US3907799A - Xanthine oxidase inhibitors - Google Patents
Xanthine oxidase inhibitors Download PDFInfo
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- US3907799A US3907799A US440989A US44098974A US3907799A US 3907799 A US3907799 A US 3907799A US 440989 A US440989 A US 440989A US 44098974 A US44098974 A US 44098974A US 3907799 A US3907799 A US 3907799A
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- Prior art keywords
- solution
- pyrimidine
- water
- compound
- mixture
- 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.)
- Expired - Lifetime
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- 239000003064 xanthine oxidase inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 108010093894 Xanthine oxidase Proteins 0.000 abstract description 16
- 102100033220 Xanthine oxidase Human genes 0.000 abstract description 16
- 229910052799 carbon Inorganic materials 0.000 abstract description 16
- 239000003112 inhibitor Substances 0.000 abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 16
- 229910052736 halogen Inorganic materials 0.000 abstract description 14
- 150000002367 halogens Chemical class 0.000 abstract description 14
- -1 phenylazo Chemical group 0.000 abstract description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 5
- 150000001340 alkali metals Chemical class 0.000 abstract description 5
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 54
- 239000000047 product Substances 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 22
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 18
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 18
- 229960003459 allopurinol Drugs 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 15
- 159000000000 sodium salts Chemical class 0.000 description 15
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 14
- 229940116269 uric acid Drugs 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 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 11
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229940075420 xanthine Drugs 0.000 description 9
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 7
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 201000005569 Gout Diseases 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- QLAJNZSPVITUCQ-UHFFFAOYSA-N 1,3,2-dioxathietane 2,2-dioxide Chemical compound O=S1(=O)OCO1 QLAJNZSPVITUCQ-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- CLRSZXHOSMKUIB-UHFFFAOYSA-M benzenediazonium chloride Chemical compound [Cl-].N#[N+]C1=CC=CC=C1 CLRSZXHOSMKUIB-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 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 2
- OELYMZVJDKSMOJ-UHFFFAOYSA-N 4-bromo-1h-pyrazol-5-amine Chemical compound NC1=NNC=C1Br OELYMZVJDKSMOJ-UHFFFAOYSA-N 0.000 description 2
- JMTFWCYVZOFHLR-UHFFFAOYSA-N 5,7-dichloropyrazolo[1,5-a]pyrimidine Chemical compound N1=C(Cl)C=C(Cl)N2N=CC=C21 JMTFWCYVZOFHLR-UHFFFAOYSA-N 0.000 description 2
- BELWUABPSOOYPK-UHFFFAOYSA-N 5-hydroxy-8h-imidazo[1,2-a]pyrimidin-7-one Chemical compound N1=C(O)C=C(O)N2C=CN=C21 BELWUABPSOOYPK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- SLHCRNWCKCTZMF-UHFFFAOYSA-N chembl3276835 Chemical compound N1=C(O)C=C(O)N2N=CC=C21 SLHCRNWCKCTZMF-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 description 2
- UHGIEBPIZUAUQA-UHFFFAOYSA-N diethyl 2-phenyldiazenylpropanedioate Chemical compound CCOC(=O)C(C(=O)OCC)N=NC1=CC=CC=C1 UHGIEBPIZUAUQA-UHFFFAOYSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000005237 imidazopyrimidines Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
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- XBYRMPXUBGMOJC-UHFFFAOYSA-N 1,2-dihydropyrazol-3-one Chemical compound OC=1C=CNN=1 XBYRMPXUBGMOJC-UHFFFAOYSA-N 0.000 description 1
- KUWRLKJYNASPQZ-UHFFFAOYSA-N 1h-imidazol-3-ium-2-amine;sulfate Chemical compound OS(O)(=O)=O.NC1=NC=CN1.NC1=NC=CN1 KUWRLKJYNASPQZ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- DISXFZWKRTZTRI-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-2-amine Chemical compound NC1=NCCN1 DISXFZWKRTZTRI-UHFFFAOYSA-N 0.000 description 1
- XGGAWFDOIDZRPI-UHFFFAOYSA-N 4,6-Dihydroxy Natural products C1=C2OCOC2=CC(C2OC(C3C(OC(O)C32)C=2C=C3OCOC3=CC=2)O)=C1 XGGAWFDOIDZRPI-UHFFFAOYSA-N 0.000 description 1
- ZQJQHZKZIQYVIK-UHFFFAOYSA-N 4-chloro-1h-pyrazol-5-amine Chemical compound NC=1NN=CC=1Cl ZQJQHZKZIQYVIK-UHFFFAOYSA-N 0.000 description 1
- JWGYPTNGYXOXPV-UHFFFAOYSA-N 4-nitro-1h-pyrazol-5-amine Chemical compound NC=1NN=CC=1[N+]([O-])=O JWGYPTNGYXOXPV-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
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- 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
- 108091006149 Electron carriers Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037884 Rash pruritic Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000287433 Turdus Species 0.000 description 1
- 229940116731 Uricosuric agent Drugs 0.000 description 1
- 231100000230 acceptable toxicity Toxicity 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
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- 239000003054 catalyst Substances 0.000 description 1
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- LVQRZMUWAKGLRI-UHFFFAOYSA-N chembl3276838 Chemical compound N1=C(O)C=C(O)N2N=CC(Cl)=C21 LVQRZMUWAKGLRI-UHFFFAOYSA-N 0.000 description 1
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- 230000001684 chronic effect Effects 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- DAKKWKYIQGMKOS-UHFFFAOYSA-N diethyl 2-nitropropanedioate Chemical compound CCOC(=O)C([N+]([O-])=O)C(=O)OCC DAKKWKYIQGMKOS-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
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- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 235000013336 milk Nutrition 0.000 description 1
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- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- a solution of benzenediazonium chloride was prepared by treating a solution of aniline [0.3lg, 3,3 m moles] in 7 ml of 1.7N hydrochloric acid with a solution of sodium nitrite [0.25g, 0.0036 formula weights] in 5 ml of water at 5.
- the benzene diazonium chloride solution was added dropwise to a stirred solution of imidazo [1.2a] pyrimidine-5,7-diol [0.5g, 3.3 m moles] in 10 ml of 1.25 N sodium hydroxide solution at 10. After the addition was complete, the mixture was stirred at 10 for 30 minutes and then at room temperature for 30 minutes. The solid was separated by filtration, and purified by reprecipitating from a dilute sodium hydroxide solution by the addition of acetic acid.
- a solution of sodium ethoxide was prepared by dissolving sodium [0.98g (0.0428 formula weights)] in 50 ml of absolute ethanol. Diethylmalonate [3.50g, 21.9 m moles] and 3-amino-4-chloropyrazolo [2.30g, 2.14 m moles] were added to the sodium ethoxide solution. The mixture was stirred and slowly warmed to reflux. After refluxing for 8 hours the mixture was allowed to cool to room temperature and the sodium salt separated by flltration. The sodium salt was dissolved in 100 ml of water and the pH adjusted to l-2 bythe addition of 6 N hydrochloric acid. The product was separated by filtration, washed with ice water, and dried. Recrystallization from water afforded 1.48g (37%) of analytically pure product that had a melting point of 270-2 (dec);
- the analytically pure material weighed 4.3g (31%) and decomposed without melting at 265-7; A max (pH 1) 221 nm (6, 20,300) and 283 nm (e, 9,870); A max (pH 1) 233 nm (a, 32,800) and 273 nm (e, 12,850).
- R is H, CH halogen, or N0 R,, is OR,, H, or halogen;
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Abstract
Compounds of the following structure are disclosed which are effective inhibitors of the enzyme xanthine oxidase:
IN WHICH Y1 and Y2 are C or N; R1 is H or an alkali metal or ammonium; R2 is H, CH3, a halogen, phenylazo or NO2; R3 is OR1, H, or a halogen; AND R4 is H, NO2 or a halogen. When Y1 is C, Y2 is N and when Y1 is N, Y2 is C.
IN WHICH Y1 and Y2 are C or N; R1 is H or an alkali metal or ammonium; R2 is H, CH3, a halogen, phenylazo or NO2; R3 is OR1, H, or a halogen; AND R4 is H, NO2 or a halogen. When Y1 is C, Y2 is N and when Y1 is N, Y2 is C.
Description
United States Patent 1191 OBrien et al.
[ Sept. 23, 1975 XANTIIINE OXIDASE INHIBITORS [73] Assignee: ICN Pharmaceuticals, Inc., Irvine,
Calif.
22 Filed: Feb. 11, 1974 21 Appl. No.: 440,989
Related US. Application Data [63] Continuation of Ser. No. 172,196, Aug. 16, 1971,
abandoned.
[52] US. Cl. 260/256.4 F; 260/154; 424/226; 424/251 [51] Int. Cl. C07D 239/00 [58] Field of Search 260/ 256.4 F
[56] References Cited UNITED STATES PATENTS 2,553,500 5/1951 Harsh 260/256.4 F 3,244,717 4/1966 Wagner... 260/256.4 F
FOREIGN PATENTS OR APPLICATIONS 375,947 6/1962 Japan 260/256.4 F 76,677 10/1970 Germany 260/256.4 F
Primary ExaminerDonald G. Daus Assistant ExaminerJames H. Turnipseed Attorney, Agent, or Firm-William E. Thomson; William C. Steffin; Kay I-l. Boswell [57] ABSTRACT Compounds of the following structure are disclosed which are effective inhibitors of the enzyme xanthine oxidase:
in which Y and Y are C or N;
R, is H or an alkali metal or ammonium; R is H, CH a halogen, phenylazo or N0 R is CR H, or a halogen; and R is H, N0 or a halogen. When Y, is C, Y is N and when Y is N, Y is C.
10 Claims, No Drawings XANTHINE OXIDASE INHIBITORS This is a continuation, of application Ser. No. 172,196, filed Aug. 16, 1971 now abandoned.
BACKGROUND OF THE INVENTION It is now well established that the enzyme xanthine oxidase is implicated in the production of uric acid by the body, converting hypoxanthine into xanthine and xanthine, in turn, into uric acid. Under normal conditions, uric acid (2,6,8-trioxypurine) is found in the body in only small amounts, a concentration in the blood on the order of about one to about 3 micrograms per 100 milliliters. Under certain pathological conditions, however, as for example gout, the concentration of uric acid increases significantly.
Gout, of course, is metabolic disturbance in the body resulting from an overproduction of uric acid, chronic hyperuricemia (elevated blood uric acid), and progressive accumulation of uric acid in the tissues. The body may also progressively lose its capacity to excrete uric acid and is, therefore, in a constant state of uric acid imbalance, accumulating a greater and greater excess. Its concentration in the blood is high, and, because of its low solubility, it tends to precipitate and form deposits at various sites where the blood flow is least active, particularly joints and cartilaginous tissues.
One approach to the control of gout commonly used in the past has been the prescription of drugs which tended to prevent the accumulation of uric acid in the body and thus diminish the likelihood of acute recurrences. Such drugs are identified as uricosuric agents" and promote the excretion of uric acid in the urine. Examples of such drugs include p-dipropylsulfamyl benzoic acid and sulfinpyrazone. These drugs cannot, however, be administered in conjunction with aspirin or any other salicylate, which might be given to relieve pain, because the agents and salicylates are mutually antagonistic, i.e., each tends to ofiset the action of the other.
A second approach to the treatment of gout which has become popular is the use of the drug allopurinol,
which blocks the production of uric acid by the body by inhibiting the enzyme xanthine oxidase, which, as noted previously, is responsible for converting hypoxanthine into xanthine and xanthine into uric acid. While allopurinol is effective to inhibit the enzyme xanthine oxidase, nevertheless there are disadvantages which limit its suitability.
First, the toxicity is higher than desirable, having a lethal dosage level, LD (the dose required to kill 50% of a group of mice in 2 weeks when injected into the intraperitone'al cavity) on the order of 150 milligrams per kilogram of body weight. Moreover, allopurinol is gradually metabolized in vivo to 4,6-dihydroxy pyrazolo [3,4-d1pyrimidine, which is not as inhibitor as is allopurinol. In addition to the foregoing disadvantages, allopurinol, because of its chemical nature, must compete with xanthine to occupy a place on the enzyme xanthine oxidase in order to inhibit the enzyme and thus prevent the formation of uric acid by the body, which likewise limits its efficiency. It is also known that acute attacks of gouty arthritis occur in the early treatment with allopurinol. It is accordingly necessary to give colchicine during the initial period of therapy to prevent such acute attacks. There have also been reports of the development of a pruritic rash in some patients and of the occasional occurence of drowsiness when allopurinol is administered. In view of the foregoing, it is apparent that xanthine oxidase inhibitors which are of acceptable toxicity and at the same time possess increased inhibition efficiency as compared to allopurinol are highly desirable.
SUMMARY OF THE INVENTION The present invention thus relates to xanthine oxidase inhibitors comprising imidazo [l,2,a] and pyrazolo [l,5,a] pyrimidine compounds of the following general structure:
Y, and Y are carbon or nitrogen; R is H or an alkali metal or ammonium; R is H, CH a halogen, phenylazo or N0 R is OR H, or a halogen; and R, is H N0 or a halogen. When Y, is carbon, Y is nitrogen, thereby forming thepyrazolo compounds, and when Y, is nitrogen, Y is carbon, thus providing the imidazo compounds.
, DETAILED DESCRIPTION OF THE INVENTION The xanthine oxidase inhibitors of this invention are represented by the foregoing structure. As will be seen from the illustrative examples which follow, such compounds, especially compounds in which R is H or phenylazo, demonstrate inhibitory activity significantly greater than that of allopurinol. Moreover, such compounds are stable to enzymatic oxidation and also are noncompetitive inhibitors of the enzyme xanthine oxidase.
The method of preparing the compounds of the present invention will be described in detail in certain of the illustrative examples. In general, an efficient and comparatively straightforward process is used for the preparation of such compounds with the precise process varying depending upon whether an imidazo or pyrazolo compound is produced.
The imidazo pyrimidines are preferably prepared from an imidazole derivative such as amino imidazolinium sulfate, rather than by the more com- .mon synthetic procedure for the preparation of imidazo pyrimidines involving the condensation of aminopyrimidine derivative with an a-halocarbonyl hyde, only polymeric materials are obtained. This is believed to be due to the fact that pyrimidines, with three F wijfi with acidification of the alcoholic mixture with ethanolic hydrogen chloride to produce the intermediate 2-amino-l -(ethoxymalonyl) imidazole. When this compound is heated'at 135C, it cylcizes to 5,7-dihydroxy imidazo[l,2,a]pyrimidine, which maybe readily purified by recrystalization from water. Alternatively, the imidazo[ l ,2,a]pyrimidine compound may be prepared directly from the imidazole derivative 2-aminoimidazolinium sulfate without isolation of the intermediate compound if the crude sodium salt which separates from the initial reaction mixture does not come in contact with hot water (in excess of 70C).
It will, of course, be understood that other of the described 5,7-imidazopyrimidines of the present invention can be prepared by the above-described process if appropriate materials are'u'sed in place of diethylmalonate. For the sake of brevity of disclosure, however, the preparation of such compounds will not be specified in greater detail at this point; I Treatment of the 5,7-dihydroxy imidazo[ 1,2,a]- pyrimidine with an aqueous solution of benzene diazonium chloride produces the corresponding 6-phenylazo derivative. This compound may also be produced by base catalyzed condensation of 2-amino imidazolinium treated with hydrochloric acid, yields 5,7-dihydroxypyrazolo[ l,5,a]pyrimidine. In an analogous manner, the condensation of 3-amino-4-chloropyrazole, 3- amino-4-bromopyrazole, and 3-amino-4-nitropyrazole with diethylmalonate in the presenceof sodium ethoxide affords 3-chloro, 3-bromo, and 3-nit'ro derivatives of 5,7-dihydroxy pyrazolo[l,5,a]pyrimidine.
The condensation of 3-aminopyrazole withimethyl diethylmalonate in the presence of sodium ethoxide afv fords -5",7 dihydroxy-6-methylpyrazolo[ 1,5 ,a]pyrimidine. Similarly, the condensation of 2-phenylazo diethylmalonate with 3-amino pyrazole in the presence of sodium ethoxide. yields 5,7-dihydroxy-6- phenylazopyrazolo[ l,5,a]pyrimidine. Y
Refluxing a solution of 5, 7-dihydroxypyrazolo[1.,- 5,a]pyrimidine in phosphorus oxychloride affords 5,7- dichloropyrazolo[1,5,a1pyrimidine (l). The
treatment of (l) .with 2.5 N sodium hydroxide solution yields 5-chloro-7-hydroxypyrazolo[ l,5a]pyrimidine (ll). The reductive dehalogenation of (ID-affords 7- hydroxypyrazolo[1,5,a]' pyrimidine (111). This product is identical in allrespects to the product obtained by the condensation of '3-aminopyrazole with the sodium salt of ethyl malonaldehydic ester in the presence of sodium ethoxide. (reaction 1V).
"The invention will be better understood by reference to the following specific but illustrative examples. The ultraviolet spectra was recorded on a Cary-l 5 spectrophotometer. Proton magnetic resonance studies were carried out with a Hitachi Perkin-Elmer R-20A spectrometer with DSS as internal reference.
EXAMPLE 1 Preparation of lmidazo [1,2a] pyrimidine 5,7-diol.
, (Method A) I A solution of sodium ethoxide was prepared by dissolving sodium [8.1g (0.352 formula weights)] in" 200 ml of absolute ethanol. Diethylmalonate [27.43 (0.171 mole)] and 2-amino imidazole hemisulfate [22.2g (0.168 mole)] were added to the sodium ethoxide solution. The resulting solution was stirred and warmed slowly to reflux. After reflux was obtained a sodium salt began to separate fromrth'e solution. The mixture was stirred and heated at reflux for 8 hours. After cooling to room temperature, the sodium salt was separated by filtration, washed with ethanol, and air dried. The sodium salt was dissolved in ml of water (30), and the product precipitated from the solution by the addition of 6" hydrochloric acid until a pH of 1-2 was obtained; The mixture was cooled to 5 and the product was separated by filtration, washed with ice water, and dried at 100. Recrystallization from water afforded l1.9g (47 of analytically pure product that had a Mp 360C; X max (pH 1) 2l6nm (e 22,200) and 263nm (A, 7,900):- Xmax-"(pl l'l l) 223nm" (19,500) and 265nm 7,600). I
" Anal. calcd, for C, 1-1;, N 0,: C, 47.7; H 3.31; N,
27.8... Found: C, 47.8; H, 3.31; N, 27.7.
EXAMPLE 11 Preparation of imidazo [1,2a]-pyrimidine-5,7-diol (Method B) A. 2-Amino-l-(ethoxymalonyl) imidazole A solution of sodium ethoxide was prepared by dissolving sodium [2.3g co.1 formula weights)] in 150 ml of absolute ethanol. Diethylmalonate [8.8g, 55 m moles] and 2-aminoimidazole, hemisulfate [6.7g, 50 m moles] were added to the sodium ethoxide solution. The solution was stirred and slowly warmed to reflux, at which time a sodium salt began to precipitate. The mixture was refluxed for 6 hours and then 50 ml of anhydrous ethanolic hydrogen chloride was added dropwise. After the addition was complete the mixture was refluxed for 20 minutes, filtered, and the filtrate evaporated to dryness. The gummy residue was dissolved in 30 ml of water and the pH of this solution brought to 6 by the addition of saturated sodium carbonate solution to afford a light yellow product. The product was separated by filtration, washed with water, and dried at 80. Recrystallization of this product from water afforded 3.35g (34%) of analytically pure product that had a melting point of 175 (slowly melts and resolidifys).
Anal. calcd. for C H N C, 48.7; H, 5.58; N, 21.3. Found: C, 48.7; H, 5.69; N, 21.4.
B. imidazo [1,2a] pyrimidine-5,7-diol. 2-amino-1- (ethoxymalonyl) imidazole [1.97g, 10 m moles] was heated at 200 for 45 minutes. The residue after cooling was recrystallized from water to afford 1.13g (75%) of analytically pure imidazo [1,2a] pyrimidine-5.7-diol; Mp 360. The ultraviolet absorption spectra of this product is identical to the ultraviolet absorption spectra of the product obtained by Method A.
Anal. calcd. for C H,, N 0 C, 47.4; H, 3.31; N, 27.8. Found: C, 47.4; H, 3.43; N, 27.5.
EXAMPLE Ill Preparation of 6-Bromoimidazo [1,2a] pyrimidine- 5,7-diol.
Bromine [0.bg (0.00375 formula weights)] in 10 ml of acetic acid was added dropwise to a solution of imidazo [1,221] pyrimidine-5,7-diol [0.5g, 3.3 m moles] in 20 ml of acetic acid with good stirring at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The solid was separated by filtration, washed with ethanol 2(25 ml), and dried to afford 0.68g (90%) of product. Recrystallization from water afforded in analytically pure sample that decomposed above 225C. Amax (pH 1) 220 nm (e, 27,100) and 276 nm (e, 9,900) :pmax (pH 11) 226 nm (e,33,600) and 274 nm (e, 7,800)
Anal. calcd. for C H, N, O Br c, 31.3; H, 1.69; N, 18.3. Found: C, 31.2; H, 1.68; N, 18.0.
EXAMPLE lV Preparation of 6-Methylimidazo [1,2a] pyrimidine-5,7-diol.
A solution of sodium ethoxide was prepared by dissolving sodium [1.84g (0.08 formula weights)] in 100 m1 of absolute ethanol. Diethyl methyl malonate [6.96g, 40 m moles] and Z-aminoimidazole, hemisulfate [5.28g, 40 m moles] were added to the sodium ethoxide solution. The mixture was refluxed with stirring for 8 hours, and then evaporated to dryness at reduced pressure. The residue was dissolved in 100 ml of water (30) and the ph adjusted to 2 by adding 6 hydrochloric acid. The product was separated by filtration, washed with cold water, and recrystallized from water to yield 2.74g (40%) of analytically pure product that had a melting point of 310-2 (dec.); umax (pH 1 218 nm (e, 28,800) and 275 nm (e, 1 1,900); umax (pH 11) 223 nm (e, 28,000) and 276 nm (6, 11,700).
Anal. calcd. for C H, N 0 C, 50.9; H, 4.24; N, 25.4. Found: C, 50.9; H, 4.38; N, 24.9.
EXAMPLE V Preparation of 6Nitroimidazo 1 ,2a] pyrimidine-5,7-diol.
A solution of sodium ethoxide was prepared by dissolving sodium [4.6g (0.2 formula weights)] in 250 ml of absolute ethanol. Diethyl nitromalonate [20.5 g (0.1 mole)] and 2-aminoimidazole, hemisulfate [13.2g (0.1 mole)] were added to the sodium ethoxide solution. The mixture was refluxed with stirring for 9 hours, and then evaporated to dryness at reduced pressure. The residue was dissolved in 250 ml of water, and the pH adjusted to l-2 by the addition of 6N hydrochloric acid. The product was separated by filtration, washed thoroughly with water and dried. Purification was afforded by reprecipitating the product from dilute sodium hydroxide solution by the addition of 6N hydrochloric acid to afford 5.9g (30%) of analytically pure product. Mp, 3057(dec); A max (pH 1) 207 nm (e, 23,300) and 320 nm (e, 6,300); A max (pH 11) 226 nm (e, 13,300) and 342 nm (5, 4,900).
Anal. calcd. for C H N 0; C 36.7; H, 2.04; N, 28.6. Found: C, 36.8; H, 2.16; N, 28.4.
EXAMPLE Vl Preparations of 6-phenylazoimidazo [1,2a] pyrimidine5,7-diol.
A. A solution of sodium ethoxide was prepared by dissolving sodium [1.98g (0.086 formula weights)] in ml of absolute ethanol. Diethylphenylazomalonate [l 1.35g, 43 m moles] and 2-aminoimidazole, hemisulfate [5.68g. 43 m moles] were added to the sodium ethoxide solution. The mixture was refluxed with stirring for 8 hours, and then evaporated to dryness at reduced pressure. The residue was dissolved in 300 ml of water and the pH adjusted to 5-6 by the addition of a glacial acetic acid. The product was separated by filtra' tion, washed with water, and purified by recrystallizing from ethanol to afford 3.40g (31%) of analytically pure product that had a melting point of 2779 (dec): A max (pH 1) 205 nm (6, 23,000) and 408 nm (e, 27,800); A max (pH 11) 217 nm (5, 19,400) and 384 nm (e, 20,900).
Anal. calcd. for C H N 0 C, 56,5; H, 3,53; N, 27.4. Found: C, 56.7; H, 3.62; N, 26.6.
B. A solution of benzenediazonium chloride was prepared by treating a solution of aniline [0.3lg, 3,3 m moles] in 7 ml of 1.7N hydrochloric acid with a solution of sodium nitrite [0.25g, 0.0036 formula weights] in 5 ml of water at 5. The benzene diazonium chloride solution was added dropwise to a stirred solution of imidazo [1.2a] pyrimidine-5,7-diol [0.5g, 3.3 m moles] in 10 ml of 1.25 N sodium hydroxide solution at 10. After the addition was complete, the mixture was stirred at 10 for 30 minutes and then at room temperature for 30 minutes. The solid was separated by filtration, and purified by reprecipitating from a dilute sodium hydroxide solution by the addition of acetic acid.
EXAMPLE VII Preparation of Pyrazolo [1,5a] pyrimidine-5,7-diol.
This compound was prepared by the procedure of Y. Makisumi as described in the Chemical and Pharmaceutical Bulletin (Tokyo), 10, 612 (1962). This procedure is as follows:
A solution of sodium. ethoxide was prepared by dissolving sodium [4.6g (0.2 formula weights)] in 300 ml of absolute ethanol. Diethylmalonate [16.0g, 0.1 mole] and 3-aminopyrazole [8.3g, 0.1 mole] were added to the sodium ethoxide solution. The solution was stirred and slowly warmed to reflux at which time a sodium salt began to precipitate. The mixture was refluxed for 6 hours and then allowed to cool to room temperature. The sodium salt was separated by filtration, washed with absolute ethanol, and dried. The sale was dissolved in 250 ml of water and the product precipitated by the addition of 6 N hydrochloric acid until a pH of l2 was obtained. The product was separated by filtration, washed with the water, and recrystallized from water to afford 7.4g (49%) of analytically pure product; mp 2478 (dec); A max (pH 1) 218 nm (6, 14,700) and 276 nm (6, 7,300); 229 nm (e, 22,200) and 270 nm (e, 10,900).
Anal. calcd. for C H; N C, 47.7; H, 3.31; N, 27.8. Found: C, 47.6; H, 3.42; N, 27.7.
EXAMPLE VllI Preparation of 6-Methylpyrazo1o [1,5a] pyrimidine-5,7-diol.
A solution of sodium ethoxide was prepared by dissolving sodium [2.3g (0.1 formula weights)] in 150 ml of absolute ethanol. Diethyl methylmalonate [8.7g, 50 m moles] and 3-aminopyrazole [4.15g, 50 m moles] were added to the sodium ethoxide solution. The mixture was refluxed and stirred for 3 hours, and then evaporated to dryness at reduced pressure. The residue was dissolved in 125 ml of water and the pH adjusted to 1-2 by the addition of 6 N hydrochloric acid. The product was separated by filtration, washed with water, and dried at 100. Purification was afforded by reprecipitating the product from dilute sodium hydroxide solution by the addition of 6 N hydrochloric acid to afford 4.37g (54%) on analytically pure product; mp, 35860 dec; A max (pH 1) 209 nm (6, 21,300) and 275 nm (e, 10,700); A max (pH 11 226 nm (6, 22,700) and 280 nm (e, 13400).
Anal. calcd. for C, H, N 0 C, 50.9; H, 4.24; N, 25.4. Found: C, 50.9; H, 4.36; N, 25.1.
EXAMPLE IX Preparation of 6-Phenylazopyrazolo [1,5a]
pyrimidine-5,7 -diol.
A solution of sodium ethoxide was prepared by dissolving sodium [l,52g (0.066 formula weights)] in 150 ml of absolute ethanol. Diethyl phenylazomalonate [8.7lg, 33 m moles] and 3-aminopyrazole [2.74g, 33
m moles] were added to the sodium ethoxide solution. The mixture was stirred and heated at reflux for 6 hours, and then evaporated to dryness at reduced pressure. The residue was'di ssolved in 300 ml of water and the pH adjusted to 2 :the addition of 6 N hydrochloric acid. The solid was separated by filutration, washed with water and ethanol, and air dried. Purification was afforded by reprecipitating the product from a dilute sodium hydroxide solution by the addition of 6 N hydrochloric acid to afford 2.34g (28%) of analytically pure product; mp. 300-2 (dec); A max (pH 1) 202 nm (5, 25,200), 246 nm (6, 9,700), and 406 nm (e, 30,100 A max (pH 11) 210 nm (6, 19,900) and 386 nm (6, 20,000).
Anal. calcd. for C H N 0 C, 56.5; H, 3.53; N, 27.5. Found: C, 57.0; H, 3.84; N, 27.9.
EXAMPLE X Preparation of 3-Chloropyrazolo [1,5a] pyrimidine-5 ,7-diol.
A solution of sodium ethoxide was prepared by dissolving sodium [0.98g (0.0428 formula weights)] in 50 ml of absolute ethanol. Diethylmalonate [3.50g, 21.9 m moles] and 3-amino-4-chloropyrazolo [2.30g, 2.14 m moles] were added to the sodium ethoxide solution. The mixture was stirred and slowly warmed to reflux. After refluxing for 8 hours the mixture was allowed to cool to room temperature and the sodium salt separated by flltration. The sodium salt was dissolved in 100 ml of water and the pH adjusted to l-2 bythe addition of 6 N hydrochloric acid. The product was separated by filtration, washed with ice water, and dried. Recrystallization from water afforded 1.48g (37%) of analytically pure product that had a melting point of 270-2 (dec);
A max (pH 1) 219 nm (e, 32,140) and 286 nm (6, 16,680); A max (pH 11) 231 nm (e, 47,000) and 275 nm (6, 18,520).
Anal. calcd. for C H; Cl N 0 C, 38.8; H, 2.16; N, 22.6. Found: C, 38.6; H, 2.46; N, 22.9.
. EXAMPLE Xl Preparation of 3-Nitropyrazolo [1,5a] pyrimidine-5,7-diol, hernihydrate.
- The mixture was stirred and refluxed for 16 hours and then allowed to cool to room temperature. The sodium salt was separated by filtration, washed with absolute ethanol and air dried. The sodium salt was dissolved in m1 of water and the pH of this solution adjusted to 1-2 by the addition of 6 N hydrochloric acid. The product was separated by filtration, washed with cold water, and recrystallized with water to afford 3.0g (77%) of analytically pure product; Mp, 2268; A max (pH 1) 218 nm (e, 17,600) and 319 nm (6, 8,700); Amax (pH 11) 227 nm (e, 12,700) and 332 nm (e, 13,700).
Anal. calcd. for C H, N; Oil 1/2H O: C, 35.1; H, 2.45; N, 27.3. Found: C', 35.1; H, 2.55; N, 27.6.
EXAMPLE xn' A solution oflsodium ethoxide was prepared by dissolving (0. 1 20 formulaweights)] in 50 m1 .ofabsolute ethanol. Diethylmalonate [9.6g, 60.2 m
moles] and 3-amino-4-bromopyrazole [9.75g (60.2 m moles)] were added to the sodium ethoxide solution. The mixture was stirred at room temperature for 3 days, and the sodium salt separated by filtration. The sodium salt was dissolved in 100 ml of water and the pH of this solution adjusted to 1-2 by the addition of 6N hydrochloric acid. The product was separated by filtration, washed with cold water, and dried. Purification was accomplished by reprecipitating the product from a dilute sodium hydroxide solution by the addition of 6 N hydrochloric acid. The analytically pure material weighed 4.3g (31%) and decomposed without melting at 265-7; A max (pH 1) 221 nm (6, 20,300) and 283 nm (e, 9,870); A max (pH 1) 233 nm (a, 32,800) and 273 nm (e, 12,850).
Anal. calcd. for C H Br N C, 31.3; H, 1.72; N, 18.2. Found: C, 31.2; H, 1.84; N, 18.3.
EXAMPLE XIII Preparation of S-Chloropyrazolo [1,5a] pyrimidine-7-ol A. 5,7-Dichloropyrazolo [1,5a] pyrimidine A mixture of pyrazolo [1,5a]-pyrimidine-5,7-diol (32g) and phosphorus oxychloride 160 ml) was stirred and heated at 1 10. At the end of 1 hour a complete solution was obtained, and this solution was heated for an additional 1% hours. The excess phosphorous oxychloride was removed at reduced pressure using the steam bath as the source of heat. The red syrup was added slowly to 400g of crushed ice with good stirring. This mixture was stirred at for 30 minutes, and then extracted with anhydrous ether 6(400ml). The etheral extract was washed with water, washed with dilute so dium bicarbonate solution, and dried over anhydrous sodium sulfate. Evaporation of the etheral extract afforded 23g of slightly yellow product, which was sublimed at reduced pressure (1 mm) and elevated temperature (70-100) to afford 11.9g (29%) of analytically pure product that had a melting point of 72-4; )t max (CH OH) 235 nm (e, 32,000) and 290 mm (6, 2,200).
Anal. calcd. for C H C1 N zC, 38.3; H, 1.59; N, 22.3. Found: C, 38.2; H, 1.78; N, 22.4.
B. 5-Chlor0pyrazo1o [1,5a] pyrimidine-7-o1 A A solution of 5,7-dichloropyrazolo [1,5a] pyrimidine [6.0g 31.9 m moles] in 1.25N sodium hydroxide solution 120 ml) was heated at 95 for 1 hour. The hot solution was treated with decolorizing carbon and filtered. Acification of the filtrate with 6 N hydrochloric acid until a pH of 2 was obtainedfafforded the desired product. Recrystallization from a mixture of water and ethylalcohol (1:1) gave 483g (89%) of analytically pure product that had a melting point of 2958 (dec); A max (pH 1) 223 nm (e, 34,000) 263 nm (a, 4,900) and 305 nm (6, 5,100); Xmax (pH 11) 227 nm (6, 18,200), 281 nm (a, 8,000) and 303 nm (e, 7,300).
Anal. calcd. for C H, N 0 Cl: C, 42.5; H, 2.35; N, 24.8. Found: C, 42.3; H, 2.76; N, 24.7.
XIV
Preparations of Pyrazolo [1,5a]-pyrimidine-7-o1.
A. A mixture of 5-chloropyrazolo [l,5a]-2- pyrimidine-7-ol [8.50g 50 m moles]; 150 ml of methanol, 10 ml of 1.25 N sodium hydroxide solution, and 10% palladium or charcoal catalyst was placed in a Paro hydrogenation apparatus and hydrogenated at a pressure of 42'lbs/in Within 5 hours, the calculated quantity of hydrogen (Ca. 4.5 lbs./in had been absorbed. The mixture was filtered and the filtrate acidified with'6 N hydrochloric acid until a pH of 2 was obtained. The acidified solution was evaporated to dryness and the residue washed with cold water. The white crystalline product was recrystallized from a mixture of methanol and water (2.5:1) to afford 3,13g (46%) of analytically pure product that had a melting point of 327-9 (dec); )t max (pH 1) 216 nm (6, 10,600), 260 nm (:2, 6,900) and 295 nm (e, 4,900); A max (pH 11) 226 nm (e, 4,900), 280 nm (5, 8,600) and 308 nm (6, 7,700).
Anal. calcd. for C H N 0: C, 53.3; H, 3.70; N, 31.1. Found: C, 53.3; H, 3.97; N, 30.9.
B. A mixture of ethylacetate [17.8g, 0.2 mole] and ethylformate [14.8g (0.2 mole] was added dropwise to a suspension of finely cut sodium [4.6g (0.2 formula weights)] in 500 ml of absolute ether with vigorous stirring. After the addition was complete the mixture was stirred vigorously for 20 hours, during which time the sodium salt of malonaldehydic ester precipitated. A solution of 3-aminopyrazole [16.6g, 0.2 mole] in 250 m1 of absolute ethanol was added to the suspension, and the resulting mixture heated at 70 until the ether had evaporated. The resulting mixture was refluxed for 8 hoursand then evaporated to dryness at reduced pressure. The residue was dissolved in 200 ml of water and this solution treated with decolorizing carbon and filtered. The filtrate was acidified to pH2 by the addition of 6 N hydrochloric acid, and the precipitated product separated by filtration. Recrystallization from a methanol and water mixture afforded 3.1g (1 1%) of analytically pure product that had a melting point of 3258 (dec). The ultra-violet absorption spectra of this compound is identical to the spectra of the compound prepared by Method A.
EXAMPLE XV introduced into the incubation mixture containing 150 micromoles of tris HCl buffer (pH 7.83), 0.6micromoles EDTA, 0.013 micromoles xanthine, and 20 to 40 micrograms of xanthine oxidase in a final volume of 3.0 milliliters. The xanthine oxidase was purified milk xanthine oxidase from Worthington Biochemical Corporation and had a specific activity of 0.29 u/mg of protein. The assay was carried out by mixing all the components in a cuvette at 25C. The reaction was started by the addition of the enzyme with the aid of a stirrer-adder. Changes in OD. were measured for several minutes, and the rate (A OD. per minute) was calculated from the spectral change over the first 15 seconds.
ln order to fully evaluate the inhibitory activity and to compare the relative inhibitory abilities of the compounds of this invention with allopurinol, experiments were carried out in which the concentration of inhibitor was varied over a range of approximately 10' to about l molar and the initial velocity of xanthine oxidation was measured. From a plot of the log of inhibitor concentration against the percent inhibition, the concentration of inhibitor giving 50% inhibition, (1,), was calculated. This value was obtained from a linear regression analysis of the straight lines obtained in this graph. The data is presented in Tables I and II which follows as (I/S) values. The lower the (1/8) value, the more potent the inhibitory capability of the compound.
TAB LE I lmidazo [l,2.a]pyrimidines Compound No. R, R, R, R, (US
l H H OH H 3 .57 (2) NH, H OH H 100. l
(3 H CH OH H l .54 (4) H Br OH H 0.92 (5) H phenyl- OH H 0.17
azo (6) NH, phenyl- OH H 55 azo (7 NH, Br OH H 7.65 (8) H N0, OH H 2.80 (9) Allopurinol 0.58
' Included for comparison only; outside scope of invention.
TABLE ll Pyrazolo l.5.a]pyrimidines Compound I No. R, R, R, R, (l/S l H H OH H 0.447 (2) H CH, OH H 5 .37 (3) H phenyl- OH H 3 .22
azo (4) H H H H l .08 (5) H H Cl H 2.42 (6) NH, H Cl H 32 7) NH, H OH H 33 .4 8) Allopurinol 0.58
Included for comparison only; outside scope of invention.
Referring now more particularly to Table I, it will be observed that Compounds (l), (3), (4), (5), and (8) demonstrated significant inhibitory activity. Compound (5), the 5,7-dihydroxyimidazo compound in which R is phenylazo, demonstrated exceptional activity, being approximately 3% times superior to allopurinol, which is also included in Table I for comparison. It will also be observed that Table 1 includes compounds in which an amino group is present at the 7 position. A comparison of the activity results between Compounds (1) and (2), (5) and (6), and (4) and (7), shows that the inhibitory activity is decreased significantly. A comparison of Compounds l) and (7) and (5) and (6) in Table II shows similar results.
It should also be noted, with respect to Table II, that Compounds (1), (2), (3), (4), and (5) demonstrated significant ability to inhibit the enzyme xanthine oxidase. Compound (I) was especially good, being superior to allopurinol, which has an (l/S) of 0.58.
EXAMPLE XVI Oxidation tests were also conducted on the compounds of the present invention to determine their stability against enzyme oxidation. The compounds were tested for their ability to serve as alternate substrate in two ways: (1) by substituting the test compound for xanthine in the basic incubation mixture described with respect to Example XV above and measuring the change in 0.D. from 220 to 380 nm over a -minute period, using the repetitive scan accessory of the Cary spectrophotometer, and (2) using the method of Johns, Spector, and Robins, Bioch. P. Col., 18, p. 2371-83 (1969) in which phenozine methosulfate and cytochrome C were substituted for oxygen as the electron carrier. Changes in 0.D. of the test compound (Method 1) or of the phenozine methosulfate (Method 2) were observed for 30 minutes at the appropriate wavelength values (550 nm for phenozine methosulfate).
As noted previously, it is known that allopurinol is oxidized to 4,6-dihydroxypyrazolo[ 3,4,dlpyrimidine by xanthine oxidase. Because, of this, the ability of the compounds of this invention to be oxidized by xanthine oxidase were determined. The reactions were carried out in vitro using the methods described above. Under the same conditions, allopurinol was slowly oxidized to 4,6-dihydroxypyrazolo [3,4,d]pyrimidine when oxygen was used to accept electrons and was completely oxidized to such compound in the presence of phenozine methosulfate in less than 5 minutes incubation at 25C.
In contrast, the compounds of this invention shown in Tables I and II above were completely stable to enzymatic oxidation under either condition.
EXAMPLE XVII The compounds of this invention shown in Tables I and II were next subjected to kinetic analysis using the methods of Lineweaver and Burke, or Hanes Enzymes, M. Dixon and E. C. Webb, 1964, Acad. Press, New York, N.Y., to determine the type of inhibition they were exhibiting. Allopurional has been shown to be a competitive inhibitor of xanthine oxidase. As can be seen from Tables [I] and IV which follow, the 5,7- dihydroxy compounds having the indicated R, substituents were non-competitive inhibitors. The K, values shown in Tables Ill and [V were calculated from a Dixon-plot (1) against l/v at the two indicated substrate concentrations.
TABLE lll lmidazol l,2,a]pyrimidines Non-inhibited Reaction TABLE IV Pyrumlol 1.5.11 [pyrimidine Non-inhihited Reaction Type of R, R- R:, R, Inhibition Km X 10" Vm'" 10 K, 10"
H H OH H Non-Comp. 1.99 l 1.3 6.08, 6.95 H phenyl- OH H 1.10 10.8 101. 116
am H CH OH H 3.23 13.3 75.9,9031
EXAMPLE XVIII Using the general procedure and conditions described with respect to Example XV, the inhibitory activity of the compounds set forth in Table V was determined. The incubation mixture again had a total reaction volume of 3.0 milliliters and the xanthine concentrations was 1.32 X 10 M. It will be seen from Table V that the compounds in which R, is N C1 or Br, demonstrated highly significant inhibitory activity. Also shown in Table V for comparison is Compound (I) of Table II. It will be appreciated that the three other compounds shown in Table V exhibited very good inhibition capability with the halogenated compounds showing significantly better Compound (ll of Table n.
(US values than Compounds( 1 It should be further noted that the toxicity level of the compounds of the present invention is less than allopurinol. As noted previously, the LD for allopurinol is 150;- 80 milligrams per kilogram.
At this point, it should be noted that the chemical structure of Compound (1) of Table II has been previously reported, Chemical & Pharmaceutical Bulletin (Tokyo), Vol. 10, No. 7, p. 612 et seq. (1962) and Japanese Pat. No. 7983, dated July 1 l, 1962. To our knowledge, however, there is no indication reported that this compound has utility as an inhibitor of the enzyme xanthine oxidase.
The xanthine oxidase inhibitors are administered as oral preparation, in capsule or tablet form. The tables or capsules will contain from about 5 to about 100 milligrams of the inhibitor per tablet or capsule. The required dose of the inhibitor, of course, will vary depending upon the condition of the patient, but will normally range from approximately to 600 milligrams per day. To effectively inhibit the enzyme xanthine oxidase, a concentration in the blood from about 1 to about 500 micrograms of the inhibitor is required, preferably about 1 to 50 micrograms per milliliter.
The capsules will be the usual gelatin capsules and will contain in addition to the inhibitor, a small quantity, for example less than 5% by weight preferably less than about 1%, magnesium stearate or other flowing agent, such as Avicel (carboxymethylcellulose). Tablets will include the inhibitor and, e.g., a binder, which may be a gelatin solution, a starch paste in water, polyvinyl pyrrilidone, polyvinyl alcohol in water, etc., with a typical sugar coating.
We claim:
1. A compound of the structure I J. p; Y!
wherein Y, and Y, are C or N;
R, is H or an alkali metal or ammonium;
R is H, CH halogen, or N0 R,, is OR,, H, or halogen;
and R,, is H, NO, or halogen; provided that when one of Y, or Y, is C, the other is N;
that when Y, is C, Y, is N and R is H, R,, is H, halogen or OR, where R, is an alkali metal or ammonium and R is H, CH NO, or halogen; and that when Y, is N and Y, is C, R, is H.
2. The compound of claim 1 in which Y, is C and Y, is N, and R,, R, and R are H and R is OH.
3. The compound of claim 1 in which Y, is C and Y, is N, and R,, R and R, are H and R is Cl.
4. The compound of claim 1 in which Y, is C and Y, is N, and R, and R are H, R, is OH and X is NO,.
5. The compound of claim 1 in which Y, is C and Y, is N, and R, and R are H, R, is OH and R, is Cl.
6. The compound of claim 1 in which Y, is C and Y, is N, and R, and R are H, R,, is OH and X is Br.
7. The compound of claim 1 in which Y, is N and Y, is C, and R,, R and R are H, and R,, is OH.
8. The compound of claim 1 in which Y, is N and Y, is C, and R, and R are H, and R is CH, and R is OH.
9. The compound of claiml in which Y, is N and Y is C, and R, and R, are H, R, is Br and R,, is OH.
10. The compound of claim 1 in which Y, a N is C, and R, and R are H, R is N0 and R is OH.
Claims (10)
1. A COMPOUND OF THE STRUCTURE
2. The compound of claim 1 in which Y1 is C and Y2 is N, and R1, R2 and R4 are H and R3 is OH.
3. The compound of claim 1 in which Y1 is C and Y2 is N, and R1, R2 and R4 are H and R3 is Cl.
4. The compound of claim 1 in which Y1 is C and Y2 is N, and R1 and R2 are H, R3 is OH and X is NO2.
5. The compound of claim 1 in which Y1 is C and Y2 is N, and R1 and R2 are H, R3 is OH and R4 is Cl.
6. The compound of claim 1 in which Y1 is C and Y2 is N, and R1 and R2 are H, R3 Is OH and X is Br.
7. The compound of claim 1 in which Y1 is N and Y2 is C, and R1, R2, and R4 are H, and R3 is OH.
8. The compound of claim 1 in which Y1 is N and Y2 is C, and R1 and R4 are H, and R2 is CH3 and R3 is OH.
9. The compound of claim 1 in which Y1 is N and Y2 is C, and R1 and R4 are H, R2 is Br and R3 is OH.
10. The compound of claim 1 in which Y1 is N and Y2 is C, and R1 and R4 are H, R2 is NO2 and R3 is OH.
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US440989A US3907799A (en) | 1971-08-16 | 1974-02-11 | Xanthine oxidase inhibitors |
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US17219671A | 1971-08-16 | 1971-08-16 | |
US440989A US3907799A (en) | 1971-08-16 | 1974-02-11 | Xanthine oxidase inhibitors |
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