CN107987006B - Indole or azaindole derivatives, preparation method and application thereof - Google Patents
Indole or azaindole derivatives, preparation method and application thereof Download PDFInfo
- Publication number
- CN107987006B CN107987006B CN201711386216.6A CN201711386216A CN107987006B CN 107987006 B CN107987006 B CN 107987006B CN 201711386216 A CN201711386216 A CN 201711386216A CN 107987006 B CN107987006 B CN 107987006B
- Authority
- CN
- China
- Prior art keywords
- mercapto
- pyrrolo
- pyridin
- indol
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title abstract description 102
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 96
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 49
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 49
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 title abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 229960002708 antigout preparations Drugs 0.000 claims abstract description 6
- 150000002475 indoles Chemical class 0.000 claims abstract description 6
- -1 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] acetic acid Chemical compound 0.000 claims description 122
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 47
- 201000005569 Gout Diseases 0.000 claims description 33
- 229940116269 uric acid Drugs 0.000 claims description 32
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 31
- 239000013078 crystal Substances 0.000 claims description 10
- 206010003246 arthritis Diseases 0.000 claims description 9
- 230000008021 deposition Effects 0.000 claims description 9
- 201000001431 Hyperuricemia Diseases 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 206010007027 Calculus urinary Diseases 0.000 claims description 6
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 6
- 208000008281 urolithiasis Diseases 0.000 claims description 5
- 229940083914 URAT1 inhibitor Drugs 0.000 claims description 4
- 108010093894 Xanthine oxidase Proteins 0.000 claims description 4
- 230000002757 inflammatory effect Effects 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 108010089503 Organic Anion Transporters Proteins 0.000 claims description 3
- 102000007990 Organic Anion Transporters Human genes 0.000 claims description 3
- 102000005773 Xanthine dehydrogenase Human genes 0.000 claims description 3
- 108010091383 Xanthine dehydrogenase Proteins 0.000 claims description 3
- 239000003064 xanthine oxidase inhibitor Substances 0.000 claims description 3
- 108010078791 Carrier Proteins Proteins 0.000 claims description 2
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 claims description 2
- 108091052347 Glucose transporter family Proteins 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000784 purine nucleoside phosphorylase inhibitor Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 149
- 229940079593 drug Drugs 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 5
- 238000011282 treatment Methods 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 183
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 90
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 90
- 125000003396 thiol group Chemical group [H]S* 0.000 description 89
- 239000002994 raw material Substances 0.000 description 85
- 238000001308 synthesis method Methods 0.000 description 55
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 47
- 238000005160 1H NMR spectroscopy Methods 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 45
- 238000000034 method Methods 0.000 description 40
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 39
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 33
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 235000019260 propionic acid Nutrition 0.000 description 24
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 24
- WEQIKOGPPFEIPX-UHFFFAOYSA-N potassium;propanoic acid Chemical compound [K].CCC(O)=O WEQIKOGPPFEIPX-UHFFFAOYSA-N 0.000 description 22
- ITKIWUNXKKMMSE-UHFFFAOYSA-N 4-bromonaphthalene-1-carbonitrile Chemical compound C1=CC=C2C(Br)=CC=C(C#N)C2=C1 ITKIWUNXKKMMSE-UHFFFAOYSA-N 0.000 description 21
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 20
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 18
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 17
- 229910052700 potassium Inorganic materials 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IBGUDZMIAZLJNY-UHFFFAOYSA-N 1,4-dibromonaphthalene Chemical compound C1=CC=C2C(Br)=CC=C(Br)C2=C1 IBGUDZMIAZLJNY-UHFFFAOYSA-N 0.000 description 15
- GXWZSHOVWDCGQD-UHFFFAOYSA-N 1-bromo-4-cyclopropylnaphthalene Chemical compound C12=CC=CC=C2C(Br)=CC=C1C1CC1 GXWZSHOVWDCGQD-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000011591 potassium Substances 0.000 description 15
- 229960003975 potassium Drugs 0.000 description 15
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 15
- 229910052708 sodium Inorganic materials 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 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 12
- 230000000694 effects Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 description 9
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 9
- SRSKXJVMVSSSHB-UHFFFAOYSA-N 1h-pyrrolo[3,2-c]pyridine Chemical compound N1=CC=C2NC=CC2=C1 SRSKXJVMVSSSHB-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 229960003838 lesinurad Drugs 0.000 description 7
- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- IAPCTXZQXAVYNG-UHFFFAOYSA-M Potassium 2,6-dihydroxytriazinecarboxylate Chemical compound [K+].[O-]C(=O)C1=NC(=O)NC(=O)N1 IAPCTXZQXAVYNG-UHFFFAOYSA-M 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 5
- 229960002327 chloral hydrate Drugs 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 5
- PQUSVJVVRXWKDG-UHFFFAOYSA-N methyl 2-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)(C)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 description 5
- 229950000193 oteracil Drugs 0.000 description 5
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- 238000003786 synthesis reaction Methods 0.000 description 5
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
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- 239000002904 solvent Substances 0.000 description 4
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- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 3
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- 206010029148 Nephrolithiasis Diseases 0.000 description 3
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- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 2
- SAYZMFSSIBFGNW-UHFFFAOYSA-N 3-bromo-1-methylindole Chemical compound C1=CC=C2N(C)C=C(Br)C2=C1 SAYZMFSSIBFGNW-UHFFFAOYSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
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- 239000011630 iodine Substances 0.000 description 2
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
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- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- ACEONLNNWKIPTM-UHFFFAOYSA-N methyl 2-bromopropanoate Chemical compound COC(=O)C(C)Br ACEONLNNWKIPTM-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004176 topiroxostat Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to a series of indole or azaindole derivatives, a preparation method of pharmaceutically acceptable salts of the indole or azaindole derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives and the pharmaceutical composition in preparation of anti-gout drugs and treatment of related diseases. The structural formula of the compound of the invention is shown as follows:
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a series of indole or azaindole derivatives, a preparation method of pharmaceutically acceptable salts of the indole or azaindole derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives and the pharmaceutical composition in preparation of anti-gout drugs and treatment of related diseases.
Background
Gout is caused by purine metabolic disorder in vivo and hyperuricemia in blood, so urate is precipitated in joints, kidneys and connective tissues, and gouty arthritis, gouty nephropathy, lithiasis and the like are caused, and the gout is generally called gout in medicine. The disease is characterized in that the monohydrate sodium urate crystal with double refraction can be found in synovial fluid and tophus. The clinical characteristics are as follows: hyperuricemia, characteristic acute arthritis, tophus and interstitial nephritis caused by urate crystallization and deposition, severe cases have joint deformity and dysfunction, are often accompanied with uric acid urinary calculus, and are often seen in middle-aged and old men with obesity and postmenopausal women.
Gout drugs can be generally classified into 3 types according to their action characteristics:
one is anti-gout attack medicine. Such drugs include indomethacin (indomethacin) and colchicine tablets.
The indometacin has mild uric acid discharging effect and can relieve pain caused by gout attack. It is commonly used for osteoarthropathy caused by gout attack. Patients need to swallow the product in whole tablet when taking the product, and patients with gastric ulcer, epilepsy and psychosis are prohibited to take the product, so the medicine is not suitable for long-term taking.
The colchicine tablets have large toxic and side effects, are limited to the acute gout attack stage at present, and also have vomiting, diarrhea and other reactions when some patients take the colchicine tablets, and the optimal dosage of the colchicine for resisting gout is yet to be further researched.
Second, uric acid excretory agents. Probenecid belongs to the class of medicines, and mainly inhibits reabsorption of urate by renal tubules, increases excretion of urate, reduces the concentration of urate in blood, prevents formation of urate crystals, promotes operation of joints, and can promote dissolution of formed urate. The product has no anti-inflammatory and analgesic effects, and can be used for treating chronic gout or recovering gout.
Thirdly, a uric acid synthesis blocking agent. Allopurinol belongs to the class of medicines, mainly inhibits xanthine oxidase to prevent hypoxanthine and xanthine in vivo from being metabolized into uric acid, so that the generation of uric acid is reduced, and the allopurinol can be used for treating primary, secondary and chronic gout diseases.
Uric acid is the result of oxidation of xanthines. Uric acid metabolism disorders include, but are not limited to, diseases associated with uric acid metabolic abnormalities such as polycythemia, myeloid metaplasia, gout, repeated gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, lesch-naphalene disembarkia, keletonema, kidney disease, kidney stone, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, sarcoidosis, and the like.
Lesinure (Lesinurad) is an orally effective URAT1 inhibitor. The clinical research results in the phases I and II show that the combination of the Lesinurad (Lesinurad) and the xanthine oxidase inhibitor can effectively regulate the uric acid level, has higher safety, and has the following molecular structure:
lesinurad has the problems of weak pharmacodynamic activity, large dosage, high renal toxicity and the like, and clinically, URAT1 inhibitors with higher pharmacodynamic effect need to be developed. Surprisingly, the study discovers that sulfur-containing heterocycles and derivatives thereof have good URAT1 inhibition effect, and the in vitro screening and pharmacological research are superior to that of lesinure, so that the invention develops an anti-gout drug with better treatment effect.
Disclosure of Invention
The invention aims to provide an indole or azaindole derivative shown as a formula I, a pharmaceutically acceptable salt, a solvate, a hydrate or a pharmaceutically acceptable prodrug thereof, and the structure of the derivative is as follows:
wherein:
X1，X2，X3，X4independently selected from CH or N;
at most one of X1, X2, X3 and X4 is N;
R1is selected from H or C1-3An alkyl group;
w represents:
wherein:
R2selected from H, cyano, halogen, C1-6 alkyl or cycloalkyl;
when R is1When H, W is in the 1-position, when R is1Is C1-3When alkyl, W is in the 3-position;
y is at position 2 or 3 and represents:
wherein:
R3，R4independently selected from H or methyl;
M1represents H or a pharmaceutically acceptable cation.
Preferably, the indole or azaindole derivatives, pharmaceutically acceptable salts, solvates, hydrates or pharmaceutically acceptable prodrugs thereof according to the present invention have the following structural formula:
wherein,
X1，X2，X3，X4，R2，R3，R4，M1the substitution method of (a) is as above,
alternatively, the structural formula is as follows:
wherein,
X1，X2，X3，X4，R2，R3，R4，M1the substitution method of (a) is as above,
alternatively, the structural formula is as follows:
wherein,
X1，X2，X3，X4，R2，R3，R4，M1the substitution method of (a) is as above,
further preferred, the compounds of the invention are:
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] acetic acid (i 1);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] sodium acetate (i 2);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] acetic acid (i 3);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] acetate (i 4);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] acetic acid (i 5);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] acetate (i 6);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] acetic acid (i 7);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] acetate (i 8);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] acetic acid (i 9);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] acetate (i 10);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] propanoic acid (i 11);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] propionate (i 12);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] propanoic acid (i 13);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] propionate (i 14);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] propanoic acid (i 15);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] propionate (i 16);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] propanoic acid (i 17);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] propionate (i 18);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] propanoic acid (i 19);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] propionate (i 20);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] -2-methylpropanoic acid (i 21);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] -2-methylpropanoate (I22);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] -2-methylpropanoic acid (I23);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] -2-methylpropionate (i 24);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] -2-methylpropanoic acid (i 25);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] -2-methylpropionate (i 26);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] -2-methylpropanoic acid (i 27);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] -2-methylpropionate (i 28);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] -2-methylpropanoic acid (i 29);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] -2-methylpropionate (i 30);
2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] acetic acid (i 31);
2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] sodium acetate (i 32);
2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] acetic acid (i 33);
sodium 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] acetate (i 34);
2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] acetic acid (i 35);
sodium 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] acetate (i 36);
2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] acetic acid (i 37);
sodium 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] acetate (i 38);
2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] acetic acid (i 39);
sodium 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] acetate (i 40);
2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] propanoic acid (i 41);
potassium 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] propionate (i 42);
2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propanoic acid (i 43);
potassium 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propionate (i 44);
2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propanoic acid (i 45);
potassium 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propionate (i 46);
2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propanoic acid (i 47);
potassium 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propionate (i 48);
2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propanoic acid (i 49);
potassium 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propionate (i 50);
2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] -2-methylpropanoic acid (i 51);
lithium 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] -2-methylpropanoate (i 52);
2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (i 53);
lithium 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 54);
2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (i 55);
lithium 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 56);
2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (i 57);
lithium 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 58);
2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (i 59);
lithium 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 60);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] acetic acid (i 61);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] sodium acetate (i 62);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] acetic acid (i 63);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] acetate (i 64);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] acetic acid (i 65);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] acetate (i 66);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] acetic acid (i 67);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] acetate (i 68);
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] acetic acid (i 69);
sodium 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] acetate (i 70);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] propanoic acid (i 71);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] propionate (i 72);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propanoic acid (i 73);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propionate (i 74);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propanoic acid (i 75);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propionate (i 76);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propanoic acid (i 77);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propionate (i 78);
2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propanoic acid (i 79);
potassium 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propionate (i 80);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] -2-methylpropanoic acid (i 81);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] -2-methylpropanoate (i 82);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid (i 83);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 84);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (i 85);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 86);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid (i 87);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 88);
2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid (i 89);
lithium 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropionate (i 90);
the compound of the invention has the following corresponding structural formula:
the compound and the pharmaceutically acceptable salts thereof are Na, K, Li, Ca and Mg salts. Preferably a Na salt.
The invention also relates to pharmaceutically acceptable prodrugs of the compounds, including but not limited to: esters, carbonates, enacarbilates, thiocarbonates, N-acyl derivatives, N-acyloxy derivatives, amino acid conjugates, and the like.
Another object of the present invention is to provide a process for the preparation of indole or azaindole derivatives represented by formula I or pharmaceutically acceptable salts or prodrugs thereof.
The preparation method of the compound with the structural formula as follows comprises the following steps:
(1) Reacting a compound shown in a formula II under the action of thiourea, iodine and potassium iodide, and then adding NaOH and a compound shown in a formula III to generate a compound shown in a formula IV:
(2) reacting a compound shown as a formula IV with a compound shown as a formula V under the action of a catalyst and a base to generate a compound shown as a formula VI:
(3) hydrolyzing a compound of formula VI under basic conditions to produce a compound of formula VII:
(4) reacting a compound of formula VII with a corresponding base to produce a compound of formula VIII, M1Represents a pharmaceutically acceptable cation:
the preparation method of the compound with the structural formula as follows comprises the following steps:
(1) Reacting a compound of formula II with methyl iodide to produce a compound of formula IX:
(2) reacting a compound of formula IX with a halogenating agent to form a compound of formula X:
(3) reacting a compound shown in a formula X with a compound shown in a formula XI under the action of a catalyst and a base to generate a compound shown in a formula XII:
(4) reacting the compound shown in the formula XII under the action of thiourea, iodine and potassium iodide, and adding NaOH and the compound shown in the formula III to generate the compound shown in the formula XIII:
(5) hydrolyzing a compound of formula XIII under basic conditions to produce a compound of formula XIV:
(6) reacting a compound of formula XIV with a corresponding base to produce a compound of formula XV, M1Represents a pharmaceutically acceptable cation:
the preparation method of the compound with the structural formula as follows comprises the following steps:
(1) Reacting a compound of formula XVI with a compound of formula XVII to produce a compound of formula XVIII:
(2) reacting a compound of formula XVIII with a compound of formula V to produce a compound of formula XIX:
(3) hydrolyzing a compound of formula XIX under basic conditions to produce a compound of formula XX:
(4) reacting a compound of formula XX with a corresponding base to produce a compound of formula XXI, M1Represents a pharmaceutically acceptable cation:
the compounds of the present invention are known compounds and are either commercially available or can be prepared by known techniques.
Another object of the present invention is to provide a pharmaceutical composition.
The pharmaceutical composition at least contains one indole or azaindole derivative represented by formula I or pharmaceutically acceptable salt thereof.
The pharmaceutical compositions of the present invention may also be supplemented with one or more pharmaceutically acceptable carriers or excipients, as desired.
The pharmaceutical composition of the invention comprises 0.1-99.9% by weight of indole or azaindole derivatives shown in formula I or pharmaceutically acceptable salts thereof, and the balance of pharmaceutically acceptable carriers.
The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage forms, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The formulations of the present invention, preferably oral dosage forms, are: capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent.
The administration route of the present invention may be oral, parenteral or topical, preferably oral and injectable. The oral administration preparation suitable for pharmaceutical use may be a tablet, capsule, granule or other liquid form preparation suitable for pharmaceutical use such as solution, emulsion, suspension, etc. Preferred oral formulations are tablets, and the tablets may be formulated as a coating, enteric, sustained release or metered release.
The pharmaceutical composition of the present invention, its preparation for oral administration, may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
The solid oral compositions can be prepared by conventional methods of mixing, filling, tabletting and the like. Repeated mixing can distribute the active throughout those compositions that use large amounts of filler.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol; preservatives, for example p-hydroxybenzyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
For injections, liquid unit dosage forms are prepared containing the active substances of the invention and a sterile carrier. Depending on the carrier and concentration, the compound may be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the composition can be frozen after filling into vials and the water removed under vacuum.
The pharmaceutical composition of the present invention, when being prepared into a medicament, can be optionally added with a suitable pharmaceutically acceptable carrier selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered alone or in the form of pharmaceutical compositions. The pharmaceutical composition of the present invention can be formulated into various suitable dosage forms according to the administration route. The use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen and may be prepared in accordance with common general knowledge in the art.
The invention aims to provide application of indole or azaindole derivatives shown in formula I or pharmaceutically acceptable salts thereof in preparation of medicines for regulating uric acid level and/or treating gout and related indications.
The invention aims to provide application of a pharmaceutical composition taking indole or azaindole derivatives shown as a formula I or pharmaceutically acceptable salts or prodrugs thereof as an active ingredient in preparation of medicines for regulating the uric acid level and/or treating gout and related indications.
Wherein the relevant indications include: hyperuricemia, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis, joint inflammation, urate crystal deposition in joints, urolithiasis, urate crystal deposition in renal parenchyma, gout flares, tophaceous gout, or a combination thereof.
The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used as a unit therapy or may be administered in combination with one or more other therapies. A method for preventing or treating any disease or condition in humans or other mammals where aberrant uric acid levels play a role, including but not limited to: hyperuricemia, gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis, joint inflammation, deposition of urate crystals in joints, urolithiasis, deposition of urate crystals in renal parenchyma, gout flares, tophaceous gout, or a combination thereof.
The specific choice of the compounds and other therapeutic agents contemplated by the present invention will depend upon the judgment of the attending physician in the diagnosis of the condition and its individual as well as the appropriate treatment regimen. Other agents are URAT1 inhibitors, xanthine oxidase inhibitors, xanthine dehydrogenase, xanthine oxidoreductase inhibitors, purine nucleoside phosphorylase inhibitors, uric acid transporter inhibitors, glucose transporter inhibitors, Organic Anion Transporter (OAT) inhibitors, OAT-4 inhibitors, or combinations. The second agent is preferably allopurinol, febuxostat, topiroxostat, or a combination thereof.
The compound of the invention has the characteristics of obvious treatment effect, low side effect, simple synthetic route, low cost, stable product quality and the like.
Detailed Description
The technical solution of the present invention will be further described below by way of specific embodiments, but the present invention is not limited thereto.
Example 12- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] acetic acid (I1)
Step 1: 2- [ (1H-indol-3-yl) mercapto ] acetic acid
Indole (2.9g) was dissolved in methanol (30mL), thiourea (12g) was added, and a mixed aqueous solution (50mL) of iodine (6.4g) and potassium iodide (4.2g) was added dropwise at room temperature, and the reaction was stirred at room temperature, and TLC monitored after completion of the reaction. NaOH solution (2M,125mL) was added and stirred at 100 ℃ for 10 min. Methyl bromoacetate (4.9g) was added and the reaction stirred at room temperature for 2 h. After the TLC reaction is complete. Ethyl acetate (300mL) and water (100mL) were extracted, the ethyl acetate phase was washed with saturated brine (100 mL. times.4), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluent, dichloromethane: methanol 10: 1, v: v) to give 800mg of pure product, 15.6% yield.
Step 2: 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] acetic acid (I1)
Reacting 2- [ (1H-indol-3-yl) mercapto group]Acetic acid (200mg), 4-bromo-1-naphthanenitrile (230mg), CuI (100mg), Cs2CO3(300mg), dimethylglycinAdding acid (50mg) into DMSO (4mL), replacing argon protection, stirring at 130 ℃ for reaction for 12h, detecting complete reaction by TLC, cooling to room temperature, adding ethyl acetate and saturated sodium bicarbonate solution, separating liquid, washing an ethyl acetate phase with saturated saline water for 3-5 times, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography (eluent, dichloromethane: methanol is 10: 1, v: v) to obtain a pure product 80mg, wherein the yield is 23.1%. LC-MS: m/z 359.1[ M + H ].]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.59(s,1H),8.38(d,J＝8,0Hz,1H),8.31(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.90(s,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),3.58(s,2H).
Example 22- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] sodium acetate (I2)
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid (100mg, 0.279mmol) was dissolved in 5mL of methanol, added with sodium hydroxide solution (1M, 0.279mL), stirred at room temperature for 10 minutes, and concentrated to dryness under reduced pressure to give 106mg of a white solid with a yield of 100%, LC-MS: m/z 359.1[ M + H ].]+。
Example 32- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] acetic acid (I3)
7-azaindole is used as a raw material to replace indole, and the synthesis method is the same as the preparation method of the compound described in the example 1, LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),8.12(s,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.79(s,2H).
Example 42- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] sodium acetate (I4)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl)) -1H-indol-3-yl]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 52- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] acetic acid (I5)
The synthesis method is the same as the preparation method of the compound described in the example 1 by using 6-azaindole as a raw material to replace indole, and LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.79(s,2H).
Example 62- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] sodium acetate (I6)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ]]Pyridin-3-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 72- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] acetic acid (I7)
5-azaindole is used as a raw material to replace indole, and the synthesis method is the same as the preparation method of the compound described in the example 1, LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.78(s,2H).
Example 82- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] sodium acetate (I8)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3, 2-c)]Pyridin-3-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 92- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] acetic acid (I9)
The synthesis method is the same as the preparation method of the compound described in the example 1 by using 4-azaindole as a raw material to replace indole, and LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.78(s,2H).
Example 102- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] sodium acetate (I10);
by 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ]]Pyridin-3-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 112- [ [1- (4-Bromnaphthol-1-yl) -1H-indol-3-yl ] mercapto ] propanoic acid (I11)
1, 4-dibromonaphthalene and methyl 2-bromopropionate are used as raw materials to replace 4-bromo-1-naphthonitrile and methyl 2-bromoacetate respectively, and the synthesis method is the same as the preparation method of the compound described in example 1, and LC-MS: m/z 426.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.60(s,1H),8.39(d,J＝8,0Hz,1H),8.34(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.90(s,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),4.48(s,1H),1.76(s,3H).
Example 122- [ [1- (4-Bromnaphthol-1-yl) -1H-indol-3-yl ] mercapto ] propionic acid potassium (I12)
With 2- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Propionic acid as raw material to replace 2- [ [1- (4-cyano naphthalene)-1-yl) -1H-indol-3-yl]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 426.0[ M + H ]]+。
Example 132- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] propanoic acid (I13)
The synthesis method is the same as the preparation method of the compound described in the example 1, and the synthesis method comprises the following steps of substituting 7-azaindole as a raw material for indole, substituting 1, 4-dibromonaphthalene for 4-bromo-1-naphthalonitrile, and substituting 2-bromomethyl propionate for 2-bromomethyl acetate, wherein LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),8.12(s,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.54(s,1H),1.79(s,3H).
Example 142- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] propionic acid potassium (I14)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 152- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] propanoic acid (I15)
The synthesis method is the same as the preparation method of the compound described in the example 1, and the synthesis method comprises the following steps of substituting 6-azaindole as a raw material for indole, substituting 1, 4-dibromonaphthalene for 4-bromo-1-naphthalonitrile, and substituting 2-bromomethyl propionate for 2-bromomethyl acetate, wherein LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.56(s,1H),1.77(s,3H).
Example 162- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] propionic acid potassium (I16)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-c ]]Pyridin-3-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 172- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] propanoic acid (I17)
The synthesis method is the same as the preparation method of the compound described in the example 1, and the synthesis method comprises the following steps of substituting 5-azaindole as a raw material for indole, substituting 1, 4-dibromonaphthalene for 4-bromo-1-naphthalonitrile, and substituting 2-bromomethyl propionate for 2-bromomethyl acetate, wherein LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.59(s,1H),1.80(s,3H).
Example 182- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] propionic acid potassium (I18)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3, 2-c)]Pyridin-3-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 192- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] propanoic acid (I19)
The synthesis method is the same as the preparation method of the compound described in the example 1, wherein 4-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.57(s,1H),1.79(s,3H).
Example 202- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] propionic acid potassium (I20)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ]]Pyridin-3-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 212- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] -2-methylpropionic acid (I21)
1-bromo-4-cyclopropylnaphthalene and methyl 2-bromoisobutyrate were used as starting materials in place of 4-bromo-1-naphthonitrile and methyl 2-bromoacetate, respectively, and the synthesis was performed according to the same method as the preparation of the compound described in example 1, LC-MS: m/z 402.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.51(s,1H),8.39(d,J＝8,0Hz,1H),8.34(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.90(s,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),2.53-2.60(m,1H),1.45(s,6H),1.13-1.17(m,2H),0.84-0.87(m,2H).
Example 222- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] -2-lithium methylpropanoate (I22)
With 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-indol-3-yl radical]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 402.1[ M + H ]]+。
Example 232- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] -2-methylpropionic acid (I23)
7-azaindole as raw material to replace indoleThe synthesis method was the same as the preparation method of the compound described in example 1, except that 1-bromo-4-cyclopropylnaphthalene was used instead of 4-bromo-1-naphthonitrile and methyl 2-bromoisobutyrate was used instead of methyl 2-bromoacetate, and LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),8.12(s,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 242- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] mercapto ] -2-lithium methylpropionate (I24)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 252- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] -2-methylpropionic acid (I25)
The synthesis method is the same as the preparation method of the compound described in the example 1, wherein 6-azaindole is used as a raw material to replace indole, 1-bromo-4-cyclopropylnaphthalene is used to replace 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.40(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.32(d,J＝8.4Hz,1H),7.96(s,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.33(d,J＝7.6Hz,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 262- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-3-yl ] mercapto ] -2-methylpropanoic acid lithium (I26)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ]]Pyridin-3-yl]Mercapto group]-2-methylPhenylpropionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 272- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] -2-methylpropionic acid (I27)
5-azaindole is used as a raw material to replace indole, 1-bromo-4-cyclopropylnaphthalene is used to replace 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate is used to replace 2-bromomethyl acetate, and the synthesis method is the same as the preparation method of the compound described in example 1, and LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 282 lithium- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-3-yl ] mercapto ] -2-methylpropionate (I28)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3, 2-c)]Pyridin-3-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 292- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] -2-methylpropionic acid (I29)
The synthesis method is the same as the preparation method of the compound described in the example 1, wherein 4-azaindole is used as a raw material to replace indole, 1-bromo-4-cyclopropylnaphthalene is used to replace 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.96(s,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.31(d,J＝7.6Hz,1H),2.53-2.61(m,1H),1.46(s,6H),1.13-1.18(m,2H),0.83-0.86(m,2H).
Example 302- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-3-yl ] mercapto ] -2-methylpropanoic acid lithium (I30)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ]]Pyridin-3-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 312- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] acetic acid (I31)
Step 1: n-methylindole
Indole (1.2g, 10mmol) was added to 20mL DMF, potassium carbonate (2.8g, 20mmol) and iodomethane (2.8g, 20mmol) were added, the mixture was heated to 40 ℃ to react for 3h, cooled to room temperature, water and ethyl acetate were added to extract, the ethyl ester phase was washed twice with water, concentrated to dryness, and column-separated (eluent PE: EA ═ 5:1) to give 1.0g oily liquid, yield 77%
Step 2: 1-methyl-3-bromoindole
N-methylindole (1.0g, 76mmol) was dissolved in 10mL DMF, NBS (1.1g, 92mmol) was added, stirred at room temperature for 2h, water and ethyl acetate were added for extraction, the organic phase was washed twice with water, concentrated to dryness, and separated on a column (eluent PE: EA ═ 5:1) to give 1.5g oily liquid, yield 94%.
And step 3: 4- (1-methyl-1H-indol-3-yl) -1-naphthacenitrile
1-methyl-3-bromoindole (1.4g, 5mmol), 4-cyanonaphthalene-1-boronic acid pinacol ester (1.5g, 5.5mmol), potassium acetate (1.5g, 15mmol) and Pd (dppf) Cl2(0.4g, 0.5mmol) were added to 10mL dioxane, 4mL water was added, argon was replaced, the mixture was heated to 90 ℃ for reaction for 3h, cooled to room temperature, water and ethyl acetate were added for extraction, the ethyl acetate phase was concentrated to dryness, and column separation (eluent PE: EA ═ 3:1) gave 1.1g of a solid in 80% yield.
And 4, step 4: 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] acetic acid (I31)
4- (1-methyl-1H-indol-3-yl) -1-naphthacenitrile (1.1g) was dissolved in methanol (10mL), thiourea (1.9g) was added, and a mixed aqueous solution (15mL) of iodine (1.0g) and potassium iodide (0.64g) was added dropwise at room temperature, and the reaction was stirred at room temperature, followed by TLC to monitor completion of the reaction. NaOH solution (2M,10mL) was added and stirred at 100 ℃ for 10 min. Methyl bromoacetate (0.78g) was added and the reaction stirred at room temperature for 2 h. After the TLC reaction is complete. Ethyl acetate (100mL) and water (70mL) were extracted, the ethyl acetate phase was washed with saturated brine (50mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluent, dichloromethane: methanol 10: 1, v: v) to give 196mg of pure product, yield 13.5%, LC-MS: m/z 373.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.60(s,1H),8.39(d,J＝8,0Hz,1H),8.32(d,J＝8.0Hz,1H),7.93(t,J＝7.2Hz,1H),7.84(d,J＝7.6Hz,1H),7.80(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),3.58(s,2H),2.90(s,3H).
Example 322- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] sodium acetate (I32)
With 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-indol-2-yl group]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 373.1[ M + H ]]+。
Example 332- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] acetic acid (I33)
7-azaindole is used as a raw material to replace indole, and the synthesis method is the same as the preparation method of the compound in the example 31, LC-MS: m/z 374.1[ M + H]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.71(s,1H),8.56(d,J＝6,4Hz,1H),8.52(t,J＝7.6Hz,1H),8.39(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.34(d,J＝7.6Hz,1H),3.79(s,2H).3.10(s,3H).
Example 342- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] sodium acetate (I34)
By 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 374.1[ M + H]+。
Example 352- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] acetic acid (I35)
The synthesis method is the same as the preparation method of the compound in the example 31 by using 6-azaindole as a raw material to replace indole, and the LC-MS: m/z 374.1[ M + H]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.79(s,2H).3.11(s,3H).
Example 362- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] sodium acetate (I36)
By 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ]]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 374.1[ M + H]+。
Example 372- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] acetic acid (I37);
5-azaindole is used as a raw material to replace indole, and the synthesis method is the same as the preparation method of the compound in the example 31, LC-MS: m/z 374.1[ M + H]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.40(s,1H),8.56(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.78(s,2H),3.11(s,3H).
Example 382- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] sodium acetate (I38)
By 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3, 2-c)]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 374.1[ M + H]+。
Example 392- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] acetic acid (I39)
The synthesis method is the same as the preparation method of the compound in the example 31 by using 4-azaindole as a raw material to replace indole, and the LC-MS: m/z 374.1[ M + H]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.78(s,2H),3.10(s,3H).
Example 402- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] sodium acetate (I40)
By 2- [ [3- (4-cyanonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ]]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 374.1[ M + H]+。
Example 412- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] propanoic acid (I41)
The synthesis method of the compound is the same as the preparation method of the compound in example 31 by using 1, 4-dibromonaphthalene as a raw material to replace 4-bromo-1-naphthonitrile and 2-bromomethyl propionate to replace 2-bromomethyl acetate, LC-MS：m/z 440.0[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.60(s,1H),8.39(d,J＝8,0Hz,1H),8.34(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),4.48(s,1H),2.90(s,3H),1.76(s,3H).
Example 422- [ [3- (4-Bromnaphthol-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] propionic acid potassium (I42)
With 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-indol-2-yl group]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 440.0[ M + H ]]+。
Example 432- [ [3- (4-Bromnaphthol-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propanoic acid (I43)
The synthesis method is the same as the preparation method of the compound described in example 31, wherein 7-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 441.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.54(s,1H),3.14(s,3H).1.79(s,3H).
Example 442- [ [3- (4-Bromnaphthol-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propionic acid potassium (I44)
By 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 441.0[ M + H ]]+。
Example 452- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propanoic acid (I45)
The synthesis method is the same as the preparation method of the compound described in example 31, wherein 6-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 441.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.56(s,1H),3.13(s,3H),1.77(s,3H).
Example 462- [ [3- (4-Bromnaphthol-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propionic acid potassium (I46)
By 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ]]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 441.0[ M + H ]]+。
Example 472- [ [3- (4-Bromomaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propanoic acid (I47)
The synthesis method is the same as the preparation method of the compound described in example 31, wherein 5-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 441.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.59(s,1H),3.14(s,3H),1.80(s,3H).
Example 482- [ [3- (4-Bromnaphthol-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propionic acid potassium (I48)
By 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3, 2-c)]Pyridine compound-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 441.0[ M + H ]]+。
Example 492- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propanoic acid (I49)
The synthesis method is the same as the preparation method of the compound described in example 31, wherein 4-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 441.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),4.57(s,1H),3.12(s,3H),1.79(s,3H).
Example 502- [ [3- (4-Bromnaphthol-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propionic acid potassium (I50)
By 2- [ [3- (4-bromonaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ]]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 441.0[ M + H ]]+。
Example 512- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] -2-methylpropionic acid (I51)
1-bromo-4-cyclopropylnaphthalene and methyl 2-bromoisobutyrate were used as starting materials in place of 4-bromo-1-naphthonitrile and methyl 2-bromoacetate, respectively, and the synthesis was performed in the same manner as the preparation of the compound described in example 31, LC-MS: m/z 416.2[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.51(s,1H),8.39(d,J＝8,0Hz,1H),8.34(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),2.92(s,3H),2.53-2.60(m,1H),1.45(s,6H),1.13-1.17(m,2H),0.84-0.87(m,2H).
Example 522- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-indol-2-yl ] mercapto ] -2-methylpropanoic acid lithium (I52)
With 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-indol-2-yl radical]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 416.2[ M + H ]]+。
Example 532- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I53)
The synthesis method of the compound of example 31 was the same as the preparation method of the compound described in example 31, except that 7-azaindole was used as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene instead of 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, and LC-MS: m/z 417.2[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.14(s,3H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 542- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid lithium (I54)
By 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 417.2[ M + H ]]+。
Example 552- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I55)
6-azaindole as a raw material substituteIndole, 4-bromo-1-naphthonitrile with 1-bromo-4-cyclopropylnaphthalene and methyl 2-bromoisobutyrate with 2-bromoacetate, the synthesis was the same as the preparation of the compound described in example 31, LC-MS: m/z 417.2[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.40(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.32(d,J＝8.4Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.33(d,J＝7.6Hz,1H),3.13(s,3H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 562- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid lithium (I56)
By 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [2,3-c ]]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 417.2[ M + H ]]+。
Example 572- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I57)
The synthesis method of the compound of example 31 was the same as that of 5-azaindole, which was used as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene instead of 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, and LC-MS: m/z 417.2[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),3.13(s,3H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 582- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid lithium (I58)
With 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-c]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 417.2[ M + H ]]+。
Example 592- [ [3- (4-Cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I59)
The synthesis method of the compound of example 31 was the same as the preparation method of the compound described in example 31, except that 4-azaindole was used as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene was used instead of 4-bromo-1-naphthonitrile, and methyl 2-bromoisobutyrate was used instead of methyl 2-bromoacetate, and LC-MS: m/z 417.2[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.31(d,J＝7.6Hz,1H),3.15(s,3H),2.53-2.61(m,1H),1.46(s,6H),1.13-1.18(m,2H),0.83-0.86(m,2H).
Example 602 lithium- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropionate (I60)
By 2- [ [3- (4-cyclopropylnaphthalen-1-yl) -1-methyl-1H-pyrrolo [3,2-b ]]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 417.2[ M + H ]]+。
Example 612- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] acetic acid (I61)
Step 1: 2- [ (1H-indol-2-yl) mercapto ] acetic acid methyl ester
Adding 2-chloroindole (3.0g, 20mmol) and anhydrous potassium carbonate (4.1g, 30mmol) into 50mL DMF, adding 2-mercaptoacetic acid methyl ester (2.7g, 25mmol) under stirring, heating to 50 ℃ for reaction for 2h, detecting complete reaction by TLC, cooling to room temperature, adding ethyl acetate and water for extraction, washing an ethyl acetate phase with water for 2 times, concentrating to dryness, and separating and purifying by a column (eluent PE: EA ═ 2:1) to obtain 3.1g oily liquid with the yield of 70%.
Step 2: 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] acetic acid methyl ester
Methyl 2- [ (1H-indol-2-yl) mercapto ] acetate (2.2g), 4-bromo-1-naphthacenitrile (2.3g), CuI (1.0g), Cs2CO3(3.0g), dimethylglycine (500mg) were added to DMSO (50mL), argon gas was replaced, the reaction was stirred at 130 ℃ for 12 hours, cooled to room temperature, ethyl acetate and saturated water were added, the mixture was separated, the ethyl acetate phase was washed with saturated saline water 2 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluent, dichloromethane: methanol ═ 10: 1, v: v) to obtain 0.9g of a pure product, with a yield of 24%.
And step 3: 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] acetic acid (I61)
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl group]Mercapto group]Dissolving methyl acetate (0.5g, 1.3mmol) in 20mL THF, adding LiOH solution (1M, 20mL), stirring at room temperature for 2h, detecting by TLC that no raw material remains, adding 2N diluted hydrochloric acid to adjust pH to 4-5, adding ethyl acetate for extraction, washing the organic phase with water for 2 times, concentrating under reduced pressure to dryness, and purifying by column chromatography (eluent, dichloromethane: methanol ═ 10: 1, v: v) to obtain 0.4g pure product with yield of 83%, LC-MS: m/z 359.1[ M + H ].]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.61(s,1H),8.35(d,J＝8,0Hz,1H),8.30(d,J＝8.0Hz,1H),7.91(t,J＝7.2Hz,1H),7.83(d,J＝7.6Hz,1H),7.80(d,J＝8.0Hz,1H),7.68(t,J＝8.0Hz,1H),7.45(d,J＝8.4Hz,1H),7.22(t,J＝8.0Hz,1H),7.15(t,J＝7.6Hz,1H),7.01(d,J＝8.0Hz,1H),6.80(s,1H),3.58(s,2H).
Example 622- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] sodium acetate (I62)
With 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-2-yl group]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis methodThe same procedure as described in example 2 for the preparation of the compound, LC-MS: m/z 359.1[ M + H ].]+。
Example 632- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] acetic acid (I63)
7-azaindole is used as a raw material to replace indole, and the synthesis method is the same as the preparation method of the compound in the example 61, LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.90(s,1H),3.79(s,2H).
Example 642- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] sodium acetate (I64)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-b ]]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 652- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] acetic acid (I65)
The synthesis method is the same as the preparation method of the compound described in example 61, and the synthesis method is carried out by taking 6-azaindole as a raw material to replace indole, wherein LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.90(s,1H),3.79(s,2H).
Example 662- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] sodium acetate (I66)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [2,3-c ]]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid and the synthetic method are carried out simultaneouslyPreparation of the compound described in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 672- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] acetic acid (I67)
5-azaindole is used as a raw material to replace indole, and the synthesis method is the same as the preparation method of the compound in the example 61, LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.92(s,1H),3.78(s,2H).
Example 682- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] sodium acetate (I68)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3, 2-c)]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthesis method the same preparation as described for the compound in example 2, LC-MS: m/z 360.1[ M + H ]]+。
Example 692- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] acetic acid (I69)
The synthesis method is the same as the preparation method of the compound described in example 61, and the synthesis method is carried out by using 4-azaindole as a raw material to replace indole, wherein LC-MS: m/z 360.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.91(s,1H),3.78(s,2H).
Example 702- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] sodium acetate (I70)
By 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-pyrrolo [3,2-b ]]Pyridin-2-yl]Mercapto group]Acetic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, synthetic method as described in example 2Process for the preparation of compounds, LC-MS: m/z 360.1[ M + H ]]+。
Example 712- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] propanoic acid (I71)
The synthesis method was the same as the preparation method of the compound described in example 61, using 1, 4-dibromonaphthalene and methyl 2-bromopropionate as raw materials instead of 4-bromo-1-naphthonitrile and methyl 2-bromoacetate, respectively, and LC-MS: m/z 426.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.60(s,1H),8.39(d,J＝8,0Hz,1H),8.34(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),6.80(s,1H),4.48(s,1H),1.76(s,3H).
Example 722- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] propionic acid potassium (I72)
With 2- [ [1- (4-bromonaphthalen-1-yl) -1H-indol-2-yl group]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 426.0[ M + H ]]+。
Example 732- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propanoic acid (I73)
The synthesis method is the same as the preparation method of the compound described in example 61, wherein 7-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.92(s,1H),4.54(s,1H),1.79(s,3H).
Example 742- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] propionic acid potassium (I74)
With 2- [ [1- (4-bromonaphthalene)-1-yl) -1H-pyrrolo [2,3-b]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 752- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propanoic acid (I75)
The synthesis method is the same as the preparation method of the compound described in example 61, wherein 6-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.41(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.92(s,1H),4.56(s,1H),1.77(s,3H).
Example 762- [ [1- (4-Bromomaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] propionic acid potassium (I76)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [2,3-c ]]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 772- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propanoic acid (I77)
The synthesis method is the same as the preparation method of the compound described in example 61, wherein 5-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.96(s,1H),4.59(s,1H),1.80(s,3H).
Example 782- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] propionic acid potassium (I78)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3, 2-c)]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 792- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propanoic acid (I79)
The synthesis method is the same as the preparation method of the compound described in example 61, wherein 4-azaindole is used as a raw material to replace indole, 1, 4-dibromonaphthalene is used to replace 4-bromo-1-naphthanenitrile, and 2-bromomethyl propionate is used to replace 2-bromomethyl acetate, and LC-MS: m/z 427.0[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.96(s,1H),4.57(s,1H),1.79(s,3H).
Example 802- [ [1- (4-Bromnaphthol-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] propionic acid potassium (I80)
By 2- [ [1- (4-bromonaphthalen-1-yl) -1H-pyrrolo [3,2-b ]]Pyridin-2-yl]Mercapto group]Propionic acid as raw material for substituting 2- [ [1- (4-cyanonaphthalene-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, potassium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 427.0[ M + H ]]+。
Example 812- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] -2-methylpropionic acid (I81)
The synthesis method was the same as the preparation method of the compound described in example 61, using 1-bromo-4-cyclopropylnaphthalene as a raw material instead of 4-bromo-1-naphthonitrile and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, and LC-MS: m/z 402.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.51(s,1H),8.39(d,J＝8,0Hz,1H),8.34(d,J＝8.0Hz,1H),7.92(t,J＝7.2Hz,1H),7.85(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(d,J＝8.4Hz,1H),7.27(t,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),6.80(s,1H),2.53-2.60(m,1H),1.45(s,6H),1.13-1.17(m,2H),0.84-0.87(m,2H).
Example 822- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-indol-2-yl ] mercapto ] -2-lithium methylpropanoate (I82)
With 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-indol-2-yl radical]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 402.1[ M + H ]]+。
Example 832- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I83)
The synthesis method was the same as the preparation method of the compound described in example 61, using 7-azaindole as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene instead of 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.70(s,1H),8.54(d,J＝6,4Hz,1H),8.51(t,J＝7.6Hz,1H),8.36(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.45(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.93(s,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 842 lithium- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] mercapto ] -2-methylpropionate (I84)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-b ]]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 852- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I85)
The synthesis method was the same as the preparation method of the compound described in example 61, using 6-azaindole as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene instead of 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.78(s,1H),9.40(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.32(d,J＝8.4Hz,1H),7.81(d,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.33(d,J＝7.6Hz,1H),6.95(s,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 862- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid lithium (I86)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [2,3-c ]]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 872- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I87)
The synthesis method was the same as the preparation method of the compound described in example 61, using 5-azaindole as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene instead of 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.77(s,1H),9.42(s,1H),8.55(d,J＝6,4Hz,1H),8.53(d,J＝7.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,1H),6.96(s,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
Example 882- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] mercapto ] -2-lithium methylpropionate (I88)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3, 2-c)]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+。
Example 892- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropionic acid (I89)
The synthesis method was the same as the preparation method of the compound described in example 61, using 4-azaindole as a raw material instead of indole, 1-bromo-4-cyclopropylnaphthalene instead of 4-bromo-1-naphthonitrile, and 2-bromomethyl isobutyrate instead of 2-bromomethyl acetate, LC-MS: m/z 403.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝12.87(s,1H),8.58(d,J＝6,4Hz,1H),8.52(d,J＝7.6Hz,1H),8.33(t,J＝8.4Hz,1H),8.18(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝6.4Hz,1H),7.31(d,J＝7.6Hz,1H),6.93(s,1H),2.53-2.61(m,1H),1.46(s,6H),1.13-1.18(m,2H),0.83-0.86(m,2H).
Example 902- [ [1- (4-Cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ] pyridin-2-yl ] mercapto ] -2-methylpropanoic acid lithium (I90)
By 2- [ [1- (4-cyclopropylnaphthalen-1-yl) -1H-pyrrolo [3,2-b ]]Pyridin-2-yl]Mercapto group]-2-methylpropanoic acid as a raw material for replacing 2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl group]Mercapto group]Acetic acid, lithium hydroxide instead of sodium hydroxide, was synthesized by the same method as the preparation of the compound described in example 2, LC-MS: m/z 403.1[ M + H ]]+. Evaluation of biological Activity in vitro
Test examples 1,
A plasmid (EX-T4563-M03, GeneCopoeia) containing a full-length human URAT1 gene (SLC22A12) was transfected into Flp-In T-REx-293 cells, URAT1 high-expression cells 293/hURAT1 were constructed, and the ability of the transfected cells to take up radioisotope-labeled uric acid was determined. The activity of the compounds was assessed by measuring their ability to block uptake of uric acid by transfected cells.
293/hURAT1 cells were seeded at 40000 cells/well in poly D-lysine coated 96-well plates (BD, 356461) and incubated overnight. The medium was removed and a pre-warmed reaction buffer (125mM sodium gluconate, 4.8mM potassium gluconate, 1.3mM calcium gluconate, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 5.6mM glucose, 25mM HEPES, pH7.4) was added and incubated at 37 ℃ for 10 minutes. The buffer was removed, reaction buffer containing 50 μ M14C-uric acid (American radio laboratory Chemicals, ARC0513) and compound or solvent was added, and incubation was performed at 37 ℃ for 5 minutes. The buffer was removed and washed 3 times with buffer. Cells were lysed for 20 min by addition of 100mM NaOH. The cell lysates were transferred to Isoplate-96 well plates (PerkinElmer, 6005040), and fluorescent scintillant was added and counted in a Microbeta2(PerkinElmer) counter.
Test compounds were dissolved in DMSO and DMSO at the same concentration was used as a solvent control without compound. Taking the uptake amount of uric acid in the cells containing the DMSO solvent control as 100%, the percentage of inhibition rate of uric acid uptake by the cells in each compound test well is calculated, and the IC50 value is calculated according to the uric acid uptake inhibition rate of the compound at different concentrations.
The compounds of the invention were tested according to the above protocol, with some results shown in the following table, wherein:
a denotes IC50 in the >10 μ M range;
b represents IC50 in the range of 2 μ M to 10 μ M;
c indicates an IC50 in the range of 0.1. mu.M-2. mu.M.
Test examples 2,
Evaluation of in vivo biological Activity
1) Experimental Material
Experimental animals: SD rats, males, received a weight of 180 and 200g, 6-8 weeks old. The experiment was started 5 days after the animals had acclimatized to the environment. The body weight is 250g over 220 and over 250g in the experiment. Purchased from bioscience, SPF, Waukang, Beijing.
Test samples: the compound of the invention, Lesinurad (positive control), 0.5% CMC-Na was ground to a uniform suspension.
Experimental reagent:
potassium Oxonate, BJ140984206E, imported from Huamai family, subpackaged, and preserved at room temperature. Weighing 12.5g of oteracil potassium by using a 1mg precision electronic balance, putting the weighed potassium oxonate into a mortar, adding a small amount of 0.5% CMC-Na for grinding and dissolving, pouring the mixture into a measuring cylinder, repeatedly adding 0.5% CMC-Na for rinsing the mortar, and finally adding 0.5% CMC-Na to a constant volume of 250mL (50mg/mL concentration). And (5) preserving in a refrigerator.
Chloral hydrate, batch No.: 20130116 chemical reagent of national drug group, Inc., preservation at room temperature. Weighing 3.5g of chloral hydrate by using a 1mg precision electronic balance, putting the chloral hydrate into a small beaker, dissolving the chloral hydrate by using a small amount of normal saline, transferring the chloral hydrate into a measuring cylinder, and metering the volume to 100ml by using the normal saline. And (5) preserving in a refrigerator. Can be used for anesthesia.
The instrument equipment comprises:
mettler ALC-210.3 electronic balance, accuracy 0.001mg, Beijing Saedodus Instrument systems, Inc. Electronic weighing scale: zhongshan City Hengji New electronics Co., Ltd, model ACS, precision 0.1g
Rat metabolic cage: suzhou von Experimental animals facilities Ltd
Full-automatic biochemical analyzer of Redu, Shenzhen Redu Instrument Co., Ltd
2) Experimental methods
A hyperuricemia model of a rat is induced by continuously intragastrically administering potassium oxonate. Test animals were randomly assigned to body weight for 7 days. 5mL/kg of potassium oxonate is administered to all rats by intragastric administration every day, each test drug is administered by intragastric administration after 1h, and the same amount of solvent is administered by intragastric administration to a model group. Transferring into a metabolism cage 1h after the drug is administered on the 5 th day, adapting to 1 day, collecting 24h urine on the 6 th day, measuring the volume, centrifuging at 2000r/min for 10min at normal temperature, and taking 1mL of supernatant for blood biochemical detection. Blood is collected from the canthus after administration for 1h on day 7, centrifuged at 5000r/min for 5min, and stored at 4 deg.C for biochemical index determination.
Serum Uric Acid (SUA) and Urine Uric Acid (UUA) levels were measured using the kit.
3) Data statistics
And (4) performing statistical test on the counting data by adopting a radius method, performing statistical test on the metering data by adopting a Student t test method, and judging the significance difference between groups.
4) Results of the experiment
The results show that the blood uric acid concentration of rats is obviously reduced and the uric acid concentration is obviously increased after the rats are orally taken with the compound for 7 days compared with a model group, which shows that the compound has the effects of promoting uric acid excretion and reducing the blood uric acid level, and the effects of I2 and I8 under the dosage of 40mg/kg are equivalent to the effects of Lesinurad 40mg/kg, which indicates that the effect of reducing uric acid in vivo is possibly stronger than that of Lesinurad.
TABLE 1 results of blood uric acid and urine uric acid tests
Note: p <0.05, P <0.01, compared to model group
In the above experiments, only some examples are given as experimental drugs, but actually, the compounds involved in the protection scope of the present invention can achieve the same or similar beneficial effects.
Claims (8)
1. An indole derivative, or a pharmaceutically acceptable salt thereof, having the structure:
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] acetic acid (I1).
2. An indole derivative, or a pharmaceutically acceptable salt thereof, having the structure:
2- [ [1- (4-cyanonaphthalen-1-yl) -1H-indol-3-yl ] mercapto ] sodium acetate (I2).
3. A pharmaceutical composition comprising the indole derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient.
4. The pharmaceutical composition of claim 3, wherein other anti-gout drugs may be added, and the other anti-gout drugs are selected from the group consisting of: URAT1 inhibitors, xanthine oxidase inhibitors, xanthine dehydrogenase, purine nucleoside phosphorylase inhibitors, uric acid transporter inhibitors, glucose transporter inhibitors, organic anion transporter inhibitors, OAT-4 inhibitors, or combinations thereof.
5. Use of the indole derivative of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for regulating uric acid levels and/or treating indications associated with gout.
6. Use of the pharmaceutical composition of claim 3 for the manufacture of a medicament for regulating uric acid levels and/or treating indications associated with gout.
7. The use according to claim 5, wherein the associated indication is hyperuricemia, gouty arthritis, inflammatory arthritis, deposition of urate crystals in joints, urolithiasis, deposition of urate crystals in renal parenchyma, gout flares, tophaceous gout, or a combination thereof.
8. The use according to claim 6, wherein the associated indication is hyperuricemia, gouty arthritis, inflammatory arthritis, deposition of urate crystals in joints, urolithiasis, deposition of urate crystals in renal parenchyma, gout flares, tophaceous gout, or a combination thereof.
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