CN116836154A - 可用于痛风的化合物 - Google Patents
可用于痛风的化合物 Download PDFInfo
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- CN116836154A CN116836154A CN202310469255.1A CN202310469255A CN116836154A CN 116836154 A CN116836154 A CN 116836154A CN 202310469255 A CN202310469255 A CN 202310469255A CN 116836154 A CN116836154 A CN 116836154A
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- CN
- China
- Prior art keywords
- alkyl
- substituted
- group
- cyano
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 201000005569 Gout Diseases 0.000 title abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 12
- 229960002708 antigout preparations Drugs 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- -1 hydroxy, amino Chemical group 0.000 claims description 76
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 23
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 22
- 229910052805 deuterium Inorganic materials 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004185 ester group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 8
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical group O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 claims description 7
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical class C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000003235 pyrrolidines Chemical class 0.000 claims description 2
- 150000003572 thiolanes Chemical class 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 15
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 14
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 abstract description 14
- 229940116269 uric acid Drugs 0.000 abstract description 14
- 210000002966 serum Anatomy 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- 239000000203 mixture Substances 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 150000003254 radicals Chemical class 0.000 description 11
- JLQQRYOWGCIMMZ-UHFFFAOYSA-N 1-(3-cyano-1-propan-2-ylindol-5-yl)pyrazole-4-carboxylic acid Chemical compound C=1C=C2N(C(C)C)C=C(C#N)C2=CC=1N1C=C(C(O)=O)C=N1 JLQQRYOWGCIMMZ-UHFFFAOYSA-N 0.000 description 10
- 229940126214 compound 3 Drugs 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000012453 sprague-dawley rat model Methods 0.000 description 8
- 239000002198 insoluble material Substances 0.000 description 7
- PIVMHSHSPPOYTK-UHFFFAOYSA-N BrC1=CC=C2N(C(C)C)C=C(C#N)C2=C1 Chemical compound BrC1=CC=C2N(C(C)C)C=C(C#N)C2=C1 PIVMHSHSPPOYTK-UHFFFAOYSA-N 0.000 description 6
- CSPIUBKLQDQFMR-UHFFFAOYSA-N CC(C)N(C=C(C1=C2)C#N)C1=CC=C2N(N=C1)N=C1C(O)=O Chemical compound CC(C)N(C=C(C1=C2)C#N)C1=CC=C2N(N=C1)N=C1C(O)=O CSPIUBKLQDQFMR-UHFFFAOYSA-N 0.000 description 6
- 108010093894 Xanthine oxidase Proteins 0.000 description 6
- 102100033220 Xanthine oxidase Human genes 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 229940126142 compound 16 Drugs 0.000 description 5
- 229960005101 febuxostat Drugs 0.000 description 5
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- QARYADFHOUHDSW-UHFFFAOYSA-M potassium 2H-oxazine-3-carboxylate Chemical compound O1NC(=CC=C1)C(=O)[O-].[K+] QARYADFHOUHDSW-UHFFFAOYSA-M 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YVRGKFXJZCTTRB-UHFFFAOYSA-N 1-chloroethyl ethyl carbonate Chemical compound CCOC(=O)OC(C)Cl YVRGKFXJZCTTRB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- OVMPROUSMUVTJY-UHFFFAOYSA-N ethyl 1-(3-cyano-1-propan-2-ylindol-5-yl)pyrazole-4-carboxylate Chemical compound C1=C(C(=O)OCC)C=NN1C1=CC=C(N(C=C2C#N)C(C)C)C2=C1 OVMPROUSMUVTJY-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RYVMILFDVUDFME-UHFFFAOYSA-N 2-(3-cyano-1-propan-2-ylindol-5-yl)pyridine-4-carboxylic acid Chemical compound C=1C=C2N(C(C)C)C=C(C#N)C2=CC=1C1=CC(C(O)=O)=CC=N1 RYVMILFDVUDFME-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920001304 Solutol HS 15 Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000016097 disease of metabolism Diseases 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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Abstract
本发明公开了一类可用于痛风的化合物,它为通式(I)所示的化合物或其药学上可接受的盐,它能够降低高尿酸血症大鼠模型的血清尿酸水平,在抗痛风药物、抗高尿酸血症药物等方面具有潜在的应用价值。
Description
技术领域
本发明属于药物化学领域,具体涉及一类可用于痛风的化合物。
背景技术
痛风是由于体内尿酸生成增多,和(或)尿酸***减少而致的血尿酸(serum uricacid,sUA)水平升高,形成单钠尿酸盐结晶沉积在关节及周围组织和肾脏中,从而引起自身炎症反应和关节形态学改变的一种代谢性疾病。痛风是成年男性中最普遍的一种炎性关节病,并且在发达国家其患病率呈上升趋势,已成为威胁人类健康的严重代谢性疾病。
目前全球有超过5500万的痛风患者,高尿酸血症患者远远高于2亿人。近二十多年来,随着人们生活水平提升,饮食结构的改变,高嘌呤食品的过量摄入,高尿酸血症和痛风患者人数大量增加,痛风市场呈现出大幅增长的趋势。有数据显示,2018年全球痛风药市场156.5亿,预计2025年可达361.5亿。痛风往往与多种疾病如高血压、肥胖、心血管疾病、糖尿病和慢性肾脏疾病等有关,这些合并疾病会让痛风的治疗更为复杂,并增加过早死亡风险(Khanna D,Fitzgerald JD,Khanna PP,et al.American College of RheumatologyGuidelines for Management of Gout.Part 1:Systematic Nonpharmacologic andPharmacologic Therapeutic Approaches to Hyperuricemia[J].Arthritis Care&Research,2012,64(10):1432-1446)。重症痛风病人可能出现关节残疾和肾功能不全,严重影响患者的生活质量和生命健康。
黄嘌呤氧化酶(XO)是药物治疗高尿酸血症和痛风的重要靶点,催化次黄嘌呤和黄嘌呤分别氧化生成黄嘌呤和尿酸,通过抑制XO能减少尿酸的合成,进而降低血清中尿酸的浓度。随着黄嘌呤氧化酶晶体结构的解析、计算机辅助药物设计和高通量筛选等技术的运用,近年涌现了许多XO抑制剂,专利CN102574839A公开了一类作为黄嘌呤氧化酶抑制剂的新化合物,其中候选化合物LC350189正在开发中,处于2期临床阶段,2期临床研究也证明了其降低sUA的充分疗效。但目前获批上市的只有3种药物(别嘌呤醇,非布司他和托比司他),临床期的在研药物仍存在疗效或安全性方面的问题。
前药策略是一种有效的药物设计方法,通过将已知有生物活性而又存在某些缺点的药物分子经过修饰改造,加上前体基团,形成可以在体内被酶或化学反应激活的化学物质。前药通常没有生理活性,或者活性极低,但可以被酶解或经非酶解转化为具有生理活性的药物。与原药相比,前药不仅保持或增强了原药的药效,又克服了原药的缺点,提高其临床疗效。前药可用来增加药物的溶解性,提高生物利用度,改善传递特性及药物动力学特性等。目前,在全球上市场药品中有将近10%属于前药,仅在2008年约有30%的小分子药物是前药。例如,血管紧张素转换酶抑制剂依那普利、贝那普利和雷米普利等在体内水解生成相应的二羧酸代谢物,从而发挥降压作用;部分他汀类降脂药洛伐他汀和辛伐他汀等为具有环状结构的前药,其发生开环反应后才具有羟甲基戊二酸单酰辅酶A还原酶抑制活性;质子泵抑制剂如奥美拉唑、兰索拉唑和艾美拉唑等,均需在胃的酸性环境中才能被激活;抗组胺药氯雷他定在体内脱甲酸乙酯基生成活性代谢物地氯雷他定。此外,很多新的前药也正在研发之中。但是在实际研发中,前药类化合物依然存在失去活性或活性差、设计出的前药化合物与设计目标效果不对应等大量问题。
发明内容
本发明的目的是一种具有黄嘌呤氧化酶抑制活性的化合物。
本发明的另一目的是提供上述化合物在医药领域的用途。
本发明的目的可以通过以下措施达到:
通式(I)所示的化合物或其药学上可接受的盐,
其中,
R为C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基或C3-6杂环烷基中的一种或多种;
Ar为取代或非取代的以下基团:Ar基团中的取代基选自氘、羟基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;
Y为O或NR3,
R1为连接键或者取代或非取代的C1-6亚烷基或者取代或非取代的C2-12亚烯基,R1基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;
R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、C4-12稠杂芳环基、C4-16稠杂芳环基吡唑基羰基氧基、C4-16稠杂芳环基吡啶基羰基氧基、C4-16稠杂芳环基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C2-20烯基、C2-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、卤代C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种;且R2基团中的C4-16稠杂芳环基中不含有吲唑基;
R3为氢或C1-6烷基。
在一种优选方案中,Ar为取代或非取代的以下基团:其中“*”为与C=O的连接位点。
在一种优选方案中,化合物选自通式(II)、(III)或(IV)所示的化合物,
在一种优选方案中,Y为O或NH。
在一种优选方案中,R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
在一种优选方案中,R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、四氢呋喃、取代的四氢呋喃、四氢噻吩、取代的四氢噻吩、四氢吡咯或取代的四氢吡咯;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
在一种优选方案中,R为C3-6烷基、取代的C1-3烷基、C3-6环烷基或者取代的C3-6环烷基,R基团中的取代基选自氘、卤素或C3-6环烷基。
在一种优选方案中,R为C3-6烷基或者C3-6环烷基。
在一种优选方案中,R为正丙基、异丙基、正丁基、异丁基、环丙基、环丁基或环戊基。
在一种优选方案中,R1为连接键或者取代或非取代的C1-4亚烷基或者取代或非取代的C2-12亚烯基,R1基团中的取代基选自氘、氨基、氰基、卤素或C1-4烷氧基中的一种或多种。
在一种优选方案中,R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、嘌呤基、喹啉基吡唑基羰基氧基、异喹啉基吡唑基羰基氧基、吲哚基吡唑基羰基氧基、苯并呋喃基吡唑基羰基氧基、嘌呤基吡唑基羰基氧基、喹啉基吡啶基羰基氧基、异喹啉基吡啶基羰基氧基、吲哚基吡啶基羰基氧基、苯并呋喃基吡啶基羰基氧基、嘌呤基吡啶基羰基氧基、喹啉基三氮唑基羰基氧基、异喹啉基三氮唑基羰基氧基、吲哚基三氮唑基羰基氧基、苯并呋喃基三氮唑基羰基氧基、嘌呤基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C6-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、卤代C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种。
在一种优选方案中,R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲哚基吡唑基羰基氧基、吲哚基吡啶基羰基氧基、吲哚基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、卤代C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种。
在一种优选方案中,R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲哚基吡唑基羰基氧基、吲哚基吡啶基羰基氧基、C2-4酯基、苯基、C1-4烷氧基、C6-14烯基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种。
在一种优选方案中,本发明的化合物选自:
本发明还包括一种药物组合物,它以本申请中所涉及的化合物或其药学上可接受的盐为活性物质,辅以药学上可接受的辅料。
本发明的化合物或其药学上可接受的盐可以应用在制备黄嘌呤氧化酶抑制剂药物方面,特别是应用在制备抗痛风药物或抗高尿酸血症药物方面。
本发明中所指出的各基团,如无其他明确限定,均具有以下含义:
“H”,即氢,是指氕(1H),它是氢元素的主要稳定同位素。
“D”,或“氘”,是指氢的一种稳定形态同位素,也被称为重氢,其元素符号为D。
“卤素”,是指氟原子,氯原子,溴原子或碘原子。
“羟基”,是指-OH基团。
“氨基”,是指-NH2基团。
“烷基”,是指含有1-10个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-10”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括10个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时,称其为未取代的低级烷基。烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。具体的烷基包括但不限于甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烯基”,是指含有2-30个碳原子的具有一个或多个“C=C”的烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“2-10”,是指该基团,此时为烯基,可以含2个碳原子、3个碳原子等,直至包括10个碳原子)。烯基可以选用C2-20烯基、C2-18烯基、C2-16烯基、C2-14烯基、C2-12烯基、C4-14烯基、C412烯基等。具体的烯基包括但不限于乙烯基、丙烯基、烯丙基、丁烯基、异丁烯基、叔丁烯基、等。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)基团,其进一步表示-O-(未取代的烷基)。其中的烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。代表性实施例包括但不限于甲氧基、乙氧基、丙氧基、环丙氧基等。
“二氧杂环戊烯-2-酮基”为基团。
“吡唑基”,是指中的任意一种。
“三氮唑基”,包括1,2,3-三氮唑基,其中“1,2,3-三氮唑基”,是指
“稠杂芳环基”,是指含有两个或多个稠和环以及杂原子的芳香基团,包括但不限于吲唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、嘌呤基、吖啶基等。
“羧基”,是指-COOH基团。
“酯基”,是指“-C(=O)-O-烷基”基团,其中的烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。代表性实施例包括但不限于甲酸甲酯基、甲酸乙酯基、甲酸正丙酯基、甲酸异丙酯基等。取代的酯基是指酯基中的氢被一个取代基所取代,或者酯基中的多个氢分别被相同或不同的取代基所取代。
“杂环烷基”,是指含有3-10个环原子的饱和的环状基团,它的环原子中含有一个或多个选自N、O、S的杂原子。本申请书中提到的数字范围,例如“3-6”,是指此时为杂环烷基的该基团,可以含3个碳原子、4个碳原子、5个碳原子等,直至包括6个碳原子作为环原子。杂环烷基可以选用C3-8杂环烷基、C3-6杂环烷基、C3-5杂环烷基、C3-4杂环烷基、C3-9杂环烷基、C4-6杂环烷基等。具体的烷基包括但不限于四氢呋喃、四氢吡咯、四氢噻吩、1,4-二氧六环、氧代螺[3,3]庚烷基、氧代螺[4,4]壬烷基、氧代螺[5,5]十一烷基、氧代螺[6,6]十三烷基、氧代二环[1,1,1]戊烷基、氧代二环[2,2,2]辛烷基、氧代二环[3,2,1]辛烷基、氮代螺[3,3]庚烷基、氮代螺[4,4]壬烷基、氮代螺[5,5]十一烷基、氮代螺[6,6]十三烷基、氮代二环[1,1,1]戊烷基、氮代二环[2,2,2]辛烷基或氮代二环[3,2,1]辛烷基等。杂环烷基可以是取代的或未取代的。
“C4-16稠杂芳环基吡唑基羰基氧基”,是指含有4-16个碳原子的-O-C(=O)-吡唑基-稠杂芳环基基团,一种具体的例子包括吲哚基吡唑基羰基氧基
“C2-8烷氧基羰基氧基”,是指含有2-8个碳原子的-O-C(=O)-O-烷基基团。
“C4-16稠杂芳环基吡啶基羰基氧基”,是指含有4-16个碳原子的-O-C(=O)-吡啶基-稠杂芳环基基团,一种具体的例子包括吲哚基吡啶基羰基氧基
“C4-16稠杂芳环基三氮唑基羰基氧基”,是指含有4-16个碳原子的-O-C(=O)-三氮唑基-稠杂芳环基基团,一种具体的例子包括吲哚基三氮唑基羰基氧基
“连接键”,是指其两端的基团直接通过共价键相连。以基团片段Y-R1-R2为例,当R1为连接键时,该基团片段即为Y-R2。
“硝基氧基”,是指-ONO2基团。
“药学上可接受的盐”是包含通式(I)的化合物与有机酸或无机酸形成的盐,表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括但不限于:
(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应而得,无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等,有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐,金属离子例如碱金属离子、碱土金属离子或铝离子,有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐和前药与其它的化学成分,例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
本发明进一步要求保护包括上面所述的任一化合物、其药学上可接受的盐或其易水解的前药与其它药用活性成分的药物组合物。
本发明也包括上述任一化合物、其药学上可接受的盐,可以用本领域已知的方式配制成临床上或药学上可接受的任一剂型。用于口服给药时,可制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,可以制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中常规方法生产,配制注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。
本发明提供的化合物能够显著降低高尿酸血症大鼠模型的血清尿酸水平,在抗痛风药物、抗高尿酸血症药物等方面具有潜在的应用价值。因为非布司他存在严重的心脏猝死、严重的肾脏毒性和肝脏毒性,本发明提供的化合物可能在降低药物毒性方面具有一定的优势,拥有良好的药物开发前景。
具体实施方式
以下结合实施例对本发明做进一步说明,但是本发明的保护范围并不局限于以下各实施例。
实施例1:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(4)的合成
步骤A:将含有5-溴-1H-吲哚-3-甲腈(10.0g,45.2mmol)、碘代异丙烷(30.8g,181mmol)、碳酸铯(29.5g,90.5mmol)和乙腈(100mL)的混合物在80℃搅拌3小时。冷却到室温,过滤除去不溶物。滤饼用乙酸乙酯(200mL)淋洗。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:15~1:3洗脱),得5-溴-1-异丙基-1H-吲哚-3-甲腈(1)(11.6g)。收率为97.5%。
步骤B:将含有1H-吡唑-4-甲酸乙酯(3.20g,22.8mmol)、化合物1(3.03g,11.5mmol)、碳酸钾(3.15g,22.8mmol)、碘化亚铜(2.17g,11.4mmol)、(1S,2S)-1,2-二氨基环己烷(1.01g,11.4mmol)和DMF(50mL)的混合物在氮气下110℃搅拌过夜。冷却到室温,加入乙酸乙酯(100mL),用饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:30~1:4洗脱),得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸乙酯(2)(3.10g)。收率为83.6%。
步骤C:将含有化合物2(600mg,1.86mmol)、2M氢氧化钠溶液(12mL)、甲醇(4mL)和THF(4mL)的混合物在30℃搅拌1小时。减压蒸除部分溶剂,加入水(10mL),用乙酸乙酯(10mL)萃取,产物在水相。水相用2M柠檬酸溶液调节pH值至4~5。过滤,滤饼用甲醇重结晶,得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(3)(400mg)。收率为73.1%。
步骤D:将含有化合物3(150mg,0.510mmol)、4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(91mg,0.613mmol)、碳酸钾(140mg,1.01mmol)、碘化钾(110mg,0.663mmol)和DMF(5mL)的混合物在室温下搅拌过夜。加入水(20mL),过滤。滤饼经柱层析纯化(200~300目硅胶,二氯甲烷洗脱),得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(4)。1HNMR(DMSO-d6,400MHz)δ9.30(s,1H),8.58(s,1H),8.23(s,1H),8.21(s,1H),7.96-7.90(m,2H),5.19(s,2H),4.96-4.89(m,1H),2.23(s,3H),1.51(d,J=6.4Hz,6H)。MS(ESI,m/z):407.1[M+H]+。
实施例2:双[1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸]丙-1,3-二酯(5)的合成
将含有化合物3(150mg,0.510mmol)、1,3-二溴丙烷(51mg,0.253mmol)、碳酸钾(141mg,1.02mmol)、碘化钾(110mg,0.663mmol)和DMF(5mL)的混合物在30℃搅拌48小时。加入水(20mL),过滤。滤饼经柱层析纯化(200~300目硅胶,二氯甲烷:石油醚=1:1洗脱),得双[1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸]丙-1,3-二酯(5)(59.4mg)。收率为37.1%。1H NMR(DMSO-d6,400MHz)δ9.19(s,2H),8.55(s,2H),8.14-8.12(m,4H),7.86-7.84(m,4H),4.93-4.86(m,2H),4.43(t,J=6.0Hz,4H),2.16(t,J=6.0Hz,2H),1.49(d,J=6.4Hz,12H)。MS(ESI,m/z):629.2[M+H]+。
实施例3:[1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-羰基]-L-缬氨酸甲酯(6)的合成
将含有化合物3(70mg,0.238mmol)、L-缬氨酸甲酯盐酸盐(47.8mg,0.285mmol)、二异丙基乙基胺(77mg,0.596mmol)、HBTU(135mg,0.356mmol)和DMF(5mL)的混合物在室温下搅拌过夜。加入水(20mL),用乙酸乙酯(30mL×2)萃取,合并的有机相用饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:二氯甲烷:三乙胺=200:100:1洗脱),得[1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-羰基]-L-缬氨酸甲酯(6)(78.5mg)。收率为80.9%。1H NMR(DMSO-d6,400MHz)δ9.16(s,1H),8.57(s,1H),8.29(d,J=8.0Hz,1H),8.22(s,1H),8.06(s,1H),7.94-7.86(m,2H),4.95-4.89(m,1H),4.38-4.34(m,1H),3.67(s,3H),2.18-2.12(m,1H),1.51(d,J=6.4Hz,6H),0.99(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H)。MS(ESI,m/z):408.2[M+H]+。
实施例4:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(3,7-二甲基辛烷-2,6-二烯-1-基)酯(7)的合成
将含有化合物3(70mg,0.238mmol)、3,7-二甲基辛烷-2,6-二烯-1-醇(44mg,0.285mmol)、DCC(74mg,0.359mmol)、DMAP(3mg,0.0246mmol)和二氯甲烷(5mL)的混合物在室温下搅拌过夜。过滤除去不溶物,滤饼用二氯甲烷(5mL)淋洗。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:二氯甲烷:三乙胺=300:100:1洗脱),得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(3,7-二甲基辛烷-2,6-二烯-1-基)酯(7)(53mg)。收率为51.7%。1H NMR(DMSO-d6,400MHz)δ9.22(s,1H),8.57(s,1H),8.22(d,J=1.6Hz,1H),8.14(s,1H),7.95-7.89(m,2H),5.44-5.41(m,1H),5.08-5.06(m,1H),4.95 -4.89(m,1H),4.77(d,J=7.2Hz,2H),2.10-2.05(m,4H),1.74(s,3H),1.63(s,3H),1.57(s,3H),1.51(s,3H),1.50(s,3H)。MS(ESI,m/z):431.2[M+H]+。
实施例5:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(3,7,11-三甲基十二烷基-2,6,10-三烯-1-基)酯(8)的合成
以化合物3和3,7,11-三甲基十二烷基-2,6,10-三烯-1-醇为原料,合成化合物8的实验操作参见实施例4。1H NMR(DMSO-d6,400MHz)δ9.20(s,1H),8.57(s,1H),8.21(s,1H),8.13(d,J=2.4Hz,1H),7.95-7.89(m,2H),5.43-5.40(m,1H),5.10-5.02(m,2H),4.95-4.89(m,1H),4.78-4.73(m,2H),2.11-1.91(m,8H),1.74(s,3H),1.64-1.50(m,15H)。MS(ESI,m/z):499.2[M+H]+。
实施例6:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[(2R,3S)-3-氨基-4-甲氧基-4-氧代丁-2-基]酯(10)的合成
步骤A:将含有化合物3(120mg,0.408mmol)、Boc-L-苏氨酸甲酯(114mg,0.489mmol)、DCC(168mg,0.814mmol)和二氯甲烷(4mL)的混合物在室温下搅拌过夜。过滤除去不溶物,滤饼用二氯甲烷(5mL)淋洗。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:二氯甲烷:三乙胺=300:100:1洗脱),得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[(2R,3S)-3-(Boc-氨基)-4-甲氧基-4-氧代丁-2-基]酯(9)(218mg)。收率为100%。
步骤B:将化合物9(218mg,0.427mmol)和三氟乙酸(0.4mL)的二氯甲烷(4mL)溶液在室温下搅拌过夜。加入水(20mL),用饱和碳酸氢钠溶液调节pH值至7~8。用二氯甲烷(20mL×2)萃取,合并的有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,所得产物用乙酸乙酯/石油醚重结晶,得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[(2R,3S)-3-氨基-4-甲氧基-4-氧代丁-2-基]酯(10)。1H NMR(DMSO-d6,400MHz)δ9.23(s,1H),8.58(s,1H),8.18-8.16(m,2H),7.93-7.92(m,2H),5.32-5.30(m,1H),4.94-4.91(m,1H),3.61-3.58(m,4H),1.51(d,J=6.4Hz,6H),1.35(d,J=6.4Hz,3H)。MS(ESI,m/z):410.1[M+H]+。
实施例7:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸{1-[(乙氧基羰基)氧基]}乙酯(11)的合成
将含有化合物3(100mg,0.340mmol)、碳酸钾(93mg,0.673mmol)、1-氯乙基乙基碳酸酯(78mg,0.511mmol)、碘化钾(73mg,0.440mmol)和DMF(2mL)的混合物在40℃搅拌48小时。加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并的有机相依次用水(10mL×2)和饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:10洗脱),得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸{1-[(乙氧基羰基)氧基]}乙酯(11)(51mg)。收率为36.5%。1H NMR(DMSO-d6,400MHz)δ9.31(s,1H),8.58(s,1H),8.23(d,J=1.6Hz,1H),8.21(s,1H),7.96-7.90(m,2H),6.87(q,J=5.6Hz,1H),4.96-4.89(m,1H),4.17(q,J=7.2Hz,2H),1.58(d,J=5.2Hz,3H),1.51(d,J=6.4Hz,6H),1.23(t,J=6.8Hz,3H)。MS(ESI,m/z):411.1[M+H]+。
实施例8:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(2-乙酰氧基)乙酯(12)的合成
以化合物3和乙二醇单乙酸酯为原料,合成化合物12的实验操作参见实施例4。1HNMR(DMSO-d6,400MHz)δ9.25(s,1H),8.58(s,1H),8.22(d,J=1.6Hz,1H),8.16(s,1H),7.96-7.90(m,2H),4.96-4.89(m,1H),4.46-4.44(m,2H),4.34-4.32(m,2H),2.05(s,3H),1.51(d,J=6.8Hz,6H)。MS(ESI,m/z):381.1[M+H]+。
实施例9:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(2-甲氧基)乙酯(13)的合成
以化合物3和乙二醇单甲醚为原料,合成化合物13的实验操作参见实施例4。1HNMR(DMSO-d6,400MHz)δ9.23(s,1H),8.58(s,1H),8.22(d,J=2.0Hz,1H),8.15(s,1H),7.96-7.89(m,2H),4.96-4.89(m,1H),4.38(t,J=4.8Hz,2H),3.65(t,J=4.8Hz,2H),3.32(s,3H),1.51(d,J=6.8Hz,6H)。MS(ESI,m/z):353.1[M+H]+。
实施例10:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸肉桂酯(14)的合成
以化合物3和肉桂醇为原料,合成化合物14的实验操作参见实施例4。1H NMR(DMSO-d6,400MHz)δ9.29(s,1H),8.57(s,1H),8.23-8.21(m,2H),7.97-7.90(m,2H),7.52-7.50(m,2H),7.38-7.29(m,3H),6.81(d,J=16.0Hz,1H),6.53-6.48(m,1H),4.95-4.91(m,3H),1.49(d,J=6.4Hz,6H)。MS(ESI,m/z):411.1[M+H]+。
实施例11:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸(1-异丁酰氧基)乙酯(15)的合成
以化合物3和1-氯乙基异丁酸酯为原料,合成化合物15的实验操作参见实施例7。1H NMR(DMSO-d6,400MHz)δ9.28(s,1H),8.57(s,1H),8.22(d,J=1.6Hz,1H),8.19(s,1H),7.96-7.90(m,2H),6.97(q,J=5.6Hz,1H),4.96 -4.89(m,1H),2.61-2.54(m,1H),1.55(d,J=5.6Hz,3H),1.51(d,J=6.8Hz,6H),1.12-1.09(m,6H)。MS(ESI,m/z):409.2[M+H]+。
实施例12:2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(17)的合成
以2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸(16)(合成化合物16的实验操作参见专利CN115160299中的实施例2和3)和4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮为原料,合成化合物17的实验操作参见实施例1中的步骤D。1H NMR(CDCl3,400MHz)δ8.56(d,J=2.0Hz,1H),8.29(s,1H),8.17(dd,J=2.0,8.8Hz,1H),7.82(s,1H),7.56(d,J=8.8Hz,1H),5.18(s,2H),4.79-4.73(m,1H),2.29(s,3H),1.62(d,J=6.4Hz,6H)。MS(ESI,m/z):408.0[M+H]+。
实施例13:双[2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸]丙-1,3-二酯(18)的合成
以化合物16和1,3-二溴丙烷为原料,合成化合物18的实验操作参见实施例2。1HNMR(CDCl3,400MHz)δ8.44(d,J=2.0Hz,2H),8.25(s,2H),8.10(dd,J=2.0,8.8Hz,2H),7.79(s,2H),7.53(d,J=8.8Hz,2H),4.79-4.72(m,2H),4.65(t,J=6.0Hz,4H),2.39(t,J=6.0Hz,2H),1.61(d,J=6.8Hz,12H)。MS(ESI,m/z):631.2[M+H]+。
实施例14:2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸{1-[(乙氧基羰基)氧基]}乙酯(19)的合成
以化合物16和1-氯乙基乙基碳酸酯为原料,合成化合物19的实验操作参见实施例7。1H NMR(CDCl3,400MHz)δ8.56(d,J=2.0Hz,1H),8.28(s,1H),8.17(dd,J=2.0,8.8Hz,1H),7.81(s,1H),7.55(d,J=8.8Hz,1H),7.10(q,J=5.2Hz,1H),4.79-4.72(m,1H),4.26(q,J=7.2Hz,2H),1.72(d,J=5.6Hz,3H),1.61(d,J=6.8Hz,6H),1.34(t,J=6.8Hz,3H)。MS(ESI,m/z):412.1[M+H]+。
实施例15:2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸(3,7,11-三甲基十二烷基-2,6,10-三烯-1-基)酯(20)的合成
以化合物16和3,7,11-三甲基十二烷基-2,6,10-三烯-1-醇为原料,合成化合物20的实验操作参见实施例4。1H NMR(DMSO-d6,400MHz)δ8.65(s,1H),8.61-8.60(m,1H),8.24(s,1H),8.06(dd,J=2.0,8.8Hz,1H),8.00(d,J=8.8Hz,1H),5.50-5.43(m,1H),5.09-4.84(m,5H),2.10-1.87(m,8H),1.76(s,3H),1.63-1.61(m,2H),1.56-1.49(m,13H)。MS(ESI,m/z):544.3[M+HCO2]-。
实施例16:2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸(吡啶-2-基)甲酯(21)的合成
将含有化合物16(80mg,0.271mmol)、吡啶-2-甲醇(36mg,0.330mmol)、DCC(84mg,0.407mmol)、DMAP(3mg,0.0246mmol)和二氯甲烷(5mL)的混合物在室温下搅拌过夜。过滤除去不溶物,滤饼用二氯甲烷(5mL)淋洗。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,二氯甲烷洗脱),得2-(3-氰基-1-异丙基-1H-吲哚-5-基)-2H-1,2,3-***-4-甲酸(吡啶-2-基)甲酯(21)(69mg)。收率为65.9%。1H NMR(CDCl3,400MHz)δ8.65-8.64(m,1H),8.57(d,J=2.0Hz,1H),8.32(s,1H),8.18(dd,J=2.0,8.8Hz,1H),7.81(s,1H),7.78-7.74(m,1H),7.57-7.50(m,2H),7.30-7.28(m,1H),5.58(s,2H),4.79-4.72(m,1H),1.61(d,J=6.8Hz,6H)。MS(ESI,m/z):387.4[M+H]+。
实施例17:2-(3-氰基-1-异丙基-1H-吲哚-5-基)异烟酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(27)的合成
步骤A:向含有5-吲哚硼酸频哪醇酯(7.29g,30.0mmol)、2-溴吡啶-4-甲酸甲酯(7.78g,36.0mmol)、碳酸钾(10.4g,75.2mmol)、二氧六环(100mL)和水(20mL)的混合物中加入[1,1’-双(二苯基膦)茂铁]二氯化钯(1.09g,1.50mmol),加完后,所得混合物在氮气下80℃搅拌3小时。减压蒸除大部分溶剂,加入水(100mL),用乙酸乙酯(100mL×3)萃取,合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:5洗脱),得2-(1H-吲哚-5-基)异烟酸甲酯(22)(1.30g)。收率为17.2%。
步骤B:向化合物22(1.30g,5.15mmol)的DMF(25mL)溶液中加入碳酸铯(3.35g,10.3mmol)和碘(2.62g,10.3mmol),加完后,所得混合物在室温下搅拌过夜。加入水(60mL)和2M硫代硫酸钠溶液(20mL)。过滤,滤饼用乙酸乙酯(200mL)溶解,过滤除去不溶物,然后用无水硫酸钠干燥。减压蒸除溶剂,得2-(3-碘-1H-吲哚-5-基)异烟酸甲酯(23)(1.10g)。收率为51.4%。MS(ESI,m/z):379.1[M+H]+。
步骤C:将含有化合物23(1.10g,2.91mmol)、碳酸钾(480mg,3.47mmol)、溴代异丙烷(530mg,4.31mmol)、碘化钾(100mg,0.602mmol)和DMF(20mL)的混合物在60℃搅拌过夜。冷却到室温,加入水(80mL),用乙酸乙酯(40mL×3)萃取,合并的有机相依次用水(30mL×2)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:10洗脱),得2-(3-碘-1-异丙基-1H-吲哚-5-基)异烟酸甲酯(24)(600mg)。收率为49.1%。
步骤D:将含有化合物24(600mg,1.43mmol)、氰化亚铜(200mg,2.33mmol)和DMF(6mL)的混合物在120℃搅拌过夜。冷却到室温,加入乙酸乙酯(30mL)和水(20mL),过滤除去不溶物。分层,水层用乙酸乙酯(20mL×3)萃取,合并的有机层依次用水(15mL×2)和饱和食盐水(15mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,得2-(3-氰基-1-异丙基-1H-吲哚-5-基)异烟酸甲酯(25)(267mg)。收率为58.5%。
步骤E:将含有化合物25(267mg,0.836mmol)、2M氢氧化钠溶液(4mL)、甲醇(1.3mL)和THF(1.3mL)的混合物在室温下搅拌30分钟。加入水(15mL),用乙酸乙酯(10mL)萃取,产物在水相。水相用2M柠檬酸溶液调节pH值至5~6。过滤,得2-(3-氰基-1-异丙基-1H-吲哚-5-基)异烟酸(26)(255mg)。收率为99.9%。
步骤F的实验操作参见实施例1中的步骤D,得2-(3-氰基-1-异丙基-1H-吲哚-5-基)异烟酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(27)。1H NMR(CDCl3,400MHz)δ8.88(d,J=5.2Hz,1H),8.44(d,J=1.6Hz,1H),8.36(s,1H),8.11(dd,J=1.6,8.8Hz,1H),7.78-7.77(m,2H),7.57(d,J=8.8Hz,1H),5.19(s,2H),4.80-4.73(m,1H),2.30(s,3H),1.61(d,J=6.4Hz,6H)。MS(ESI,m/z):418.2[M+H]+。
实施例18:2-(3-氰基-1-异丙基-1H-吲哚-5-基)异烟酸{1-[(乙氧基羰基)氧基]}乙酯(28)的合成
以化合物26和1-氯乙基乙基碳酸酯为原料,合成化合物28的实验操作参见实施例7。1H NMR(CDCl3,400MHz)δ8.86(d,J=4.8Hz,1H),8.44(d,J=1.6Hz,1H),8.36(s,1H),8.09(dd,J=1.6,8.8Hz,1H),7.80-7.78(m,2H),7.56(d,J=8.8Hz,1H),7.09(q,J=5.2Hz,1H),4.80-4.73(m,1H),4.26(q,J=7.2Hz,2H),1.72(d,J=5.6Hz,3H),1.61(d,J=6.8Hz,6H),1.34(t,J=7.2Hz,3H)。MS(ESI,m/z):422.4[M+H]+。
实施例19:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[4-(硝基氧基)]丁酯(30)的合成
步骤A:将含有4-溴丁基乙酸酯(1.0g,5.13mmol)、硝酸银(1.30g,7.65mmol)和乙腈(15mL)的混合物在避光下回流搅拌过夜。冷却到室温,过滤除去不溶物。加入水(60mL),用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,然后向剩余物中加入2M氢氧化钠溶液(2.5mL)和甲醇(5mL)。加完后,所得混合物在室温下搅拌2小时。加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并的有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯=5:1洗脱),得硝酸(4-羟基)丁酯(29)(400mg)。收率为57.5%。
步骤B的实验操作参见实施例4,得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[4-(硝基氧基)]丁酯(30)。1H NMR(DMSO-d6,400MHz)δ9.22(s,1H),8.57(s,1H),8.20(d,J=1.6Hz,1H),8.16(s,1H),7.95-7.89(m,2H),4.96-4.89(m,1H),4.61(t,J=6.0Hz,2H),4.28(t,J=6.0Hz,2H),1.87-1.78(m,4H),1.51(d,J=6.8Hz,6H)。MS(ESI,m/z):412.5[M+H]+。
实施例20:1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[3-(硝基氧基)甲基]苯酯(32)的合成
步骤A:将含有间羟基苄基溴(500mg,2.67mmol)、硝酸银(500mg,2.94mmol)和乙腈(5mL)的混合物在冰水浴下避光搅拌5小时。过滤除去不溶物。加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并的有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯=35:1洗脱),得硝酸(3-羟基)苄酯(31)(230mg)。收率为50.9%。
步骤B的实验操作参见实施例4,得1-(3-氰基-1-异丙基-1H-吲哚-5-基)-1H-吡唑-4-甲酸[3-(硝基氧基)甲基]苯酯(32)。1H NMR(DMSO-d6,400MHz)δ9.49(s,1H),8.58(s,1H),8.36(s,1H),8.27(s,1H),7.98-7.94(m,2H),7.57-7.53(m,1H),7.44-7.35(m,3H),5.64(s,2H),4.97-4.90(m,1H),1.52(d,J=6.4Hz,6H)。MS(ESI,m/z):446.1[M+H]+。
实施例21:化合物对治疗大鼠高尿酸血症的实验研究
1.实验材料
(1)受试药物
化合物30和32均为类白色粉末,临用前采用0.5% CMC-Na研磨,配成0.4mg/mL混悬液供灌胃。
非布司他,购自Sigma,临用前采用0.5% CMC-Na研磨,配成0.4mg/mL混悬液供灌胃。
(2)动物及饲养
a.动物种属和来源
Sprague Dawley(SD)大鼠,SPF级,30只,雄性,体重230-250g,购自上海斯莱克实验动物有限责任公司,生产许可证号:SCXK(沪)2022-0004,质量合格证号:20220004017238。
b.饲养条件
大鼠均饲养于独立送风笼具中,空气洁净度10000级,实验室温度26±2℃;相对湿度60%~80%;每小时空气交换次数:10-15次/小时;光照周期:12(日)/12(夜)小时,每笼3只。
饲料:鼠全价颗粒饲料,购自江苏省协同医药生物工程有限责任公司,其质量符合GB14924.1-2001《实验动物配合饲料通用质量标准》。
垫料:灭菌颗粒垫料,购自江苏省协同医药生物工程有限责任公司。
饮水:饮用纯化水,经酸化后自由饮用。
(3)主要仪器设备
Varioskan LUX多功能微孔板读数仪购自美国Thermo;BS210S精密电子天平(0.1mg~10g)购自德国赛多利斯;FEJ-200电子天平(0.1~200g)购自福州富日衡之宝电子有限公司;Pacific TII+Genpure XCAD PLUS UV/TOC/UF纯水超纯水***购自美国Thermo。
(4)主要试剂
尿酸检测试剂盒(磷钨酸还原法),批号:20230224,购自南京建成生物工程研究所;氧嗪酸钾,货号00164,批号T6GKM-TA,购自日本东京化成工业株式会社(TCI);羧甲基纤维素钠(CMC-Na),批号20170810,化学纯,购自国药集团化学试剂有限公司。
2.实验方法
(1)分组
SD大鼠30只,雄性,适应一周后,体重约为220-240g。按体重分层随机分为5组,每组6只,分别为:(1)正常组(0.5% CMC-Na),(2)模型组(0.5% CMC-Na),(3)非布司他2mg/kg,(4)化合物30,2mg/kg,(5)化合物32,2mg/kg。各组药物配成相应浓度混悬液,给药体积均为0.5mL/100g。
(2)模型建立、给药方案与及检测指标
各组大鼠购入适应饲养完毕,禁食12h,分别用氧嗪酸钾按300mg/kg剂量ip造模,造模后0.5h各受试药物组分别灌胃给药1次。连续给药3天,第3天分别于氧嗪酸钾注射前以及氧嗪酸钾注射后1、3、5h经眼眶后静脉丛采血,3500rpm离心10min,取血清30μL测定各时间点尿酸水平。
(3)数据处理与统计方法
各试验计量数据均以(平均数)±s(标准差)表示,组间比较采用ANOVA-Dunnett T检验考察显著性,以P<0.05作为显著性指标,P<0.01作为极显著性指标。
3.实验结果
与溶剂组相比,氧嗪酸钾模型组在造模后1、3、5h血清尿酸水平显著升高(P<0.01)。与同时间点模型组相比,非布司他可显著降低造模后的血清尿酸水平(P<0.01)。与相同时间点模型组相比,化合物30和化合物32可显著降低造模后的血清尿酸水平(P<0.01或P<0.05)。结果见表1。
表1.给药3天对氧嗪酸钾诱发的高尿酸血症大鼠血清尿酸水平的影响/>
##P<0.01,与同时间点溶剂组比较;*P<0.05,**P<0.01,与同时间点模型组比较。
实施例22:化合物11的SD大鼠体内药物代谢动力学实验
1.实验材料
(1)受试药物
化合物储备液配制:分别称取适量化合物固体粉末,加入一定量的DMSO,涡旋超声,得10mg/mL的储备液。
用于灌胃的试验化合物配制:分别移取适量化合物储备液,加入一定量SolutolHS15溶液,涡旋1分钟,再加入一定量生理盐水,充分混合均匀,得1mg/mL的溶液。
用于静脉注射的试验化合物配制:分别移取适量化合物储备液,加入一定量Solutol HS15溶液,涡旋1分钟,再加入一定量生理盐水,充分混合均匀,得0.5mg/mL的溶液。
(2)实验动物
SD大鼠,雄性,SPF级,6-8周龄。购自JH Laboratory Animal Co.LTD。许可证号:SCXK(SH)2022-0009,合格证编号:20220009004139。
2.实验方法
(1)给药剂量及方式
试验动物在灌胃给药前禁食过夜,给药4小时后再给予食物,期间自由饮水。每个试验化合物均设2个组别,分别为静脉给药组合口服给药组,具体给药剂量及方式见下表2。
表2化合物11对SD大鼠的给药剂量和方式
组别 | 动物数量 | 给药剂量(mg/kg) | 给药体积(mL/kg) | 浓度(mg/mL) | 给药途径 |
静脉给药组 | 3 | 1 | 2 | 0.5 | 静脉注射 |
口服给药组 | 3 | 10 | 10 | 1 | 口服 |
(2)实验操作
分别于给药前和给药后5分钟(仅静脉给药组)、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时和24小时,采集SD大鼠颈静脉血样(150μL/样本),并置于含有抗凝剂肝素钠的离心管中,4℃,2000g离心5分钟分离血浆。采用LC/MS/MS对血浆样品进行分析,检测血浆样本中各受试化合物的浓度。
(3)药物代谢动力学分析
非房室模型相关参数由Professional软件计算获得。
3.实验结果
依据上述方法获得的受试化合物的SD大鼠药物代谢动力学参数如表3所示。本发明的实施例化合物的药物代谢动力学相关参数良好,生物利用度高。
表3.口服或静脉注射给予各化合物的SD大鼠药物代谢动力学参数
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Claims (10)
1.通式(I)所示的化合物或其药学上可接受的盐,
其中,
R为C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基或C3-6杂环烷基中的一种或多种;
Ar为取代或非取代的以下基团:Ar基团中的取代基选自氘、羟基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;
Y为O或NR3,
R1为连接键或者取代或非取代的C1-6亚烷基或者取代或非取代的C2-12亚烯基,R1基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;
R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、C4-12稠杂芳环基、C4-16稠杂芳环基吡唑基羰基氧基、C4-16稠杂芳环基吡啶基羰基氧基、C4-16稠杂芳环基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C2-20烯基、C2-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、卤代C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种;且R2基团中的C4-16稠杂芳环基中不含有吲唑基;
R3为氢或C1-6烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中化合物选自通式(II)、(III)或(IV)所示的化合物,
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中Y为O或NH,R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
4.根据权利要求3所述的化合物或其药学上可接受的盐,其中R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、四氢呋喃、取代的四氢呋喃、四氢噻吩、取代的四氢噻吩、四氢吡咯或取代的四氢吡咯;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中R1为连接键或者取代或非取代的C1-4亚烷基或者取代或非取代的C2-12亚烯基,R1基团中的取代基选自氘、氨基、氰基、卤素或C1-4烷氧基中的一种或多种。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其中R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、嘌呤基、喹啉基吡唑基羰基氧基、异喹啉基吡唑基羰基氧基、吲哚基吡唑基羰基氧基、苯并呋喃基吡唑基羰基氧基、嘌呤基吡唑基羰基氧基、喹啉基吡啶基羰基氧基、异喹啉基吡啶基羰基氧基、吲哚基吡啶基羰基氧基、苯并呋喃基吡啶基羰基氧基、嘌呤基吡啶基羰基氧基、喹啉基三氮唑基羰基氧基、异喹啉基三氮唑基羰基氧基、吲哚基三氮唑基羰基氧基、苯并呋喃基三氮唑基羰基氧基、嘌呤基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C6-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、卤代C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种。
7.根据权利要求5所述的化合物或其药学上可接受的盐,其中R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲哚基吡唑基羰基氧基、吲哚基吡啶基羰基氧基、吲哚基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基、硝基氧基取代的C1-4烷基或C1-4烷氧基中的一种或多种。
8.根据权利要求1所述的化合物或其药学上可接受的盐,其中化合物选自:
9.一种药物组合物,它以权利要求1所述的化合物或其药学上可接受的盐为活性物质,辅以药学上可接受的辅料。
10.权利要求1所述的化合物或其药学上可接受的盐在制备抗痛风药物或抗高尿酸血症药物方面的用途。
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