derivatives Chemical class 0.000 description 20
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
239000002243 precursor Substances 0.000 description 20
230000009467 reduction Effects 0.000 description 20
238000006722 reduction reaction Methods 0.000 description 20
YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 19
239000003921 oil Substances 0.000 description 19
BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 18
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
238000009472 formulation Methods 0.000 description 18
125000003729 nucleotide group Chemical group 0.000 description 18
235000019198 oils Nutrition 0.000 description 18
235000021317 phosphate Nutrition 0.000 description 18
238000006366 phosphorylation reaction Methods 0.000 description 18
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 16
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
239000002253 acid Substances 0.000 description 16
239000004480 active ingredient Substances 0.000 description 16
239000003153 chemical reaction reagent Substances 0.000 description 16
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WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
238000004128 high performance liquid chromatography Methods 0.000 description 15
150000000185 1,3-diols Chemical class 0.000 description 14
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
238000001816 cooling Methods 0.000 description 14
239000012071 phase Substances 0.000 description 14
239000000725 suspension Substances 0.000 description 14
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
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238000010168 coupling process Methods 0.000 description 12
238000005859 coupling reaction Methods 0.000 description 12
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
239000002904 solvent Substances 0.000 description 12
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 11
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239000001257 hydrogen Substances 0.000 description 11
125000006413 ring segment Chemical group 0.000 description 11
238000006467 substitution reaction Methods 0.000 description 11
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
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UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
239000011734 sodium Substances 0.000 description 9
239000007858 starting material Substances 0.000 description 9
239000000126 substance Substances 0.000 description 9
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150000001412 amines Chemical class 0.000 description 8
ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical class OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 8
239000012043 crude product Substances 0.000 description 8
238000010828 elution Methods 0.000 description 8
239000000284 extract Substances 0.000 description 8
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238000013459 approach Methods 0.000 description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
238000005810 carbonylation reaction Methods 0.000 description 7
230000003197 catalytic effect Effects 0.000 description 7
229910052801 chlorine Inorganic materials 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
125000000524 functional group Chemical group 0.000 description 7
210000003494 hepatocyte Anatomy 0.000 description 7
125000000623 heterocyclic group Chemical group 0.000 description 7
230000037361 pathway Effects 0.000 description 7
239000000758 substrate Substances 0.000 description 7
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
210000001519 tissue Anatomy 0.000 description 7
VJGRFGFLZJIODS-VIFPVBQESA-N (1s)-1-(3-chlorophenyl)propane-1,3-diol Chemical compound OCC[C@H](O)C1=CC=CC(Cl)=C1 VJGRFGFLZJIODS-VIFPVBQESA-N 0.000 description 6
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125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 6
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 6
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