TWI768467B - 用於治療及預防病毒感染之新穎磺醯亞胺醯基嘌呤酮化合物及衍生物 - Google Patents

Info

Publication number

TWI768467B

TWI768467B TW109131169A TW109131169A TWI768467B TW I768467 B TWI768467 B TW I768467B TW 109131169 A TW109131169 A TW 109131169A TW 109131169 A TW109131169 A TW 109131169A TW I768467 B TWI768467 B TW I768467B

Authority

TW

Taiwan

Prior art keywords

methyl

compound

purin

amino

chlorophenyl

Prior art date

2015-05-08

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 320
• 238000011282 treatment Methods 0.000 title claims description 25
• 230000009385 viral infection Effects 0.000 title description 5
• 238000011321 prophylaxis Methods 0.000 title 1
• 150000003839 salts Chemical class 0.000 claims abstract description 59
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 405
• 238000002360 preparation method Methods 0.000 claims description 297
• -1 2-methylpyrimidin-5-yl Chemical group 0.000 claims description 191
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 113
• 239000003814 drug Substances 0.000 claims description 19
• 229940044616 toll-like receptor 7 agonist Drugs 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 208000002672 hepatitis B Diseases 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 102000006992 Interferon-alpha Human genes 0.000 claims description 6
• 108010047761 Interferon-alpha Proteins 0.000 claims description 6
• 230000002265 prevention Effects 0.000 claims description 6
• 108091027076 Spiegelmer Proteins 0.000 claims description 5
• 239000013543 active substance Substances 0.000 claims description 2
• 229940126601 medicinal product Drugs 0.000 claims description 2
• 239000000203 mixture Substances 0.000 abstract description 43
• 229940002612 prodrug Drugs 0.000 abstract description 23
• 239000000651 prodrug Substances 0.000 abstract description 23
• 238000000034 method Methods 0.000 abstract description 18
• 238000004949 mass spectrometry Methods 0.000 description 320
• GTYRLXXHXBTNQV-UHFFFAOYSA-N 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one Chemical compound NC1=C2NC(N(C2=NC(=N1)S(=O)CCC)CC1=C(C=CC=C1)Cl)=O GTYRLXXHXBTNQV-UHFFFAOYSA-N 0.000 description 316
• 239000007787 solid Substances 0.000 description 255
• 150000002576 ketones Chemical class 0.000 description 175
• IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 154
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 153
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 130
• 238000005481 NMR spectroscopy Methods 0.000 description 101
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 100
• 150000001412 amines Chemical class 0.000 description 81
• 239000000460 chlorine Substances 0.000 description 71
• 229910052801 chlorine Inorganic materials 0.000 description 68
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
• 239000001301 oxygen Substances 0.000 description 54
• 229910052760 oxygen Inorganic materials 0.000 description 54
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 52
• UTKOWHRNPQDYNX-UHFFFAOYSA-N 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one Chemical compound NC1=C2NC(N(C2=NC(=N1)SCCC)CC1=C(C=CC=C1)Cl)=O UTKOWHRNPQDYNX-UHFFFAOYSA-N 0.000 description 52
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 49
• 125000000217 alkyl group Chemical group 0.000 description 41
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• UJMGBGIFVTZJHH-UHFFFAOYSA-N 6-amino-9-benzyl-2-methylsulfanyl-7h-purin-8-one Chemical compound C12=NC(SC)=NC(N)=C2N=C(O)N1CC1=CC=CC=C1 UJMGBGIFVTZJHH-UHFFFAOYSA-N 0.000 description 35
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
• 239000011541 reaction mixture Substances 0.000 description 33
• 239000000243 solution Substances 0.000 description 33
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 32
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 30
• 210000004027 cell Anatomy 0.000 description 29
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
• XTZYFTXASKYXGM-UHFFFAOYSA-N 6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanylpyrimidin-4-amine Chemical compound ClC1=C(C(=NC(=N1)SCCC)NCC1=C(C=CC=C1)Cl)[N+](=O)[O-] XTZYFTXASKYXGM-UHFFFAOYSA-N 0.000 description 27
• RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 27
• KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 26
• 235000019439 ethyl acetate Nutrition 0.000 description 25
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 238000000926 separation method Methods 0.000 description 24
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 23
• GNMOFFHKLDZUBH-UHFFFAOYSA-N 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one Chemical compound ClC1=C2NC(N(C2=NC(=N1)SCCC)CC1=C(C=CC=C1)Cl)=O GNMOFFHKLDZUBH-UHFFFAOYSA-N 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 23
• 150000004985 diamines Chemical class 0.000 description 23
• WPYNEOHJXNKMSR-UHFFFAOYSA-N 9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one Chemical compound ClC1=C(C=CC=C1)CN1C2=NC(=NC(=C2NC1=O)NCC1=CC=C(C=C1)OC)SCCC WPYNEOHJXNKMSR-UHFFFAOYSA-N 0.000 description 22
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 20
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
• 229910052736 halogen Inorganic materials 0.000 description 19
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 17
• SRMFHHGQKBMKFJ-UHFFFAOYSA-N 6-chloro-4-N-[(2-chlorophenyl)methyl]-2-propylsulfanylpyrimidine-4,5-diamine Chemical compound ClC1=C(C(=NC(=N1)SCCC)NCC1=C(C=CC=C1)Cl)N SRMFHHGQKBMKFJ-UHFFFAOYSA-N 0.000 description 17
• 230000006698 induction Effects 0.000 description 17
• 238000012360 testing method Methods 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 16
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 14
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 14
• 238000000746 purification Methods 0.000 description 14
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 13
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 13
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
• 238000003556 assay Methods 0.000 description 13
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 13
• 229960003180 glutathione Drugs 0.000 description 13
• 150000002367 halogens Chemical class 0.000 description 13
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 13
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
• 238000004296 chiral HPLC Methods 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• 229950003036 vesatolimod Drugs 0.000 description 12
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 11
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 11
• 229940079593 drug Drugs 0.000 description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
• 150000002500 ions Chemical class 0.000 description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
• LNJMHEJAYSYZKK-UHFFFAOYSA-N 2-methylpyrimidine Chemical compound CC1=NC=CC=N1 LNJMHEJAYSYZKK-UHFFFAOYSA-N 0.000 description 10
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 10
• 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 10
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 125000004803 chlorobenzyl group Chemical group 0.000 description 10
• 238000001990 intravenous administration Methods 0.000 description 10
• 230000002503 metabolic effect Effects 0.000 description 10
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
• 239000000523 sample Substances 0.000 description 10
• 238000002560 therapeutic procedure Methods 0.000 description 10
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
• 239000012267 brine Substances 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 229940095102 methyl benzoate Drugs 0.000 description 9
• 125000006178 methyl benzyl group Chemical group 0.000 description 9
• 239000002244 precipitate Substances 0.000 description 9
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 8
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 8
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 8
• YVHWMATXRMXZJI-UHFFFAOYSA-N 6-amino-9-benzyl-2-sulfanylidene-1,7-dihydropurin-8-one Chemical compound OC1=NC=2C(N)=NC(S)=NC=2N1CC1=CC=CC=C1 YVHWMATXRMXZJI-UHFFFAOYSA-N 0.000 description 8
• YVIPOEKXWHBWFI-UHFFFAOYSA-N CCCSC1=NC=C2NC=NC2=N1.[O] Chemical compound CCCSC1=NC=C2NC=NC2=N1.[O] YVIPOEKXWHBWFI-UHFFFAOYSA-N 0.000 description 8
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
• 102100033110 Toll-like receptor 8 Human genes 0.000 description 8
• 238000004458 analytical method Methods 0.000 description 8
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
• 229910052731 fluorine Inorganic materials 0.000 description 8
• 229910052739 hydrogen Inorganic materials 0.000 description 8
• 210000001853 liver microsome Anatomy 0.000 description 8
• 238000002953 preparative HPLC Methods 0.000 description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
• GYIUDLLQLVWKPP-UHFFFAOYSA-N 2-propylpentanoyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OC(=O)C(CCC)CCC GYIUDLLQLVWKPP-UHFFFAOYSA-N 0.000 description 7
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
• JHNLZOVBAQWGQU-UHFFFAOYSA-N 380814_sial Chemical compound CS(O)(=O)=O.O=P(=O)OP(=O)=O JHNLZOVBAQWGQU-UHFFFAOYSA-N 0.000 description 7
• HONIKIYFGCHQSJ-UHFFFAOYSA-N 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one Chemical compound NC1=C2NC(N(C2=NC(=N1)S(=O)C)CC1=CC=CC=C1)=O HONIKIYFGCHQSJ-UHFFFAOYSA-N 0.000 description 7
• XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 7
• 125000003545 alkoxy group Chemical group 0.000 description 7
• 230000015572 biosynthetic process Effects 0.000 description 7
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• 239000011737 fluorine Substances 0.000 description 7
• LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 7
• 239000000411 inducer Substances 0.000 description 7
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 7
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• FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 6
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• KEKCCGBGTHCKGI-UHFFFAOYSA-N CCCS(C1=NC=C2NC=NC2=N1)=O.[O] Chemical compound CCCS(C1=NC=C2NC=NC2=N1)=O.[O] KEKCCGBGTHCKGI-UHFFFAOYSA-N 0.000 description 6
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• 229910052757 nitrogen Inorganic materials 0.000 description 5
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