CN116535361A - Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof - Google Patents
Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof Download PDFInfo
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- CN116535361A CN116535361A CN202210094766.5A CN202210094766A CN116535361A CN 116535361 A CN116535361 A CN 116535361A CN 202210094766 A CN202210094766 A CN 202210094766A CN 116535361 A CN116535361 A CN 116535361A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- -1 hydroxypyrimidine xanthine Chemical class 0.000 title claims abstract description 16
- 239000003064 xanthine oxidase inhibitor Substances 0.000 title claims abstract description 7
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 8
- 201000005569 Gout Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 125000002757 morpholinyl group Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000004193 piperazinyl group Chemical class 0.000 claims description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 18
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 17
- 238000004896 high resolution mass spectrometry Methods 0.000 description 17
- 229940116269 uric acid Drugs 0.000 description 17
- 108010093894 Xanthine oxidase Proteins 0.000 description 16
- 102100033220 Xanthine oxidase Human genes 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- LIYGCLJYTHRBQV-UHFFFAOYSA-N 3,5-dichloro-4-hydroxybenzaldehyde Chemical compound OC1=C(Cl)C=C(C=O)C=C1Cl LIYGCLJYTHRBQV-UHFFFAOYSA-N 0.000 description 12
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229940075420 xanthine Drugs 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- PIAZYBLGBSMNLX-UHFFFAOYSA-N 4-(3-chloropropyl)morpholine Chemical compound ClCCCN1CCOCC1 PIAZYBLGBSMNLX-UHFFFAOYSA-N 0.000 description 4
- 230000029142 excretion Effects 0.000 description 4
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 229960005101 febuxostat Drugs 0.000 description 3
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 3
- 229960004198 guanidine Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- OBOBUDMMFXRNDO-UHFFFAOYSA-N 1-(3-chloropropyl)piperidine;hydron;chloride Chemical compound Cl.ClCCCN1CCCCC1 OBOBUDMMFXRNDO-UHFFFAOYSA-N 0.000 description 1
- SKOYTQILPMNZQO-UHFFFAOYSA-N 3,5-difluoro-4-hydroxybenzaldehyde Chemical compound OC1=C(F)C=C(C=O)C=C1F SKOYTQILPMNZQO-UHFFFAOYSA-N 0.000 description 1
- ITSXSHQWMYYQQY-UHFFFAOYSA-N 3-bromo-5-chloro-4-hydroxybenzaldehyde Chemical compound OC1=C(Cl)C=C(C=O)C=C1Br ITSXSHQWMYYQQY-UHFFFAOYSA-N 0.000 description 1
- FSLFKQZWBRMALB-UHFFFAOYSA-N 3-bromo-5-fluoro-4-hydroxybenzaldehyde Chemical compound OC1=C(F)C=C(C=O)C=C1Br FSLFKQZWBRMALB-UHFFFAOYSA-N 0.000 description 1
- VGSOCYWCRMXQAB-UHFFFAOYSA-N 3-chloro-4-hydroxybenzaldehyde Chemical group OC1=CC=C(C=O)C=C1Cl VGSOCYWCRMXQAB-UHFFFAOYSA-N 0.000 description 1
- QSBHJTCAPWOIIE-UHFFFAOYSA-N 3-fluoro-4-hydroxybenzaldehyde Chemical group OC1=CC=C(C=O)C=C1F QSBHJTCAPWOIIE-UHFFFAOYSA-N 0.000 description 1
- ZLMUFCNWTPSOSN-UHFFFAOYSA-N 4-hydroxy-3-(trifluoromethyl)benzaldehyde Chemical compound OC1=CC=C(C=O)C=C1C(F)(F)F ZLMUFCNWTPSOSN-UHFFFAOYSA-N 0.000 description 1
- KNQVIRRXVOTGGT-UHFFFAOYSA-N 4-hydroxy-3-iodobenzaldehyde Chemical group OC1=CC=C(C=O)C=C1I KNQVIRRXVOTGGT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102100030935 Solute carrier family 2, facilitated glucose transporter member 9 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- ANLMKUQEPXRMGV-UHFFFAOYSA-N n-butyl-n-(3-chloropropyl)butan-1-amine Chemical compound CCCCN(CCCC)CCCCl ANLMKUQEPXRMGV-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a substituted hydroxypyrimidine xanthine oxidase inhibitor, a preparation method and a pharmaceutical application thereof.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to substituted hydroxypyrimidine compounds in a general formula (I) and physiologically acceptable salts thereof. The use of these compounds in the treatment of xanthine oxidase-related diseases, as well as to methods for their use in therapy, and to pharmaceutical compositions containing them.
Background
Xanthine oxidase is a metabolic enzyme that is widely found in mammals and is responsible for the oxidation of hypoxanthine to xanthine and further to uric acid. However, hyperuricemia is caused when uric acid is excessively accumulated in the body. Hyperuricemia is not only a direct cause of gout, but is also associated with a variety of metabolic and chronic diseases. Hyperuricemia has now become the second most metabolic disease next to diabetes mellitus and has a rising trend year by year.
Uric acid levels in the body are regulated by both uric acid production and uric acid excretion, either in excess uric acid production or reduced uric acid excretion, which leads to elevated blood uric acid levels. When uric acid concentration exceeds its solubility in blood, urate crystals are generated and deposited in joints or soft tissues, causing inflammatory reactions and gout.
At present, three main means are adopted for treating hyperuricemia: inhibitors of uric acid-producing xanthine oxidase, inhibitors of urate transporter that promote uric acid excretion, and urokinase that accelerates the excretion of uric acid by converting uric acid into a readily water-soluble substance. Xanthine Oxidase (XO) is an important enzyme regulating uric acid production pathways, and XO inhibitors play a central role in the treatment of hyperuricemia. The XO inhibitors currently on the market are only allopurinol, febuxostat and tobipstat, and have serious adverse reactions. Therefore, there is a need to continue to develop XO inhibitors with better efficacy while having lower side effects.
The invention aims to provide a novel substituted hydroxypyrimidine compound which has higher xanthine oxidase inhibition activity and can be used for treating hyperuricemia and gout.
Disclosure of Invention
The invention aims at providing a substituted hydroxypyrimidine compound shown in a formula (I) or physiologically acceptable salt thereof.
It is another object of the present invention to provide a process for preparing substituted hydroxypyrimidines of formula (I) or a physiologically acceptable salt thereof.
It is a further object of the present invention to provide the use of substituted hydroxypyrimidines of formula (I) or a physiologically acceptable salt thereof for the preparation of xanthine oxidase inhibitors and for the preparation of a medicament for the prevention and/or treatment of hyperuricemia or gout.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a substituted hydroxypyrimidine compound represented by the following general formula (I) or a physiologically acceptable salt thereof,
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5; x is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, piperidinyl, piperazinyl, N-methylpiperazinyl, and morpholinyl; y is selected from O, S or NH.
Preferred compounds are those of formula (IA) or a physiologically acceptable salt thereof:
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
Preferred compounds are those of formula (IB) or a physiologically acceptable salt thereof:
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
Preferred compounds are those of the general formula (IC):
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
Preferred compounds are those of the general formula (ID) or a physiologically acceptable salt thereof:
wherein R is a single or multiple substituent group on the benzene ring and is selected from hydrogen, halogen and trifluoromethyl; n is 2,3,4 or 5.
The most preferred compounds are those selected from the group consisting of:
according to a second aspect of the present invention, there is provided a method for synthesizing the compound of the first aspect, comprising the steps of:
the compound of formula II reacts with the compound of formula III to obtain a compound of formula IV, and the compound of formula IV reacts with cyano compound and urea, thiourea or guanidine to generate a compound of formula I:
wherein R, n, X, Y is as defined in claim 1.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising an effective amount of any one of the substituted hydroxypyrimidines of the first aspect of the present invention, and a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, solutions, emulsions, pills and injections.
For the preparation of medicaments, the compounds of the general formula (I) can be admixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavourings and colours in a known manner and formulated as tablets or coated tablets or suspended or dissolved in water or oil with other additional substances. The compounds of the present invention may be administered orally or parenterally. The oral administration can be tablet, capsule, granule, solution, emulsion, pill, and parenteral administration can be injection. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, granules, pills are conventional adjuvants such as starch, gelatin, acacia, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils such as corn oil, peanut oil, olive oil, etc. Other adjuvants may also be present in the formulations containing the compounds of the invention, such as surfactants, lubricants, disintegrants, preservatives, flavouring agents, pigments and the like.
According to a fourth aspect of the present invention there is provided the use of a substituted hydroxypyrimidine compound of the first aspect or a physiologically acceptable salt thereof in the preparation of a xanthine oxidase inhibitor.
The fourth aspect of the technical scheme of the invention also provides the application of the substituted hydroxypyrimidine compound or the physiologically acceptable salt thereof in preparing a medicament for preventing and/or treating hyperuricemia and gout.
Pharmacological studies show that the compound of the general formula II has the activity of inhibiting xanthine oxidase, and can effectively reduce the blood uric acid level in vivo, thereby achieving the purpose of treatment.
The beneficial technical effects are as follows:
xanthine oxidase inhibitors are the main uric acid lowering drugs used clinically. The compound related by the invention has a large structural difference from the existing medicines and has obvious xanthine oxidase inhibition effect. Wherein, the inhibition activity of most compounds to xanthine oxidase at the concentration of 10 mu M exceeds 90%, which is equivalent to the activity of febuxostat of similar clinical products.
Detailed Description
The invention is further illustrated below with reference to examples, which are not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). NMR displacements (δ) are given in parts per million (ppm). The melting point (m.p.) is the melting point given in degrees celsius, the temperature being uncorrected. Column chromatography generally uses 200-300 mesh silica gel. NMR was performed using JEOL ECZ-400S and INOVA-500MHz in DMSO-d as the solvent 6 Internal standard is TMS and chemical shifts are given in ppm. The MS was determined using an Agilent LC/MSD TOF LC/MS.
Example 1: TM-1
a) To a 100mL round bottom flask was added 3, 5-dichloro-4-hydroxybenzaldehyde (382 mg,2 mmol), N- (3-chloropropyl) morpholine (360 mg,2.2 mmol), potassium carbonate (414 mg,3 mmol), potassium iodide (33 mg,0.2 mmol), DMF (15 mL), stirring at 80℃for 12h, the solvent was distilled off after completion of the reaction, the residue was dissolved in water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, the solvent was removed by swirling, and dried for further use.
b) Sequentially adding the above materials into a 100mL round bottom flaskThe product, ethyl cyanoacetate (399 mg,3 mmol), guanidine hydrochloride (280 mg,3 mmol), sodium acetate (408 mg,3 mmol), pyridine (8 mL) were reacted at 120℃and the reaction was complete by TLC, the solvent was removed by spinning, the residue was dissolved in water, extracted with ethyl acetate, the organic phases were combined, and the solvent was removed by spinning, followed by elution with 1M dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated brine, methanol/dichloromethane gradient (0% methanol-15% methanol) to give 59mg of a pale yellow solid. 206-208 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.77(s,1H),8.31(s,1H),7.91(s,2H),7.03(s,1H),4.13(t,J=6.3Hz,2H),3.58(t,J=4.5Hz,4H),2.55(d,J=7.2Hz,2H),2.41(brs,4H),1.96(m,2H);HR-MS:m/z=424.09534[M+H] + ,calcd for C 18 H 20 O 3 N 5 Cl 2 :424.09377.
example 2: TM-2
The preparation was carried out in a similar manner to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced with 3-chloro-4-hydroxybenzaldehyde. 47mg of white solid was obtained. 192-194 ℃ in m.p.; 1 H NMR(400MHz,DMSO-d 6 ):δ11.70(s,1H),8.15(s,1H)7.91(d,J=2.2Hz,1H),7.86(m,1H),7.29(d,J=8.8Hz,1H),7.17(s,1H),4.20(t,J=6.3Hz,2H),3.61–3.54(m,4H),2.46(t,J=7.2Hz,2H),2.37(d,J=4.4Hz,4H),1.93(m,2H);HR-MS:m/z=390.13419[M+H] + ,calcd for C 18 H 21 O 3 N 5 Cl:390.13274.
example 3: TM-3
The preparation was carried out in a similar manner to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced with 3-fluoro-4-hydroxybenzaldehyde, to obtain 89mg of a black solid. 132-134 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.64(s,1H),8.19(s,1H),7.71(m,1H),7.67(m,1H),7.31(t,J=8.7Hz,1H),7.01(s,1H),4.18(t,J=6.4Hz,2H),3.61–3.54(m,4H),2.46(overlap,2H),2.40(brs,4H),1.93(m,2H);HR-MS:m/z=374.16312[M+H] + ,calcd for C 18 H 21 O 3 N 5 F:374.16229.
example 4: TM-4
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 60mg of a pale yellow solid was obtained. 218-220 ℃ in m.p.; 1 H NMR(400MHz,DMSO-d 6 ):δ11.65(s,1H),8.18(s,1H),8.06(d,J=2.2Hz,1H),7.90(dd,J=8.7,2.2Hz,1H),7.25(d,J=8.7Hz,1H),7.00(S,1H),4.19(t,J=6.2Hz,2H),3.63–3.53(m,4H),2.40(brs,4H),1.93(m,2H);HR-MS:m/z=434.08383[M+H] + ,calcd for C 18 H 21 O 3 N 5 Br:434.08223.
example 5: TM-5
The preparation was carried out in a similar manner to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced with 3-iodo-4-hydroxybenzaldehyde. 78mg of a pale yellow solid was obtained. 237-238 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.64(s,1H),8.25(d,J=2.2Hz,1H),8.14(s,1H),7.92(dd,J=8.6,2.2Hz,1H),7.12(d,J=8.7Hz,1H),6.86(s,1H),4.17(t,J=6.0Hz,2H),3.58(brs,4H),2.52(overlap,2H),2.42(overlap,4H),1.94(m,2H);HR-MS:m/z=482.06772[M+H] + ,calcd for C 18 H 21 O 3 N 5 I:482.06836.
example 6: TM-6
The preparation was carried out in a similar manner to example 1, except that 4-hydroxy-3-trifluoromethylbenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 132mg of a pale yellow solid was obtained. 238-239 ℃ at m.p.; 1 H NMR(400MHz,DMSO-d 6 ):δ11.67(s,1H),8.30(s,1H),8.15(m,1H),8.09(m,1H),7.41(d,J=8.8Hz,1H),6.93(s,1H),4.25(t,J=6.1Hz,2H),3.59–3.54(m,4H),2.48–2.43(overlap,2H),2.38(brs,4H),1.92(m,2H);HR-MS:m/z=424.15939[M+H] + ,calcd for C 19 H 21 O 3 N 5 F 3 :424.15910.
example 7: TM-7
The preparation was carried out in a similar manner to example 1, except that 3, 5-difluoro-4-hydroxybenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 47mg of pale yellow solid was obtained. 236-238 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.79(s,1H),8.21(s,1H),7.59(d,J=8.4Hz,2H),7.01(s,1H),4.27(t,J=6.2Hz,2H),3.62–3.49(m,4H),2.46(t,J=7.3Hz,2H),2.36(s,4H),1.87(m,2H);HR-MS:m/z=392.15253[M+H] + ,calcd for C 18 H 20 O 3 N 5 F 2 :392.15287.
example 8: TM-8
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde was used instead of 3, 5-dichloro-4-hydroxybenzaldehyde in example 1. 38mg of a pale yellow solid was obtained. 163-166 ℃ in m.p.; 1 H NMR(400MHz,DMSO-d 6 ):δ11.83(s,1H),8.24(s,1H),8.09(s,2H),7.01(s,1H),4.09(t,J=6.4Hz,2H),3.60–3.54(m,4H),2.54(s,2H),2.39(s,4H),1.98(m,2H);HR-MS:m/z=513.99200[M+H] + ,calcd for C 18 H 20 O 3 N 5 Br [81] Br:513.99069.
example 9: TM-9
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced by 3-bromo-5-fluoro-4-hydroxybenzaldehyde. 44mg of pale yellow solid was obtained. 206-208 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ12.07(s,1H),8.14(s,1H),7.93–7.89(m,1H),7.29(s,1H),7.76(m,1H),4.23(t,J=6.2Hz,2H),3.59–3.52(m,4H),2.47(overlap,2H),2.35(brs,4H),1.90(m,2H);HR-MS:m/z=452.07379[M+H] + ,calcd for C 18 H 20 O 3 N 5 BrF:452.07281.
example 10: TM-10
The preparation was carried out in analogy to example 1, except that 3, 5-dichloro-4-hydroxybenzaldehyde in example 1 was replaced by 3-bromo-5-chloro-4-hydroxybenzaldehyde. 41mg of a pale yellow solid was obtained. 156-159 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.70(s,1H),8.31(s,1H),8.05(m,1H),7.97–7.94(m,1H),6.98(s,1H),4.11(t,J=6.3Hz,2H),3.59(s,4H),2.58(overlap,2H),2.43(overlap,4H),2.04–1.94(m,2H);HR-MS:m/z=470.03979[M+H] + ,calcd for C 18 H 20 O 3 N 5 [81] BrC l1 :470.04121.
example 11: TM-11
The preparation is similar to example 1, except that N- (3-chloropropyl) dibutyl is usedThe amine replaces the N- (3-chloropropyl) morpholine in example 1. 48mg of a pale yellow solid was obtained. 169-172 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ12.01(s,1H),8.05(s,1H),7.92(s,2H),7.45(s,1H),4.13(t,J=6.3Hz,2H),2.65(t,J=6.4Hz,2H),2.47–2.39(m,4H),1.92(p,J=6.8,6.3Hz,2H),1.38(m,4H),1.27(m,4H),0.87(t,J=7.3Hz,6H);HR-MS:m/z=466.17804[M+H] + ,calcd for C 22 H 30 O 2 N 5 Cl 2 :466.17711.
example 12: TM-12
The preparation was carried out in analogy to example 1, except that N- (3-chloropropyl) morpholine in example 1 was replaced by N- (3-chloropropyl) piperidine hydrochloride. 13mg of a pale yellow solid was obtained. 146-149 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ12.00(s,1H),8.06(s,1H),7.91(s,2H),7.54(s,1H),4.11(t,J=6.3Hz,2H),2.57(t,J=7.3Hz,2H),2.45(overlap,4H),1.97(p,J=6.7Hz,2H),1.52(m,4H),1.39(m,6.4Hz,2H);HR-MS:m/z=422.11487[M+H] + ,calcd for C 19 H 22 O 2 N 5 Cl 2 :422.11451.
example 13: TM-13
The preparation was similar to example 1, except that thiourea was used instead of guanidine in example 1. 13mg of a pale yellow solid was obtained. 194.6-196.4 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.94(s,1H),7.87(s,2H),4.15(t,J=6.0Hz,2H),3.75(s,4H),3.12(m,6H),2.13(m,2H);HR-MS:m/z=441.05441[M+H] + ,calcd for C 18 H 19 O 3 N 4 Cl 2 S:441.05494.
example 14: TM-14
The preparation is similar to example 1, except that urea is used instead of guanidine in example 1. 15mg of a pale yellow solid was obtained. 228.1-230.7 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ11.52(s,1H),7.81(s,2H),4.09(t,J=6.2Hz,2H),3.58(t,J=4.7Hz,4H),2.66(brs,2H),2.54(brs,4H),1.97(m,2H);HR-MS:m/z=425.07932[M+H] + ,calcd for C 18 H 19 O 4 N 4 Cl 2 :425.07779.
example 15: TM-15
The preparation was carried out in analogy to example 1, except that N- (3-chloropropyl) morpholine in example 1 was replaced by N- (3-chloropropyl) dibutylamine. 48mg of a pale yellow solid was obtained. 169-172 deg.c; 1 H NMR(400MHz,DMSO-d 6 ):δ12.01(s,1H),8.05(s,1H),7.92(s,2H),7.45(s,1H),4.13(t,J=6.3Hz,2H),2.65(t,J=6.4Hz,2H),2.47–2.39(m,4H),1.92(p,J=6.8,6.3Hz,2H),1.38(m,4H),1.27(m,4H),0.87(t,J=7.3Hz,6H);HR-MS:m/z=466.17804[M+H] + ,calcd for C 22 H 30 O 2 N 5 Cl 2 :466.17711.
pharmacological experiments
Experimental example 1: inhibition of xanthine oxidase by the compounds of the invention
The method comprises the following steps:
the inhibition of xanthine oxidase by each compound at a specific concentration was determined by colorimetry using febuxostat as a positive control.
The specific method comprises the following steps: test samples were dissolved in DMSO to prepare 10mM stock solutions. The effect of each compound on the hydrolysis of Xad-catalyzed Xanthine (XAN) was measured at 37℃and pH7.4 using 96-well plates. The reaction system contains 10 mu mol.L -1 3U/L XOD (vsNo addition of the control group, 0.01% DMSO instead) and buffer (3.5 mM KH 2 PO 4 ,15.2mM K 2 HPO 4 0.25mM EDTA, and 50. Mu.M XAN, pH 7.4). And detecting the luminosity of uric acid serving as a product at the wavelength of 293nm by adopting an enzyme-labeled instrument to determine the Xad-catalyzed Xanthine (XAN) hydrolysis, and calculating the inhibition rate according to the OD value.
Results:
the final concentration of the above-mentioned compounds was measured to be 10. Mu. Mol.L -1 Inhibition of xanthine oxidase at the time and determination of IC of a part of the compounds 50 Values. The results are shown in Table 1:
TABLE 1 inhibition of xanthine oxidase by Compounds
ND: not measured.
Claims (11)
1. A substituted hydroxypyrimidine compound represented by the following general formula (I) or a physiologically acceptable salt thereof,
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5;
x is selected from C 1 -C 6 Alkyl-substituted amino, C 3 -C 6 Cycloalkyl-substituted amino, piperidinyl, piperazinyl, N-methylpiperazinyl, and morpholinyl;
y is selected from O, S or NH.
2. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (IA):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
3. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (IB):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
4. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (IC):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
5. The compound of claim 1, or a physiologically acceptable salt thereof, wherein the compound is of formula (ID):
wherein,,
r is a single or multiple substituent group on benzene ring, selected from hydrogen, halogen and trifluoromethyl;
n is 2,3,4 or 5.
6. A compound according to claim 1, or a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of:
7. a process for the preparation of a compound according to any one of claims 1 to 6, comprising the steps of:
the compound of formula II reacts with the compound of formula III to obtain a compound of formula IV, and the compound of formula IV reacts with cyano compound and urea, thiourea or guanidine to generate a compound of formula I:
wherein R, n, X, Y is as defined in claim 1.
8. A pharmaceutical combination comprising an effective amount of a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition of any one of claims 8, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, solutions, emulsions, pills, and injections.
10. Use of a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, for the preparation of a xanthine oxidase inhibitor.
11. Use of a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, for the preparation of a medicament for the prophylaxis and/or treatment of hyperuricemia or gout.
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