TW201617317A - 吡啶酮衍生物 - Google Patents
吡啶酮衍生物 Download PDFInfo
- Publication number
- TW201617317A TW201617317A TW104123125A TW104123125A TW201617317A TW 201617317 A TW201617317 A TW 201617317A TW 104123125 A TW104123125 A TW 104123125A TW 104123125 A TW104123125 A TW 104123125A TW 201617317 A TW201617317 A TW 201617317A
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- mmol
- oxo
- compound
- tolyl
- Prior art date
Links
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 208000036142 Viral infection Diseases 0.000 claims description 10
- 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 10
- 230000009385 viral infection Effects 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000001177 retroviral effect Effects 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000013160 medical therapy Methods 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 230000003612 virological effect Effects 0.000 abstract description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- 239000012043 crude product Substances 0.000 description 27
- 239000011734 sodium Substances 0.000 description 26
- 239000012267 brine Substances 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- -1 (E)-2-(4-Hydroxybut-2-enylamino)-4,4-dimethylpentanoic acid ethyl ester Chemical compound 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 229940070710 valerate Drugs 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 7
- 208000031886 HIV Infections Diseases 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 102100036220 PC4 and SFRS1-interacting protein Human genes 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- JORVRJNILJXMMG-OLNQLETPSA-N brecanavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=C2OCOC2=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C(C=C1)=CC=C1OCC1=CSC(C)=N1 JORVRJNILJXMMG-OLNQLETPSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- NAYOGGQFBZAZIV-UHFFFAOYSA-N 1-methyl-4-prop-1-ynylbenzene Chemical compound CC#CC1=CC=C(C)C=C1 NAYOGGQFBZAZIV-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102100034343 Integrase Human genes 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 3
- 229910018286 SbF 6 Inorganic materials 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 230000000798 anti-retroviral effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 108010093345 lens epithelium-derived growth factor Proteins 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000009118 salvage therapy Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- OVBFMEVBMNZIBR-UHFFFAOYSA-N -2-Methylpentanoic acid Natural products CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 2
- YBBUFCHRVBHVDA-UHFFFAOYSA-N 2-[4-(3,4-dimethylphenyl)-3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]-4,4-dimethylpentanoic acid Chemical compound CC=1C=C(C=CC=1C)C1=CC(N(C(=C1C)C1=CC=C(C=C1)C)C(C(=O)O)CC(C)(C)C)=O YBBUFCHRVBHVDA-UHFFFAOYSA-N 0.000 description 2
- GENBZKIZEPVKAX-UHFFFAOYSA-N 2-[4-(3,4-dimethylphenyl)-5-(methanesulfonamido)-3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]-4,4-dimethylpentanoic acid Chemical compound CC=1C=C(C=CC=1C)C1=C(C(N(C(=C1C)C1=CC=C(C=C1)C)C(C(=O)O)CC(C)(C)C)=O)NS(=O)(=O)C GENBZKIZEPVKAX-UHFFFAOYSA-N 0.000 description 2
- KSMVBYPXNKCPAJ-UHFFFAOYSA-N 4-Methylcyclohexylamine Chemical compound CC1CCC(N)CC1 KSMVBYPXNKCPAJ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000037357 HIV infectious disease Diseases 0.000 description 2
- 108700020129 Human immunodeficiency virus 1 p31 integrase Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940124522 antiretrovirals Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 229950009079 brecanavir Drugs 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229940124524 integrase inhibitor Drugs 0.000 description 2
- 239000002850 integrase inhibitor Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- FUVFAUBWEXSLEY-AATRIKPKSA-N (e)-3-(3,4-dimethylphenyl)prop-2-enoic acid Chemical compound CC1=CC=C(\C=C\C(O)=O)C=C1C FUVFAUBWEXSLEY-AATRIKPKSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HRFIOBHTXZSEGE-UHFFFAOYSA-N 2-[5-(cyclohexylmethylsulfonylamino)-3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]-4,4-dimethylpentanoic acid Chemical compound C1(CCCCC1)CS(=O)(=O)NC=1C(N(C(=C(C=1)C)C1=CC=C(C=C1)C)C(C(=O)O)CC(C)(C)C)=O HRFIOBHTXZSEGE-UHFFFAOYSA-N 0.000 description 1
- LPBSHGLDBQBSPI-UHFFFAOYSA-N 2-azaniumyl-4,4-dimethylpentanoate Chemical compound CC(C)(C)CC(N)C(O)=O LPBSHGLDBQBSPI-UHFFFAOYSA-N 0.000 description 1
- RMQJECWPWQIIPW-OWOJBTEDSA-N 4-hydroxy-crotonic acid Chemical compound OC\C=C\C(O)=O RMQJECWPWQIIPW-OWOJBTEDSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000029483 Acquired immunodeficiency Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101100025412 Arabidopsis thaliana XI-A gene Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010016948 Food interaction Diseases 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- JCUYKJIVFPLSFL-UHFFFAOYSA-N P.C1=CC=CC=2OC3=CC=CC=C3CC12 Chemical compound P.C1=CC=CC=2OC3=CC=CC=C3CC12 JCUYKJIVFPLSFL-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011225 antiretroviral therapy Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- AAZKJJLBNOMHFP-UHFFFAOYSA-N ethyl 2-[4-(3,4-dimethylphenyl)-5-(methanesulfonamido)-3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]-4,4-dimethylpentanoate Chemical compound CC=1C=C(C=CC=1C)C1=C(C(N(C(=C1C)C1=CC=C(C=C1)C)C(C(=O)OCC)CC(C)(C)C)=O)NS(=O)(=O)C AAZKJJLBNOMHFP-UHFFFAOYSA-N 0.000 description 1
- QVSXBCFVIGFLIO-UHFFFAOYSA-N ethyl 2-[5-amino-3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]-4,4-dimethylpentanoate Chemical compound NC=1C(N(C(=C(C=1)C)C1=CC=C(C=C1)C)C(C(=O)OCC)CC(C)(C)C)=O QVSXBCFVIGFLIO-UHFFFAOYSA-N 0.000 description 1
- AVFUUMWLRLXLGY-UHFFFAOYSA-N ethyl 2-[5-bromo-3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]-4,4-dimethylpentanoate Chemical compound BrC=1C(N(C(=C(C=1)C)C1=CC=C(C=C1)C)C(C(=O)OCC)CC(C)(C)C)=O AVFUUMWLRLXLGY-UHFFFAOYSA-N 0.000 description 1
- FGAFDMQUGIMOHR-UHFFFAOYSA-N ethyl 2-amino-4,4-dimethylpentanoate Chemical compound CCOC(=O)C(N)CC(C)(C)C FGAFDMQUGIMOHR-UHFFFAOYSA-N 0.000 description 1
- CLQYSYLJNDMAFR-UHFFFAOYSA-N ethyl 4,4-dimethyl-2-[3-methyl-2-(4-methylphenyl)-6-oxopyridin-1-yl]pentanoate Chemical compound CC(CC(C(=O)OCC)N1C(C=CC(=C1C1=CC=C(C=C1)C)C)=O)(C)C CLQYSYLJNDMAFR-UHFFFAOYSA-N 0.000 description 1
- PUJGGPCGKBGBAD-UHFFFAOYSA-N ethyl 4,4-dimethylpentanoate Chemical compound CCOC(=O)CCC(C)(C)C PUJGGPCGKBGBAD-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本發明揭示式I化合物及以包含此等化合物之組合物治療病毒感染之方法。
□
Description
本發明係關於經取代之吡啶酮化合物、醫藥組合物,及使用其之方法,該方法藉由投與此等化合物,來(i)抑制感染HIV個體中HIV複製;及(ii)治療感染HIV之個體。
人類免疫缺乏病毒類型1(HIV-1)會導致後天免疫缺乏症(AIDS)之害病。HIV病例數量持續上升,且目前全世界超過2500萬個體罹患該病毒。目前,以抗逆轉錄藥物長期抑制病毒複製係治療HIV-1感染之唯一選項。事實上,美國食品與藥品管理局已核准6種不同抑制劑類別內之25種藥品,其已顯示可極大增加患者存活及提高生活品質。然而,由於非所欲的藥物與藥物相互作用;藥物與食物相互作用;對療法無遵從性;及由於目標酶突變之耐藥性,故仍需要額外療法。
目前,幾乎所有HIV陽性患者皆使用抗逆轉錄藥物組合之治療方案(稱為高活性抗逆轉錄病毒療法(「HAART」))來治療。然而,由於不同藥物組合必須經常每天投與患者以防止耐藥性HIV-1變異體迅速出現,所以HAART療法通常係複雜的。儘管HAART對患者存活具有正影響,但是耐藥性仍會出現。耐多藥性HIV-1隔離群之出現具有嚴重臨床後果且必須用一種新穎藥物方案來抑制,稱為挽救療法。
目前指導方針建議挽救療法包括至少兩種,及較佳三種完全活性藥物。典型地,一線療法組合三至四種靶向病毒酶反轉錄酶及蛋白
酶之藥物。挽救療法之一選項係投與自保持抗耐藥性隔離群活性之相同機制類別之藥物之不同組合。然而,本方法之選項通常受限,因為耐藥性突變經常賦予相同類別中不同藥物廣泛交叉耐藥性。在開發融合、進入及整合酶抑制劑下,近期替代療法策略變得可行。然而,對所有三種新藥物類別之耐藥性已經於實驗室及於患者中進行報導。因此,用抗逆轉錄藥物持續成功治療HIV-1感染患者,仍需要持續開發具有新穎目標及作用機制的新穎且改良之藥物。
例如,在過去十年間已經報導HIV抑制劑靶向HIV-1整合酶與晶狀體上皮源性生長因子/p75(「LEDGF」)間之蛋白質與蛋白質相互作用。LEDGF係HIV-1整合酶之細胞轉錄輔助因子,其藉由繫接預整合複合物至染色質來促進反轉綠病毒cDNA之病毒整合入宿主細胞基因組中。由於LEDGF與整合酶間之相互作用在早期HIV複製階段之重要作用,因此其代表HIV藥物療法之另一有吸引力目標。
簡言之,在一態樣中,本發明揭示式I化合物:
其中:R1係視情況經一至四個選自C1-3烷基、鹵素或-CH2CH2CH2O-之取代基取代之苯基,其中該基團係鍵結至苯基上之相鄰碳原子以形成
環;L係鍵、C1-3伸烷基、-SO2-、-SO2CH2-、-NHSO2-、-NHSO2CH2-、-C(O)-、-C(O)NH-、-C(O)NHCH2-、-C(O)OCH2-、-C(O)C(O)-、-CH2C(O)-、C3-7雜芳基、或-C3-7雜芳基NH-,其中各雜芳基包括一至三個選自S、N、及O之雜原子;R2係H、環己基或苯基,其中該環己基及苯基視情況經一至三個選自C1-3烷基及鹵素之取代基取代;R3係H或-NHSO2R4,其中R4係C1-8烷基及其中該烷基可包括環烷基部分。
在本發明之另一態樣揭示式I化合物之醫藥上可接受的鹽。
在另一態樣中,本發明揭示醫藥組合物,其包含式I化合物或其醫藥上可接受的鹽。
在另一態樣中,本發明揭示一種用於治療患者之病毒感染的方法,該病毒感染至少部分由逆轉錄病毒科病毒中之病毒介導,該方法包括投與該患者包含式I化合物或其醫藥上可接受之鹽的組合物。在一些實施例中,該病毒感染係由HIV病毒介導。
在另一態樣中,本發明之一特定實施例提供一種治療感染HIV之個體之方法,其包括投與該個體治療上有效量之式I化合物或其醫藥上可接受之鹽。
在又一態樣中,本發明之一特定實施例提供一種抑制處於感染HIV危險之個體之HIV感染進展的方法,其包括投與該個體治療上有效量之式I化合物或其醫藥上可接受之鹽。彼等及其他實施例係進一步述於下文中。
根據本發明之另一實施例,提供一種預防或治療哺乳動物之至少部分由逆轉錄病毒科病毒中之病毒介導之病毒感染的方法,該方法包括投與式I定義之化合物給已被確診該病毒感染或處於發展該病毒
感染之危險的哺乳動物,其中該病毒係HIV病毒及進一步包括投與治療上有效量之一或多種抗HIV病毒之活性藥劑,其中該抗HIV病毒之活性藥劑選自由核苷酸逆轉錄酶抑制劑;非核苷酸逆轉錄酶抑制劑;蛋白酶抑制劑;進入、附著及融合抑制劑;整合酶抑制劑;成熟抑制劑;CXCR4抑制劑;及CCR5抑制劑組成之群。
較佳地,R1係視情況經甲基取代之苯基。
較佳地,L係鍵、-噁二唑基-NH-、-C(O)NH-或-C(O)NHCH2-。
較佳地,R2係H、環己基、或苯基,其中該環己基及苯基視情況經1或2個甲基取代。
較佳地,R3係H、-NHSO2CH3、或-NHSO2CH2環己基。
較佳地,第三丁基所鍵結之碳上的立體化學係如下所描繪:
「醫藥上可接受之鹽」係指衍生自技術上熟知之多種有機及無機抗衡離子之醫藥上可接受的鹽,及包括,僅舉例言之,鈉、鉀、鈣、鎂、銨、及四烷基銨,及當該分子包含鹼性官能度時,有機或無機酸之鹽,諸如鹽酸鹽、氢溴酸鹽、酒石酸鹽、甲磺酸鹽、乙酸鹽、馬來酸鹽及草酸鹽。合適鹽包括彼等描述於P.Heinrich Stahl,Camille G.Wermuth(編輯),Handbook of Pharmaceutical Salts Properties,Selection,and Use;2002中者。
實例
本發明化合物可藉由多種方法,包括熟知的標準合成方法製得。說明性一般合成方法陳述於下,然後於工作實例中製備本發明之特定化合物。
實例1:4,4-二甲基-2-(5-甲基-4-(((1r,4r)-4-甲基環己基)胺甲醯基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
步驟1:(E)-2-(4-羥基丁-2-烯醯胺基)-4,4-二甲基戊酸乙酯
向含於DMF(5mL)中之(E)-4-羥基丁-2-烯酸(418mg,4.09mmol)之溶液添加DIPEA(3.5mL,20.5mmol)、HBTU(3.2g,8.2mmol)及2-胺基-4,4-二甲基戊酸乙酯(1.05g,6.1mmol)。30分鐘後,將反應混合物分配在DCM與水之間。分離層及用DCM(20mL×2)萃取水層。用NaHCO3(水溶液)及鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=1:1)純化,以得到呈黃色固體之標題化合物(1.05g,64%產率)。LC-MS(ESI):m/z(M+1)=258.23。
步驟2:(E)-2-(4-(第三丁基二甲基矽烷氧基)丁-2-烯醯胺基)-4,4-二甲基戊酸乙酯
向含於DCM(10mL)中之(E)-(4-羥基丁-2-烯醯胺基)-4,4-二甲基戊酸乙酯之溶液添加DMAP(498mg,4.1mmol)、咪唑(833mg,12.3mmol)及TBSCl(922mg,6.2mmol)。2小時後,用水驟冷反應混合物及用DCM(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=5:1)純化,以提供呈黃色油之標題化合物(800mg,53%產率)。LC-MS(ESI):m/z(M+1)=372.24。
步驟3:2-(4-((第三丁基二甲基矽烷氧基)甲基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
自如Angew.Chem.Int.Edit.,2012 51,1287-1294中所述之已知程序製備1-甲基-4-(丙-1-炔-1-基)苯。
於80℃下,攪拌含於DCE(10mL)中之(E)-2-(4-(第三丁基二甲基矽烷氧基)丁-2-烯醯胺基)-4,4-a二甲基戊酸乙酯(300mg,0.81mmol)、1-甲基-4-(丙-1-炔基)苯(132mg,1.0mmol)、RhCp*(MeCN)3(SbF6)2(33.7mg,0.04mmol)及Cu(OAc)2.H2O(340mg,1.7mmol)之混合物。18小時後,將該混合物冷卻至環境溫度及用含於飽和NH4Cl(水溶液)中之10% NH3.H2O驟冷及用DCM(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,含於DCM中之2%MeOH)純化,以提供呈黃色固體之標題化合物(114mg,28%產率)。LC-MS(ESI):m/z(M+1)=500.31。
步驟4:2-(4-(羥甲基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於THF(3mL)中之2-(4-((第三丁基二甲基矽烷氧基)甲基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(114mg,0.23mmol)之溶液添加TBAF(120mg,0.46mmol)。1小時後,將該反應混合物分配在EtOAc與水之間。分離該等層及用H2O及鹽水洗
滌有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到呈黃色油之標題化合物(108mg,定量產率),將其用於下一步驟而無需進一步純化。LC-MS(ESI):m/z(M+1)386.18。
步驟5:2-(4-甲醯基-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於DCM(5mL)中之2-(4-(羥甲基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(108mg,0.28mmol)之溶液添加DMP(214mg,0.50mmol)。1小時後,用NaHCO3(水溶液)驟冷反應混合物及用DCM(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以提供呈黃色固體之標題化合物(63mg,58%產率)。LC-MS(ESI):m/z(M+1)=384.3。
步驟6:1-(1-乙氧基-4,4-二甲基-1-側氧基戊-2-基)-5-甲基-2-側氧基-6-對甲苯基-1,2-二氫吡啶-4-甲酸
於密封管中,向含於THF(2.2mL)、t-BuOH(2.2mL)及異丁烯(4.5ml)中之2-(4-甲醯基-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(63mg,0.16mmol)之溶液添加含於H2O(5mL)中之NaH2PO4及NaClO2溶液。18小時後,用1N HCl(0.5mL)酸化反應混
合物及用乙酸乙酯(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到呈黃色固體之標題化合物(51mg,80%產率),將其用於下一步驟而無需進一步純化。LC-MS(ESI):m/z(M+1)=400.1。
步驟7:4,4-二甲基-2-(5-甲基-4-((1r,4r)-4-甲基環己基胺甲醯基)-2-側氧基-6-對甲苯基吡啶-1(2H)-基)戊酸乙酯
用DIPEA(0.06mL,0.35mmol)、HBTU(54.2mg,0.14mmol)及反式-4-甲基環己基胺(0.02ml,0.14mmol)處理含於DMF(2mL)中之1-(1-乙氧基-4,4-二甲基-1-側氧基戊-2-基)-5-甲基-2-側氧基-6-對甲苯基-1,2-二氫吡啶-4-甲酸(28mg,0.07mmol)溶液。18小時後,用水稀釋反應混合物及用DCM(20ml×3)萃取。用NaHCO3(水溶液)及鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由製備型TLC(PE:EA=1:1)純化,以提供呈黃色固體之標題化合物(30mg,86%)。LC-MS(ESI):m/z(M+1)=495.37。
步驟8:4,4-二甲基-2-(5-甲基-4-((1r,4r)-4-甲基環己基胺甲醯基)-2-側氧基-6-對甲苯基吡啶-1(2H)-基)戊酸
向含於MeOH(2mL)中之4,4-二甲基-2-(5-甲基-4-((1r,4r)-4-甲基環
己基胺甲醯基)-2-側氧基-6-對甲苯基吡啶-1(2H)-基)戊酸乙酯(30mg,0.06mmol)溶液添加1N NaOH(0.6mL)及加熱至回流。18小時後,將反應混合物冷卻至環境溫度,用1N HCl(0.6mL)酸化(pH=6~7)及於減壓下濃縮,以得到粗製產物,其藉由反相HPLC(C18具有0.1%甲酸之含於水中的70~100% CH3CN)純化,以提供呈白色粉末之標題化合物(12mg,40%產率)。1H NMR(400MHz,DMSO)δ 8.43(d,J=8.0Hz,1H),7.46-7.31(m,3H),7.28(d,J=8.1Hz,1H),6.24(s,1H),4.19(s,1H),3.63-3.58(m,1H),2.39(s,3H),2.31-2.23(m,1H),1.92-1.77(m,3H),1.76-1.60(m,5H),1.32-1.23(m,3H),1.05-0.95(m,2H),0.87(d,J=6.5Hz,3H),0.58(s,9H)。LC-MS(ESI):m/z(M+1)=467.33。
實例2:2-(4-(3,4-二甲苯基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸
步驟1:(E)-2-(3-(3,4-二甲苯基)胺甲醯基)-4,4-二甲基戊酸乙酯
於r.t下攪拌含於DCM(10mL)中之(E)-3-(3,4-二甲苯基)丙烯酸(200mg,1.14mmol)、2-胺基-4,4-二甲基戊酸乙酯(240mg,1.4mmol)、HBTU(880mg,2.3mmol)及DIPEA(733mg,5.7mmol)之混合物40分鐘。用飽和NaHCO3(水溶液)稀釋反應混合物及用DCM(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=3:1)純化,以提供呈黃色油之標題化合物(228mg,77%產率)。LC-MS(ESI):m/z(M+1)=332.3。
步驟2:2-(4-(3,4-二甲苯基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
於100℃下,攪拌含於DCE(2mL)中之(E)-2-(3-(3,4-二甲苯基)胺甲醯基)-4,4-二甲基戊酸乙酯(60mg,0.18mmol)、1-甲基-4-(丙-1-炔基)苯(24mg,0.18mmol)、RhCp*(MeCN)3(SbF6)2(7.5mg,0.01mmol)及Cu(OAc)2.H2O(152mg,0.76mmol)之混合物。24小時後,將該混合物冷卻至環境溫度及用含於飽和NH4Cl(水溶液)中之10% NH3.H2O驟冷及用DCM(10ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱
層析(矽膠,PE:EA=3:1)純化,以提供呈黃色油之標題化合物(50mg,60%產率)。LC-MS(ESI):m/z(M+1)=460.5。
步驟3:2-(4-(3,4-二甲苯基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸
向含於MeOH(2mL)中之2-(4-(3,4-二甲苯基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(50mg,0.11mmol)溶液添加1N NaOH(1.0mL)及加熱至回流。12小時後,將反應混合物冷卻至環境溫度,用1N HCl(1.0mL)酸化(pH=6~7)及於減壓下濃縮,以得到粗製產物,其藉由反相HPLC(C18具有0.1%甲酸之含於水中的50~100% CH3CN)純化,以提供呈白色粉末之標題化合物(37mg,77%產率)。1H NMR(400MHz,DMSO)δ 12.86(br,1H),7.57-6.99(m,7H),6.24(s,1H),4.27(s,1H),2.39(s,3H),2.36-2.15(m,7H),1.96-1.79(m,1H),1.58(s,3H),0.61(s,9H)。LC-MS(ESI):m/z(M+1)=432.4。
反應圖3
實例3:2-(4-(3,4-二甲苯基)-5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸
步驟1:2-(4-(3,4-二甲苯基)-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
在O2氛圍下,向含於DCM(5mL)中之2-(4-(3,4-二甲苯基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(153mg,0.33mmol)及NaNO2(28mg,0.37mmol)之混合物添加TFA(0.5mL)。12小時後,用飽和NaHCO3(水溶液)驟冷反應混合物及用DCM(20ml×
3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=3:1)純化,以提供呈黃色油之標題化合物(140mg,83%產率)。LC-MS(ESI):m/z(M+1)=505.3。
步驟2:2-(3-胺基-4-(3,4-二甲苯基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
使用H2淨化含於EtOAc(5mL)中之2-(4-(3,4-二甲苯基)-5-甲基-3-硝基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(140mg,0.28mmol)及Pd/C(130mg)之混合物三次。2小時後,通過矽藻土墊過濾反應混合物及於減壓下濃縮濾液,以提供呈黃色固體之標題化合物(133mg,99%產率)。LC-MS(ESI):m/z(M+1)=475.4。
步驟3:2-(4-(3,4-二甲苯基)-5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於吡啶(1mL)中之2-(4-(3,4-二甲苯基)-5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(36mg,0.076mmol)及DMAP(5mg,0.003mmol)溶液添加MsCl(44mg,0.38mmol)。12小時後,用飽和NH4Cl(水溶液)稀釋反應混合物
及用EtOAc(10ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以提供呈黃色油之標題化合物(24mg,57%產率)。LC-MS(ESI):m/z(M+1)=553.4。
步驟4:2-(4-(3,4-二甲苯基)-5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸
向含於MeOH(2mL)中之2-(4-(3,4-二甲苯基)-5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(30mg,0.054mmol)溶液添加1N NaOH(0.6mL)及加熱至回流。12小時後,將反應混合物冷卻至環境溫度,用1N HCl(0.6mL)酸化(pH=6~7)及於減壓下濃縮,以得到粗製產物,其藉由反相HPLC(C18具有0.1%甲酸之含於水中的70~100% CH3CN)純化,以提供呈白色粉末之標題化合物(14mg,49%產率)。1H NMR(400MHz,DMSO)δ 12.93(br,1H),8.30(s,1H),7.51-7.27(m,4H),7.28-7.16(m,H),7.08-6.92(m,2H),4.31(s,1H),2.91(d,J=4.6Hz,3H),2.41-2.31(m,4H),2.31-2.18(m,6H),1.94-1.86(m,1H),1.41(s,3H),0.61(s,9H)。LC-MS(ESI):m/z(M+1)=525.8。
反應圖4
實例4:4,4-二甲基-2-(5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
步驟1:2-丙烯醯胺基-4,4-二甲基戊酸乙酯
向含於DCM(4mL)中之2-胺基-4,4-二甲基戊酸乙酯(150mg,0.86mmol)溶液添加丙烯醯氯(156mg,1.72mmol)。1小時後,用飽和NaHCO3(水溶液)稀釋反應混合物及用DCM(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗
製產物,其藉由管柱層析(矽膠,DCM:MeOH=20:1)純化,以提供呈黃色固體之標題化合物(190mg,96%產率)。LC-MS(ESI):m/z(M+1)=228.3。
步驟2:4,4-二甲基-2-(5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯
於100℃下,攪拌含於DCE(2mL)中之2-丙烯醯胺基-4,4-二甲基戊酸乙酯(200mg,0.18mmol)、1-甲基-4-(丙-1-炔基)苯(250mg,0.35mmol)、RhCp*(MeCN)3(SbF6)2(30mg,0.01mmol)及Cu(OAe)2.H2O(365mg,0.37mmol)之混合物。24小時後,將混合物冷卻至環境溫度及用含於飽和NH4Cl(水溶液)中之10% NH3.H2O驟冷及用DCM(10ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以提供呈黃色油之標題化合物(50mg,16%產率)。LC-MS(ESI):m/z(M+1)=356.2。
步驟3:2-(3-溴-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於CHCl3(4mL)中之4,4-二甲基-2-(5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯(105mg,0.3mmol)溶液添加NBS(61
mg,0.33mmol)及加熱至40℃。12小時後,用水稀釋反應混合物及用DCM(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=5:1)純化,以提供呈黃色油之標題化合物(115mg,90%產率)。LC-MS(ESI):m/z(M/M+2)=434.2/436.2。
步驟4:2-(3-((二苯基亞甲基)胺基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
於90℃下,N2氛圍下,攪拌含於二噁烷(3mL)中之2-(3-溴-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(130mg,0.30mmol)、二苯基甲亞胺(165mg,0.90mmol)、Pd2(dba)3(30mg,0.03mmol)、氧雜蒽膦(17mg,0.03mmol)及Cs2CO3(292mg,0.90mmol)混合物。20小時後,將混合物冷卻至環境溫度及用水稀釋及用EtOAc(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=3:1)純化,以提供呈黃色油之標題化合物(100mg,63%產率)。LC-MS(ESI):m/z(M+1)=535.3。
步驟5:2-(3-胺基-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於MeOH(5mL)中之2-(3-((二苯基亞甲基)胺基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(100mg,0.19mmol)溶液添加1N HCl(1mL)。1小時後,用飽和NaHCO3(水溶液)中和反應混合物及用DCM(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以提供呈黃色油之標題化合物(53mg,77%產率)。1H NMR(400MHz,DMSO)δ 7.31(t,J=6.9Hz,2H),7.23(dd,J=8.7,7.1Hz,2H),6.40(s,1H),5.13(s,2H),4.32(s,1H),4.22-4.11(m,1H),4.10-3.95(m,2H),2.36(s,3H),2.28-2.19(m,1H),1.89-1.79(m,1H),1.74(s,3H),1.17(q,J=7.1Hz,3H),0.56(s,9H).LC-MS(ESI):m/z(M+1)=371.2。
步驟6:4,4-二甲基-2-(5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯
向含於吡啶(2mL)中之2-(3-胺基-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(13mg,0.035mmol)及DMAP(1mg,0.008mmol)溶液添加MsCl(12mg,0.105mmol)。1小時後,用
飽和NH4Cl(水溶液)驟冷反應混合物及用DCM(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以提供呈黃色油之標題化合物(53mg,77%產率),將其用於下一步驟而無需進一步純化。LC-MS(ESI):m/z(M+1)=449.3。
步驟7:4,4-二甲基-2-(5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
向含於MeOH(3mL)中之4,4-二甲基-2-(5-甲基-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯(15mg,0.033mmol)溶液添加1N NaOH(0.3mL)及加熱至回流。6小時後,將反應混合物冷卻至環境溫度,用1N HCl(0.3mL)酸化(pH=6~7)及於減壓下濃縮,以得到粗製產物,其藉由反相HPLC(C18具有0.1%甲酸之含於水中的60~100% CH3CN)純化,以提供呈白色粉末之標題化合物(7mg,50%產率)。1H NMR(400MHz,DMSO)δ 12.93(br,1H),8.88(s,1H),7.45-7.22(m,5H),4.34(s,1H),3.09(s,3H),2.39(s,3H),2.23(dd,J=15.1,3.7Hz,1H),1.98-1.91(m,1H),1.81(s,3H),0.57(s,9H).LC-MS(ESI):m/z(M+1)=421.2。
反應圖5
實例5:4,4-二甲基-2-(5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
步驟1:2-(4-(((第三丁基二甲基矽烷基)氧基)甲基)-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
在O2氛圍下,向含於DCM(5mL)中之2-(4-((第三丁基二甲基矽烷氧基)甲基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(50mg,0.10mmol)、NaNO2(7.5mg,0.11mmol)之混合物添加TFA(0.05mL)。12小時後,用飽和NaHCO3(水溶液)驟冷反應混合物
及用DCM(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=5:1)純化,以提供呈黃色油之標題化合物(54mg,92%產率)。LC-MS(ESI):m/z(M+1)=545.6。
步驟2:2-(4-(羥甲基)-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於THF(10mL)中之2-(4-(((第三丁基二甲基矽烷)氧基)甲基)-5-甲基-3-硝基2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(138mg,0.25mmol)溶液添加TBAF(133mg,0.51mmol)。30分鐘後,將反應混合物分配在EtOAc與水之間。分離該等層及用H2O及鹽水洗滌有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以得到呈黃色油之標題化合物(104mg,95%產率)。LC-MS(ESI):m/z(M+1)431.4。
步驟3:2-(4-甲醯基-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於DCM(5mL)中之2-(4-(羥甲基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(33mg,0.08mmol)溶液添加DMP(49mg,0.12mmol)。1小時後,用NaHCO3(水溶液)驟冷反應混
合物及用DCM(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,DCM)純化,以提供呈黃色固體之標題化合物(27mg,82%產率)。LC-MS(ESI):m/z(M+1)=429.5。
步驟4:1-(1-乙氧基-4,4-二甲基-1-側氧基戊-2-基)-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)-1,2-二氫吡啶-4-甲酸
於密封管中,向含於THF(1mL)、t-BuOH(1mL)及異丁烯(1ml)中之2-(4-甲醯基-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(27mg,0.06mmol)溶液添加含於H2O(1mL)中之NaH2PO4(59mg,0.38mmol)及NaClO2(46mg,0.50mmol)溶液。12小時後,用1N HCl酸化反應混合物及用EtOAc(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到呈黃色固體之標題化合物(30mg,99%產率),將其用於下一步驟而無需進一步純化。LC-MS(ESI):m/z(M+1)=445.5。
步驟6:4,4-二甲基-2-(5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯
用DIPEA(35mg,0.27mmol)、HBTU(52mg,0.13mmol)及反式-4-甲基環己基胺(15mg,0.14mmol)處理含於DMF(3mL)中之1-(1-
乙氧基-4,4-二甲基-1-側氧基戊-2-基)-5-甲基-3-硝基-2-側氧基-6-(對甲苯基)-1,2-二氫吡啶-4-甲酸(30mg,0.067mmol)溶液。30分鐘後,用水稀釋反應混合物及用EtOAC(20ml×3)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以提供呈黃色油之標題化合物(18mg,50%)。LC-MS(ESI):m/z(M+1)=540.8。
步驟7:2-(3-胺基-5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
用H2淨化含於EtOAc(5mL)中之4,4-二甲基-2-(5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-3-硝基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯(18mg,0.03mol)及Pd/C(10mg)混合物三次。12小時後,通過矽藻土墊過濾反應混合物及於減壓下濃縮濾液,以提供呈黃色固體之標題化合物(10mg,65%產率)。LC-MS(ESI):m/z(M+1)=510.6。
步驟8:4,4-二甲基-2-(5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯
向含於吡啶(2mL)中之2-(3-胺基-5-甲基-4-(((1s,4s)-4-甲基環己
基)胺甲醯基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(19mg,0.037mmol)及DMAP(1mg,0.008mmol)溶液添加MsCl(0.03mL,0.37mmol)。2小時後,用水稀釋反應混合物及用EtOAc(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=2:1)純化,以提供呈黃色油之標題化合物(5mg,23%產率)。LC-MS(ESI):m/z(M+1)=588.7。
步驟9:4,4-二甲基-2-(5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
向含於MeOH(2mL)中之4,4-二甲基-2-(5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-3-(甲基磺醯胺基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯(5mg,0.008mmol)溶液添加1N NaOH(0.2mL)及加熱至回流。12小時後,將反應混合物冷卻至環境溫度,用1N HCl(0.2mL)酸化(pH=6~7)及於減壓下濃縮,以得到粗製產物,其藉由反相HPLC(C18具有0.1%甲酸之含於水中的10~100% CH3CN)純化,以提供呈白色粉末之標題化合物(3mg,67%產率)。1H NMR(400MHz,DMSO)δ 8.33(s,1H),7.87(d,J=7.2Hz,1H),7.48-7.34(m,3H),7.26(d,J=7.6Hz,1H),4.19(s,1H),3.65-3.61(m,1H),3.14(s,3H),2.39(s,3H),2.31-2.26(m,1H),1.93-1.80(m,3H),1.75-1.56(m,5H),1.32-1.20(m,3H),1.03-0.94(m,2H),0.87(d,J=6.4Hz,3H),0.57(s,9H)。LC-MS(ESI):m/z(M+1)=560.6。
實例6:4,4-二甲基-2-(5-甲基-4-(5-(((1r,4r)-4-甲基環己基)胺基)-1,3,4-噁二唑-2-基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
步驟1:2-(4-(肼羰基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯
向含於THF(3mL)中之1-(1-乙氧基-4,4-二甲基-1-側氧基戊-2-基)-5-甲基-2-側氧基-6-對甲苯基-1,2-二氫吡啶-4-甲酸(66mg,0.165mmol)溶液添加CDI(107mg,0.66mmol)。30分鐘後,添加肼(0.1mL,1.65mmol)及攪拌1小時。於減壓下濃縮反應混合物,以得到粗製產物,其藉由管柱層析(矽膠,DCM:MeOH=10:1)純化,以提供呈
無色油之標題化合物(44mg,64%產率)。LC-MS(ESI):m/z(M+1)=414.4。
步驟2:4,4-二甲基-2-(5-甲基-2-側氧基-4-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯
向含於DCM(2mL)中之2-(4-(肼羰基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸乙酯(44mg,0.11mmol)及DIPEA(0.04mL,0.22mmol)溶液添加三光氣(13mg,0.04mmol)。30分鐘後,用水驟冷反應混合物及用DCM(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=1:1)純化,以提供呈黃色油之標題化合物(46mg,100%產率)。LC-MS(ESI):m/z(M+1)=440.4。
步驟3:4,4-二甲基-2-(5-甲基-4-(5-(((1r,4r)-4-甲基環己基)胺基)-1,3,4-噁二唑-2-基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯
於環境溫度下攪拌含於DMF(2mL)中之4,4-二甲基-2-(5-甲基-2-側氧基-4-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯(25mg,0.06mmol)、(1r,4r)-4-甲基環己胺(0.015mL,0.11mmol)、BOP(28mg,0.063mmol)及DIPEA(0.02mL,0.11
mmol)混合物12小時。用水稀釋反應混合物及用EtOAc(20ml×2)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾及於減壓下濃縮,以得到粗製產物,其藉由管柱層析(矽膠,PE:EA=1:1)純化,以提供呈黃色油之標題化合物(20mg,66%產率)。LC-MS(ESI):m/z(M+1)=535.6。
步驟4:4,4-二甲基-2-(5-甲基-4-(5-(((1r,4r)-4-甲基環己基)胺基)-1,3,4-噁二唑-2-基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸
向含於MeOH(2mL)中之4,4-二甲基-2-(5-甲基-4-(5-(((1r,4r)-4-甲基環己基)胺基)-1,3,4-噁二唑-2-基)-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)戊酸乙酯(20mg,0.037mmol)溶液添加1N NaOH(0.4mL)及加熱至回流。12小時後,將反應混合物冷卻至環境溫度,用1N HCl(0.4mL)酸化(pH=6~7)及於減壓下濃縮,以得到粗製產物,其藉由反相HPLC(C18具有0.1%甲酸之含於H2O中的60~100% CH3CN)純化,以提供呈白色粉末之標題化合物(8mg,42%產率)。1H NMR(400MHz,DMSO)δ 12.86(s,1H),7.96(d,J=7.5Hz,1H),7.45-7.30(m,4H),6.75(s,1H),4.28(s,1H),3.39-3.36(m,1H),2.41(s,3H),2.26-2.22(m,1H),2.06-1.93(m,5H),1.92-1.87(m,1H),1.75-1.68(m,2H),1.37-1.27(m,3H),1.08-1.01(m,2H),0.89(d,J=6.5Hz,3H),0.59(s,9H)。LC-MS(ESI):m/z(M+1)=507.6。
下列化合物以與上述實例1至6之程序類似之方式製備。
實例7:2-(4-(環己基胺甲醯基)-5-甲基-2-側氧基-6-對甲苯基吡啶
-1(2H)-基)-4,4-二甲基戊酸
1H NMR(400MHz,DMSO)δ=12.78(br,1H),8.47(d,J=8.0Hz,1H),7.36(m,4H),6.27(s,1H),4.22(s,1H),3.71-3.63(m,1H),2.39(s,3H),2.32-2.26(m,1H),1.84-1.64(m,7H),1.60-1.54(m,1H),1.34-1.06(m,6H),0.58(s,9H)。LC-MS(ESI):m/z(M+1)=453.6。
實例8:2-(4-(環己基甲基胺甲醯基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸
1H NMR(400MHz,DMSO)δ=12.92(br,1H),8.57(t,J=5.9Hz,1H),7.42-7.28(m,4H),6.29(s,1H),4.23(s,1H),3.08-3.01(m,2H),2.39(s,3H),2.32-2.24(m,1H),1.90-1.80(m,1H),1.74-1.58(m,8H),1.52-1.44(m,1H),1.24-1.13(m,3H),0.96-0.86(m,2H),0.59(s,9H)。LC-MS(ESI):m/z(M+1)=467.6。
實例9:2-(4-(苄基胺甲醯基)-5-甲基-2-側氧基-6-對甲苯基吡啶-1(2H)-基)-4,4-二甲基戊酸
1H NMR(400MHz,DMSO)δ 12.86(br,1H),9.15(t,J=5.8Hz,1H),7.67-6.96(m,9H),6.38(s,1H),4.41(d,J=4.7Hz,2H),4.25(s,1H),2.39(s,3H),2.32-2.22(m,1H),1.92-1.78(m,1H),1.67(s,3H),0.59(s,9H)。LC-MS(ESI):m/z(M+1)=461.3
實例10:2-(3-(環己基甲基磺醯胺基)-5-甲基-2-側氧基-6-(對甲苯基)吡啶-1(2H)-基)-4,4-二甲基戊酸
1H NMR(400MHz,DMSO)δ 12.93(br,1H),8.82(s,1H),7.46-7.25(m,5H),4.31(s,1H),3.05(d,J=6.1Hz,2H),2.39(s,3H),2.25-2.19(m,1H),2.04-1.97(m,1H),1.92-1.78(m,5H),1.68-1.56(m,3H),1.24-0.99(m,5H),0.56(s,9H)。LC-MS(ESI):m/z(M+1)=503.3。
實例11:2-(6-(8-氟-5-甲基色滿-6-基)-5-甲基-4-(((1s,4s)-4-甲基環己基)胺甲醯基)-2-側氧基吡啶-1(2H)-基)-4,4-二甲基戊酸
1H NMR(400MHz,DMSO)δ 8.45(d,J=8.1Hz,1H),7.03-6.84(m,1H),6.23(s,1H),4.23-4.15(m,3H),3.61-3.55(m,1H),2.72-2.56(m,2H),2.42-2.32(m,1H),2.05-1.88(m,5H),1.85-1.75(m,2H),1.71-1.62(m,2H),1.55(d,J=24.2Hz,3H),1.33-1.16(m,4H),
1.03-0.91(m,2H),0.85(d,J=6.5Hz,3H),0.61(d,J=33.7Hz,9H)。LC-MS(ESI):m/z(M+1)=541.9。
生物實例
抗-HIV活性
MT4分析
基於先前描述之方法(Hazen等人,2007,In vitro antiviral activity of the novel,tyrosyl-based human immunodeficiency virus (HIV)type 1 protease inhibitor brecanavir(GW640385)in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV(Hazen等人,「In vitro antiviral activity of the novel,tyrosyl-based human immunodeficiency virus(HIV)type 1 protease inhibitor brecanavir(GW640385)in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV」,Antimicrob.Agents Chemother,2007,51:3147-3154;及Pauwels等人,「Sensitive and rapid assay on MT-4 cells for the detection of antiviral compounds against the AIDS virus」,J.of Virological Methods 1987,16:171-185),於HTLV-1轉形細胞系MT-4中平行量測表1中本發明化合物之抗病毒HIV活性及細胞毒性值。
藉由添加cell titer glo(Promega,Madison,Wis.)96小時後量測螢光素酶活性。將相對於無化合物對照之細胞保護數據之抑制百分比繪製曲線。在同一條件下,使用cell titer GloTM(Promega,Madison,Wis)測定化合物之細胞毒性。使用每種化合物之3至4倍連續稀釋,自10點劑量反應曲線測定IC50,該反應曲線,其跨濃度範圍>1000倍。
使用以下標準四參數邏輯方程,將此等值對莫耳化合物濃度繪製曲線:y=((Vmax * x^n)/(K^n+x^n))+Y2
其中:Y2=y最小值 n=斜率因子
Vmax=y最大值 x=化合物濃度[M]
K=EC50
當在MT4分析中測試時,可發現化合物具有表2所列之IC50值。
Claims (15)
- 一種式I化合物:
- 如請求項1之化合物,其中R1係視情況經甲基取代之苯基。
- 如請求項1或2之化合物,其中L係鍵、-噁二唑基-NH-、-C(O)NH-、或-C(O)NHCH2-。
- 如請求項1或2之化合物,其中R2係H、環己基、或苯基,其中該環己基及苯基視情況經1或2個甲基取代。
- 如請求項1或2之化合物,其中R3係H、-NHSO2CH3、或- NHSO2CH2環己基。
- 如請求項1或2之化合物,其中第三丁基所鍵結之碳上的立體化學係如下所描繪:
- 如請求項1或2之化合物,其用於醫學療法。
- 如請求項1或2之化合物,其用於治療人類之病毒感染。
- 一種如請求項1至6中任一項之化合物之醫藥上可接受的鹽。
- 如請求項9之鹽,其用於醫學療法。
- 如請求項9之鹽,其用於治療人類之病毒感染。
- 一種包含如請求項1至11中任一項之化合物或鹽之醫藥組合物。
- 一種如請求項12之組合物之用途,其用於製造用於治療患者之病毒感染的藥物,該病毒感染至少部分係由逆轉錄病毒科病毒中之病毒介導。
- 如請求項13之用途,其中該病毒感染係由HIV病毒介導。
- 一種如請求項1至11中任一項所定義之化合物或鹽之用途,其用於製造用於治療人類之病毒感染的藥物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462026782P | 2014-07-21 | 2014-07-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201617317A true TW201617317A (zh) | 2016-05-16 |
Family
ID=53718072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW104123125A TW201617317A (zh) | 2014-07-21 | 2015-07-16 | 吡啶酮衍生物 |
Country Status (16)
Country | Link |
---|---|
US (1) | US9802898B2 (zh) |
EP (1) | EP3172189A1 (zh) |
JP (1) | JP2017521455A (zh) |
KR (1) | KR20170032324A (zh) |
CN (1) | CN106536482A (zh) |
AR (1) | AR101222A1 (zh) |
AU (1) | AU2015293578B2 (zh) |
CA (1) | CA2954724A1 (zh) |
CL (1) | CL2017000151A1 (zh) |
IL (1) | IL249560A0 (zh) |
MA (1) | MA40220A (zh) |
RU (1) | RU2016151973A (zh) |
TW (1) | TW201617317A (zh) |
UY (1) | UY36217A (zh) |
WO (1) | WO2016012913A1 (zh) |
ZA (1) | ZA201608598B (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190284136A1 (en) | 2016-07-25 | 2019-09-19 | Viiv Healthcare Uk Limited | Indoline derivatives |
JP7168556B2 (ja) | 2017-04-10 | 2022-11-09 | 三井化学アグロ株式会社 | ピリドン化合物およびそれを有効成分とする農園芸用殺菌剤 |
US10293012B2 (en) | 2017-05-04 | 2019-05-21 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods of using extracts of melissa officinalis against filoviruses |
WO2018208739A1 (en) * | 2017-05-08 | 2018-11-15 | Thomas Cahill | Pharmaceutical compositions comprising caffeic acid chelates |
US11117863B2 (en) | 2017-06-08 | 2021-09-14 | Mitsui Chemicals Agro, Inc. | Pyridone compounds and agricultural and horticultural fungicides containing the same as active ingredients |
TWI828725B (zh) | 2018-07-25 | 2024-01-11 | 日商三井化學植保股份有限公司 | 吡啶酮化合物及以吡啶酮化合物作為有效成分的農園藝用殺菌劑 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL1026826C2 (nl) * | 2003-08-13 | 2007-01-04 | Pharmacia Corp | Gesubstitueerde pyridinonen. |
US7939545B2 (en) * | 2006-05-16 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
US8338441B2 (en) * | 2009-05-15 | 2012-12-25 | Gilead Sciences, Inc. | Inhibitors of human immunodeficiency virus replication |
GB0913636D0 (en) * | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
WO2013002357A1 (ja) * | 2011-06-30 | 2013-01-03 | 塩野義製薬株式会社 | Hiv複製阻害剤 |
US9012642B2 (en) * | 2011-09-22 | 2015-04-21 | Viiv Healthcare Uk Limited | Pyrrolopyridinone compounds and methods for treating HIV |
ES2647437T3 (es) * | 2012-07-12 | 2017-12-21 | Viiv Healthcare Uk Limited | Compuestos y procedimientos para tratar el VIH |
-
2015
- 2015-07-16 KR KR1020177002216A patent/KR20170032324A/ko unknown
- 2015-07-16 CA CA2954724A patent/CA2954724A1/en not_active Abandoned
- 2015-07-16 US US15/326,070 patent/US9802898B2/en not_active Expired - Fee Related
- 2015-07-16 AU AU2015293578A patent/AU2015293578B2/en not_active Ceased
- 2015-07-16 RU RU2016151973A patent/RU2016151973A/ru not_active Application Discontinuation
- 2015-07-16 JP JP2017503126A patent/JP2017521455A/ja not_active Ceased
- 2015-07-16 MA MA040220A patent/MA40220A/fr unknown
- 2015-07-16 UY UY0001036217A patent/UY36217A/es not_active Application Discontinuation
- 2015-07-16 CN CN201580039443.4A patent/CN106536482A/zh active Pending
- 2015-07-16 WO PCT/IB2015/055385 patent/WO2016012913A1/en active Application Filing
- 2015-07-16 EP EP15741363.4A patent/EP3172189A1/en not_active Withdrawn
- 2015-07-16 TW TW104123125A patent/TW201617317A/zh unknown
- 2015-07-16 AR ARP150102265A patent/AR101222A1/es unknown
-
2016
- 2016-12-13 ZA ZA2016/08598A patent/ZA201608598B/en unknown
- 2016-12-14 IL IL249560A patent/IL249560A0/en unknown
-
2017
- 2017-01-19 CL CL2017000151A patent/CL2017000151A1/es unknown
Also Published As
Publication number | Publication date |
---|---|
UY36217A (es) | 2016-02-29 |
CL2017000151A1 (es) | 2017-07-28 |
CN106536482A (zh) | 2017-03-22 |
US20170217890A1 (en) | 2017-08-03 |
RU2016151973A (ru) | 2018-08-22 |
US9802898B2 (en) | 2017-10-31 |
EP3172189A1 (en) | 2017-05-31 |
CA2954724A1 (en) | 2016-01-28 |
WO2016012913A1 (en) | 2016-01-28 |
AU2015293578A1 (en) | 2017-01-19 |
KR20170032324A (ko) | 2017-03-22 |
AR101222A1 (es) | 2016-11-30 |
IL249560A0 (en) | 2017-02-28 |
ZA201608598B (en) | 2019-06-26 |
MA40220A (fr) | 2017-05-31 |
RU2016151973A3 (zh) | 2018-11-09 |
AU2015293578B2 (en) | 2017-10-05 |
JP2017521455A (ja) | 2017-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6517928B2 (ja) | キナーゼ阻害剤として有用なインドールカルボキシアミド | |
TW201617317A (zh) | 吡啶酮衍生物 | |
JP2024037954A (ja) | Rip1阻害化合物ならびにそれを作製および使用するための方法 | |
JP4982482B2 (ja) | Hivインテグラ−ゼ阻害剤 | |
IL299784A (en) | RIP1 inhibitory compounds and methods for their preparation and use | |
TWI656122B (zh) | 作為hiv整合酶抑制劑之稠合三環雜環化合物 | |
JP6908536B2 (ja) | ムスカリンm2受容体の正のアロステリックモジュレーター | |
JP7353707B2 (ja) | 多環性ピリドン誘導体 | |
WO2000044726A1 (fr) | Derives 2h-phthalazine-1-one et medicaments renfermant ces derives comme principe actif | |
CN110437153A (zh) | 乙型肝炎核心蛋白变构调节剂 | |
JP7395730B2 (ja) | ヘテロ環式rip1阻害化合物 | |
PT3013814T (pt) | Compostos de tetrahidrocarbazol e carbazol carboxamida substituídos úteis como inibidores de quinases | |
KR20170024115A (ko) | 바이러스 감염의 치료에 사용하기 위한 이소인돌린 유도체 | |
JP7089596B2 (ja) | 肝がんの治療及び予防のための7位置換スルホンイミドイルプリノン化合物及び誘導体 | |
JP2020525490A (ja) | 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 | |
TW201617315A (zh) | 異吲哚啉酮衍生物 | |
WO2021107065A1 (ja) | 多環性ピリドピラジン誘導体 | |
WO2021107066A1 (ja) | インテグラーゼ阻害剤及び抗hiv薬を組み合わせることを特徴とするhiv感染症の予防及び治療用医薬 | |
EP3191452A1 (de) | Substituierte n,2-diarylchinolin-4-carboxamide und ihre anti-inflammatorische verwendung | |
KR20230019880A (ko) | Lpa 수용체 길항제 및 이의 용도 | |
JP7436454B2 (ja) | B型肝炎ウイルスの三環式阻害剤 | |
BR112019004982A2 (pt) | 1-arilnaftiridina-3-carboxamidas 7-substituídas e seu uso. | |
TW202138352A (zh) | 經取代之雙環及三環脲類及醯胺類、其類似物及使用其之方法 | |
TW202208374A (zh) | 經取代三環醯胺類、其類似物及使用其之方法 | |
JP2018527379A (ja) | ベンゾアゼピン誘導体 |