US3892858A - Method for lowering uric acid levels using 7-alkylsufonyl substituted benzothiadiazine-1,1-dioxides - Google Patents
Method for lowering uric acid levels using 7-alkylsufonyl substituted benzothiadiazine-1,1-dioxides Download PDFInfo
- Publication number
- US3892858A US3892858A US456947A US45694774A US3892858A US 3892858 A US3892858 A US 3892858A US 456947 A US456947 A US 456947A US 45694774 A US45694774 A US 45694774A US 3892858 A US3892858 A US 3892858A
- Authority
- US
- United States
- Prior art keywords
- chloro
- dioxide
- benzothiadiazine
- active agent
- lower alkyl
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 87
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title claims abstract description 13
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229940116269 uric acid Drugs 0.000 title claims abstract description 13
- UOCUSOBVEHOMMB-UHFFFAOYSA-N 2h-1$l^{6},2,3-benzothiadiazine 1,1-dioxide Chemical class C1=CC=C2S(=O)(=O)NN=CC2=C1 UOCUSOBVEHOMMB-UHFFFAOYSA-N 0.000 title 1
- 239000008280 blood Substances 0.000 claims abstract description 8
- 210000004369 blood Anatomy 0.000 claims abstract description 8
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- 125000001309 chloro group Chemical class Cl* 0.000 claims description 30
- 239000013543 active substance Substances 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical class F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000003647 oxidation Effects 0.000 abstract description 10
- 238000007254 oxidation reaction Methods 0.000 abstract description 10
- 108010093894 Xanthine oxidase Proteins 0.000 abstract description 7
- 102100033220 Xanthine oxidase Human genes 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 238000007796 conventional method Methods 0.000 abstract description 4
- 210000002700 urine Anatomy 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 125000005140 aralkylsulfonyl group Chemical group 0.000 abstract description 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 2
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- YAZSBRQTAHVVGE-UHFFFAOYSA-N 2-aminobenzenesulfonamide Chemical compound NC1=CC=CC=C1S(N)(=O)=O YAZSBRQTAHVVGE-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 5
- 239000000155 melt Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RFBFVLGFLNFWNY-UHFFFAOYSA-N 2-amino-4-chloro-5-propan-2-ylsulfanylbenzenesulfonamide Chemical compound CC(C)SC1=CC(S(N)(=O)=O)=C(N)C=C1Cl RFBFVLGFLNFWNY-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 2
- 229910000497 Amalgam Inorganic materials 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical compound C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000003451 thiazide diuretic agent Substances 0.000 description 2
- 239000011135 tin Substances 0.000 description 2
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 description 1
- USWINTIHFQKJTR-UHFFFAOYSA-N 3-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C=C(S(O)(=O)=O)C(O)=CC2=C1 USWINTIHFQKJTR-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 101000596892 Homo sapiens Neurotrimin Proteins 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
- 102100035107 Neurotrimin Human genes 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000007658 benzothiadiazines Chemical class 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- RGUQWGXAYZNLMI-UHFFFAOYSA-N flumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O RGUQWGXAYZNLMI-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
Definitions
- Jerome Behan [5 7 ABSTRACT Method for decreasing the concentration of uric acid in the blood and urine of a mammal by the administration of a 7-alkyl(or aralkyl)sulfonyl-1,2,4- benzothiadiazine-l,l-dioxide product.
- the products employed in this method of treatment are prepared by conventional methods such as oxidizing a 7-alkylor aralkylthio substituent to the 7-alkylor aralkylsulfonyl group or cyclizing a 4-alkylor aralkylthioorthanilamide by known methods followed by oxidation of the 7-thio to the 7-sulfonyl moiety.
- the products effect the lowering of the uric acid level by virtue of their xanthine oxidase inhibiting properties.
- This invention is concerned with a method of lowering the uric acid level in the blood and urine of a mampound having a 7-alkylsulfonylor a 7-aralkylsulfonyl substituent, which products have been found to exhibit xanthine oxidase inhibiting properties, many comparable to or greater than that exhibited by allopurinol when all compounds are evaluated in the same in vitro test.
- the products employed in the method of this invention have the structural formula Y R 5 ENH and pharmacologically acceptable salts thereof ma] by the administration of a benzothiadiazine coml0 x fi-R (1.50 5m! R -Acid Halide Rs 1 S0 cll.
- the active products can be prepared by one or another of the well known procedures for making benzothiadiazine compounds of structure I, advantageously as illustrated below
- the 7-R-thio substituent in compound C can be oxidized by any conventional method, suitably by treatment with potassium permanganate, as illustrated above, or with other oxidizing substances such as a peroxide, as hydrogen peroxide.
- the reaction advantageously is carried out in the presence of an organic solvent such as acetic acid, acetone and the like, and with slight warming suitably between about ambient temperature to about C.
- Pharmacologically acceptable salts of these products generally are the alkali metal salts which can be prepared by conventional methods, for example by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent such as a lower alkanol or in water and evaporating the solvent or by reacting the free compound, for example, in an ether, e.g. pdioxane or diethyleneglycol dimethyl ether solution with an alkali metal hydride or amide and removing the solvent. Monoor poly-salts may be obtained.
- an alkali metal hydroxide e.g. sodium or potassium hydroxide
- a solvent such as a lower alkanol or in water
- evaporating the solvent or by reacting the free compound, for example, in an ether, e.g. pdioxane or diethyleneglycol dimethyl ether solution with an alkali metal hydride or amide and removing the solvent.
- X@ H RS NH 2 clll Preparation of compound C initially involves the reiction of the 7-chloro sulfonyl substituent of the hen thiadiazine, A. Reduction advantageously is effected ith slight warming of compound A with a mixture of annous chloride and hydrochloric acid, zinc amalgam 1d sulfuric acid, zinc dust and sulfuric acid or tin and Idl'OChlOIlC acid. Alkylation of the 7-mercapto prod- :t thus obtained, B, provides product C. which can be nployed as starting substance in preparing the active gents employed in the method of this invention.
- the orthanilamide, D can sometimes be used more lvantageously to prepare starting substances for the )mpounds of this invention which are either unsubstited in the 3-position or where certain specific substit- :nts are desired in this position.
- the appropriate orthanilamide derivative, D can be acted with an acid halide which, for practical purses can be the acid chloride, followed by treatment ith an organic base to provide product C wherein R other than hydrogen or a haloalkyl substituent.
- R other than hydrogen or a haloalkyl substituent.
- the orthanilamide, D is cyclized by :ating with formic acid or an alkyl orthoformate.
- 'hen R is a haloalkyl group the orthanilamide is re- :ted with an haloalkanoic acid halide, followed by eatment with a salt of a weak acid and strong base.
- alkyl and 110 substituents in the alkoxalyl halide is not critical 1d can be any lower alkyl or halide and suitably, for 'actical purposes, ethyl oxalyl chloride can be emoyed.
- the R-acid chloride can be preformed and emoyed in the reaction or it can be prepared in situ by e addition of phosphorus oxychloride to a mixture of e orthanilamide and the R-carboxylic acid.
- e acid chloride When e acid chloride is preformed, the reaction advantaously is conducted in the presence of an inert solvent ch as dioxane, tetrahydrofuran, benzene, toluene, 1d the like and is facilitated by heating up to the reflux mperature of the reaction mixture.
- an inert solvent ch as dioxane, tetrahydrofuran, benzene, toluene, 1d the like and is facilitated by heating up to the reflux mperature of the reaction mixture.
- the phosphorus oxychloride When the acid lloride is formed in situ, the phosphorus oxychloride rves not only to form the acid chloride but as
- the active agents, 1, of the method of this invenm are inhibitors of xanthine oxidase, they effectively :crease the concentration of uric acid in the blood .d urine of mammals, and additionally increase the cretion of hypoxanthine and xanthine.
- the method this invention therefore is particularly useful in the :atment and management of gout preferably by oral ministration of from about 100 to 800 mg. per day the active products in divided doses as prescribed by e physician.
- xanthine oxidase inhibitors useful in'the method of this invention are products I having a 6-chloro, a 7-lower-alkylsulfonyl substituent and attached to the 3-position 4-pyridyl, methyl, a CO Alkyl or -CONl-l
- Any of the known methods for formulating thiazide products can be used in the preparation of suitable dosage forms of the active agents employed in the method of this invention.
- the following formulation is illustrative of one suitable dosage form:
- the thiazide is granulated with the starch paste and while moist passed through a No. 14 screen, dried at 45 C. for 20 hours and then passed 3 times through a No. 14 screen.
- the starch is passed through a No. 90 bolting cloth onto the granulation and all ingredients are blended thoroughly.
- the magnesium stearate then is passed through a No. 90 bolting cloth onto the granulation and all ingredients are blended after which the granulation is compressed into tablets using 14/32 in. flat, bevelled, scored punch having a thickness of 0.205 t 0.005 in. yielding 1,000 tablets, each weighing 0.543
- a solution of stannous chloride dihydrate (180.5 g., 0.80 mole) in concentrated hydrochloric acid ml.) is added to a stirred solution of 6-chloro-7- chlorosulfonyl-l ,2,4-benzothiadiazine-1 l -dioxide (50.4 g., 0.16 mole) at 75 C. and maintained at this temperature for an additional 20-30 minutes.
- the solution is concentrated in vacuo to one-tenth its original volume and poured into 8 liters of ice water containing concentrated hydrochloric acid (200 ml.).
- the solid formed is collected and added with stirring to one liter of saturated sodium bicarbonate solution. After one hour, the solution is filtered and the filtrate acidified with hydrochloric acid, the product collected on a filter, washed with water and recrystallized from ethanol providing product melting at 270272 C.
- the solid is collected, stirred with 5% sodium hydroxide solution 1500 ml.) at room temperature and filtered.
- the filtrate is acidified with concentrated hydrochloric acid and the product collected and recrystallized from a mixture of methanol and water to provide 6-chloro-7-isopropylthio-l ,2,4-benzothiadiazine-1,1-dioxide, m.p. 23l232 C.
- Step C Preparation of 6-chloro-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel l -dioxide
- a solution of potassium premanganate (0.003 mole) in water ml.) is added dropwise to a solution of 6- chloro-7-isopropylthio-l ,2,4'benzothiadiazine-l ,1- dioxide (0.002 mole) in acetic acid (30 ml.) and water (10 ml.).
- the mixture is stirred at 30 C. for 1 hour, treated with sodium bisulfite and diluted with water.
- the product following recrystallization from acetone, melts at 280282 C.
- Step B Process 6-Chloro-7-n-pr0pylthio-l ,2,4-benzothiadiazinel l dioxide, m.p. l93-l94 C.
- Step C Process 6-Chloro-7-n-propylsulfonyl-l ,2,4-benzothiadiazine- 1,1-dioxide, m.p. 246-248 C.
- Step C Process 6-Chloro-7-( l-ethylpropylsulfonyl)-l ,2,4- benzothiadiazine-l,l-dioxide, m.p. 263-265 C.
- the mixture is then heated r two hours on the steam bath, cooled and poured no a mixture of ice and water.
- the solid product is llected on the filter, washed with cold water and air- 'ied at room temperature and recrystallized from acene-hexane.
- Step B Preparation of 6-Trifluoromethyl-7-isopropylsulfonyl-l ,2,4- benzothiadiazine-l l -dioxide 6-Trifluoromethyl-7-mercapto-l ,2,4-benzothiadiane-l ,l-dioxide is prepared by reducing ifluoromethyl-7-chlorosulf0nyl-l ,2,4-benzothiadiane-l,l-dioxide with stannous chloride dihydrate by bstantially the same procedure described in Example Step A, employing equivalent quantities of all reacnts and reagents.
- Example 6 Metal-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel 1 -dioxide
- 6-triflu0romethyl-7-sulfamoyl- 2,4-benzothiadiazinel l dioxide employed in Step A 'Example 5 By replacing the 6-triflu0romethyl-7-sulfamoyl- 2,4-benzothiadiazinel l dioxide employed in Step A 'Example 5 by an equivalent quantity of 6-methyl-7- lfamoyl-l,2,4-benzothiadiazine-l,1-dioxide and then llowing substantially the same procedure described in eps A and B of Example 5, there is obtained 6- ethyl-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel-dioxide.
- Step B is dissolved in 10% aqueous sodium hydroxide ml.) and heated on the steam bath for one hour. The solution is chilled, acidified with hydrochloric acid and the product upon recrystallization from a mixture of ethanol and water melts at l37-l 38 Analysis calculated for c HmclNgo-gsgi C. 38.50; H, 4.66; N. 9.98; Found: C. 38.71: H. 4.60; N. 9.81.
- Step B Preparation of 3-(4-Pyridyl)-6-chloro-7-isopropylthio-1,2,4- benzothiadiazinel l -dioxide
- An intimate mixture of the orthanilamide derivative prepared as described in Step A (0.01 mole) and 4- pyridine carboxylic acid (0.01 mole) is heated with 20 ml. of phosphorus oxychloride for l5 minutes at 50 C. and 45 minutes on the steam bath.
- the solution is cooled, poured onto ice and the product heated on the steam bath with ethanol (50 ml.) and concentrated ammonia hydroxide (50 ml.) for two hours. After concentration in vacuo, the residue is treated with 50 ml.
- Step C 9 v 10 Preparation of chloro-7-methylthio-l ,2,4-benzothiadiazine-l ,1- 3-(4-Pyridy1)-6-chloro-7-isopropylsulfonyl-l .2,4- dioxide. This compound then is converted to the corre benzothiadiazine-1,l-dioxide sponding orthanilamide by the process of Example 10,
- Step A the orthanilamide reacted with 4-pyridine carisopropylthio-l,2,4-ber1zothiadiazine-l ,l-dioxide by 5 boxyhcacld by the pmcedur? i g m.
- step B of the process described in Step C of Example 1 provides Example followed by Oxldatlon accordmg to the the 7 isopropylsulfonyl derivative, o o method described in Example 1, Step C, to provide 3- 4-pyridyl )-6-chloro-7-methylsulfonyl-l ,2,4-
- Step B using n-propyl chloride instead of isopropyl chloride followed by treatment with sodium hydroxide by the method described in Example 10, Step A] and ethyl oxalyl chloride (0.022 mole) in dioxane (40 ml.) is heated under reflux for 18 hours and then concentrated to dryness in vacuo.
- the residue is dissolved in a mixture of ethanol (30 ml.) and concentrated ammonium hydroxide (30 ml.) and stirred at room temperature for 2-3 days. The solution is concentrated to dryness in vacuo and the residue stirred in sodium bicarbonate solution and filtered.
- EXAMPLE 34 3-Carbamoyl-6-chloro-7-isopropylsulfonyl-1 ,2,4- benzothiadiazine-l l -dioxide
- 3-carbamoyl-6-chloro-7-isopropylsulfonyll,2.4-benzothiadiazine-l,l-dioxide 3-carbamoyl-6-chloro-7-isopropylsulfonyll,2.4-benzothiadiazine-l,l-dioxide. m.p. 228230 C.
- the solution then is concentrated to dryness in vacuo, the residue dissolved in ethanol ml.) and heated under reflux with potassium acetate (0.022 mole) and water 10 ml.) for two hours.
- the alcohol is removed in vacuo and the solution then acidified with hydrochloric acid.
- the precipitated product is recrystallized from a mixture of methanol and water to provide 3-chloromethyl-6-chloro-7-isopropylthio-l ,2,4- benzothiadiazine-l .l-dioxide, m.p. 248250 C.
- Step B Preparation of 3-Chloromethyl-6-chloro-7-isopropylsulfonyll ,2,4- benzothiadiazine- 1 l -dioxide
- EXAMPLE 37 3-Chloromethyl-6-chloro-7-n-propylsulfonyl-l ,2,4- benzothiadiazine-l l -dioxide
- This product prepared following substantially the same procedure described in Example 36 with the exception that an equivalent quantity of 2-sulfamoyl-4-npropylthio-S-chloroaniline is employed in place of the aniline reactant used in Example 36, melts at 268-269 C.
- EXAMPLE 38 3-Dichloromethyl-6-chloro-7-isopropylsulfonyl-1 ,2,4- benzothiadiazine-l 1 -dioxide
- Step A Preparation of 3-Dichloromethyl-6-chloro-7-isopropylthio-1.2.4- benzothiadiazine-l l-dioxide
- Step A there is obtained 3-dich1oromethyl-6-chloro-7-isopropylthiol,2,4-benzothiadiazine-l.l-dioxide. m.p. 287-289 C.
- Step B Preparation of -Dichloromethyl-6-chloro-7-isopropylsulfonyl-l ,2,4- benzothiadiazine- 1 1 -dioxide Oxidation of the 7-isopropyl compound of Step A by e process described in Example 1, Step C, gives 3- chloromethyl-6-chloro-7-isopropylsulfonyll ,2,4-
- a reference cuvette is filled with 0.05M pH 7.4 buffer. For the control, mix quickly in a cuvette 2 ml. hy-
- test AA control X where AA is the change in absorbance in one minute. If the inhibition is I percent. the test solution is serially diluted to determine the concentration required for 50 percent inhibition.
- the percent inhibition effected by certain representative products employed in the method of this invention is provided in the following table.
- the concentration of the test compound was 2 X ""M unless otherwise noted.
- 3.2 X 10"M of allopurinol, a known xanthine oxidase inhibiting agent effects 50 percent inhibition of xanthine oxidase by this protocol.
- a method which comprises orally administering to a mammal having an elevated blood uric acid level a dose sufficient to lower the blood uric acid level to normal for that species a 3'R"6-X-7-ROgS-1,2,4- benzothiadiazine-l ,l-dioxide or a pharmacologically acceptable salt thereof wherein X represents C alkyl, chloro and trifluoromethyl; R represents hydrogen. lower alkyl, halo-lower alkyl. phenyl-lower alkyl, carboxy, CO lower alkyl and -CONH- and R represents lower alkyl and phenyl lower alkyl.
- tive agent X is chloro, and R is halo-lower alkyl.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Method for decreasing the concentration of uric acid in the blood and urine of a mammal by the administration of a 7-alkyl(or aralkyl)sulfonyl-1,2,4-benzothiadiazine-1,1-dioxide product. The products employed in this method of treatment are prepared by conventional methods such as oxidizing a 7-alkyl- or aralkylthio substituent to the 7-alkyl- or aralkylsulfonyl group or cyclizing a 4-alkyl- or aralkylthio-orthanilamide by known methods followed by oxidation of the 7-thio to the 7-sulfonyl moiety. The products effect the lowering of the uric acid level by virtue of their xanthine oxidase inhibiting properties.
Description
United States Patent Novello METHOD FOR LOWERING URIC ACID LEVELS USING 7-ALKYLSUFONYL SUBSTITUTED BENZOTHIADIAZINE-l,l-DIOXIDES Related U.S. Application Data Division of Ser. No. 265,132, June 22, 1972, Pat. No. 3,816,625.
Inventor:
U.S. Cl. 424/246; 424/250; 424/251;
424/263 Int. Cl A16k 27/00 Field of Search 424/246 Primary ExaminerStanley J. Friedman Attorney, Agent, or Firm-Daniel T. Szura; .1. Jerome Behan [5 7 ABSTRACT Method for decreasing the concentration of uric acid in the blood and urine of a mammal by the administration of a 7-alkyl(or aralkyl)sulfonyl-1,2,4- benzothiadiazine-l,l-dioxide product. The products employed in this method of treatment are prepared by conventional methods such as oxidizing a 7-alkylor aralkylthio substituent to the 7-alkylor aralkylsulfonyl group or cyclizing a 4-alkylor aralkylthioorthanilamide by known methods followed by oxidation of the 7-thio to the 7-sulfonyl moiety. The products effect the lowering of the uric acid level by virtue of their xanthine oxidase inhibiting properties.
16 Claims, N0 Drawings v l r METHOD FOR LOWERING URIC ACID LEVELS USING 7-ALKYLSUFONYL SUBSTITUTED BENZOTHIADIAZINE-l,l-DIOXIDES This application is a Division of co-pending application Ser. No. 265,132, filed June 22, 1972 which issued June ll, 1974 as US. Pat. No. 3,816,625.
This invention is concerned with a method of lowering the uric acid level in the blood and urine of a mampound having a 7-alkylsulfonylor a 7-aralkylsulfonyl substituent, which products have been found to exhibit xanthine oxidase inhibiting properties, many comparable to or greater than that exhibited by allopurinol when all compounds are evaluated in the same in vitro test.
The products employed in the method of this invention have the structural formula Y R 5 ENH and pharmacologically acceptable salts thereof ma] by the administration of a benzothiadiazine coml0 x fi-R (1.50 5m! R -Acid Halide Rs 1 S0 cll.
2 atoms, (4) the group -CONH or (5) an azine optionally substituted with one or more lower alkyl having 1 to 3 carbon atoms or a diazine optionally substituted with one or more lower alkyl having from 1 to 3 carbon atoms.
The active products can be prepared by one or another of the well known procedures for making benzothiadiazine compounds of structure I, advantageously as illustrated below The 7-R-thio substituent in compound C can be oxidized by any conventional method, suitably by treatment with potassium permanganate, as illustrated above, or with other oxidizing substances such as a peroxide, as hydrogen peroxide. The reaction advantageously is carried out in the presence of an organic solvent such as acetic acid, acetone and the like, and with slight warming suitably between about ambient temperature to about C.
Pharmacologically acceptable salts of these products generally are the alkali metal salts which can be prepared by conventional methods, for example by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent such as a lower alkanol or in water and evaporating the solvent or by reacting the free compound, for example, in an ether, e.g. pdioxane or diethyleneglycol dimethyl ether solution with an alkali metal hydride or amide and removing the solvent. Monoor poly-salts may be obtained.
Starting substance, C, is prepared by one of the following procedures:
X R Reduct ion 5 HS 6N Alkylation M1 x I fi-IQ' base so rm W RS /NH Formic Acid etc.
X@ H RS NH 2 clll Preparation of compound C initially involves the reiction of the 7-chloro sulfonyl substituent of the hen thiadiazine, A. Reduction advantageously is effected ith slight warming of compound A with a mixture of annous chloride and hydrochloric acid, zinc amalgam 1d sulfuric acid, zinc dust and sulfuric acid or tin and Idl'OChlOIlC acid. Alkylation of the 7-mercapto prod- :t thus obtained, B, provides product C. which can be nployed as starting substance in preparing the active gents employed in the method of this invention.
The orthanilamide, D, can sometimes be used more lvantageously to prepare starting substances for the )mpounds of this invention which are either unsubstited in the 3-position or where certain specific substit- :nts are desired in this position. This substance can be ade by moderate heating of C (R=H) in the preslce of base.
The appropriate orthanilamide derivative, D, can be acted with an acid halide which, for practical purses can be the acid chloride, followed by treatment ith an organic base to provide product C wherein R other than hydrogen or a haloalkyl substituent. When is hydrogen, the orthanilamide, D, is cyclized by :ating with formic acid or an alkyl orthoformate. 'hen R is a haloalkyl group the orthanilamide is re- :ted with an haloalkanoic acid halide, followed by eatment with a salt of a weak acid and strong base.
.itably sodium or potassium acetate or potassium fluo- When an organic base is employed following the re- :tion of the orthanilamide and acid chloride the base choice is ammonia or a tertiary amine particularly rtiary lower alkylamines. Employment of a tertiary nine in alcoholic solution provides the 3-carboxylic :id' ester derivative. The 3-carbamoyl substituent is 'epared employing ammonia following reaction of the 'thanilamide with an alkoxalyl halide. Ammonia emoyed following reaction with a mono-carboxylic acid llide provides product where R is alkyl, phenalkyl, an vine or diazine substituent. The nature of the alkyl and 110 substituents in the alkoxalyl halide is not critical 1d can be any lower alkyl or halide and suitably, for 'actical purposes, ethyl oxalyl chloride can be emoyed.
The R-acid chloride can be preformed and emoyed in the reaction or it can be prepared in situ by e addition of phosphorus oxychloride to a mixture of e orthanilamide and the R-carboxylic acid. When e acid chloride is preformed, the reaction advantaously is conducted in the presence of an inert solvent ch as dioxane, tetrahydrofuran, benzene, toluene, 1d the like and is facilitated by heating up to the reflux mperature of the reaction mixture. When the acid lloride is formed in situ, the phosphorus oxychloride rves not only to form the acid chloride but as solvent well.
As the active agents, 1, of the method of this invenm are inhibitors of xanthine oxidase, they effectively :crease the concentration of uric acid in the blood .d urine of mammals, and additionally increase the cretion of hypoxanthine and xanthine. The method this invention therefore is particularly useful in the :atment and management of gout preferably by oral ministration of from about 100 to 800 mg. per day the active products in divided doses as prescribed by e physician.
Especially effective xanthine oxidase inhibitors useful in'the method of this invention are products I having a 6-chloro, a 7-lower-alkylsulfonyl substituent and attached to the 3-position 4-pyridyl, methyl, a CO Alkyl or -CONl-l Any of the known methods for formulating thiazide products can be used in the preparation of suitable dosage forms of the active agents employed in the method of this invention. The following formulation is illustrative of one suitable dosage form:
Compressed Tablet Containing 0.5 g. of Active Ingredient Grams 3-(4-Pyridyl)-6-ch1oro-7-isopropylsulfonyll .ZA-benZothiadiaZinel l -dioxide 500.0 Starch paste 12.5%. cc., allow 12.5 512.5 Starch. U.S.P. corn 25.0 Magnesium stearate 5.5 543.0
The thiazide is granulated with the starch paste and while moist passed through a No. 14 screen, dried at 45 C. for 20 hours and then passed 3 times through a No. 14 screen. The starch is passed through a No. 90 bolting cloth onto the granulation and all ingredients are blended thoroughly. The magnesium stearate then is passed through a No. 90 bolting cloth onto the granulation and all ingredients are blended after which the granulation is compressed into tablets using 14/32 in. flat, bevelled, scored punch having a thickness of 0.205 t 0.005 in. yielding 1,000 tablets, each weighing 0.543
gram.
The following methods were employed to prepare the products of Structure I.
EXAMPLE 1 6-Chloro-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel l -dioxide Step A Preparation of 6-Chloro-7-mercaptol ,2,4-benzothiadiazine'l ,1-
dioxide A solution of stannous chloride dihydrate (180.5 g., 0.80 mole) in concentrated hydrochloric acid ml.) is added to a stirred solution of 6-chloro-7- chlorosulfonyl-l ,2,4-benzothiadiazine-1 l -dioxide (50.4 g., 0.16 mole) at 75 C. and maintained at this temperature for an additional 20-30 minutes. The solution is concentrated in vacuo to one-tenth its original volume and poured into 8 liters of ice water containing concentrated hydrochloric acid (200 ml.). The solid formed is collected and added with stirring to one liter of saturated sodium bicarbonate solution. After one hour, the solution is filtered and the filtrate acidified with hydrochloric acid, the product collected on a filter, washed with water and recrystallized from ethanol providing product melting at 270272 C.
Analysis calculated for C H-,C1N.,O S. C, 33.80; H, 2.03; N. 11.26; Found: C, 34.24; H. 2.14; N. 11.26.
By replacing the stannous chloride and concentrated hydrochloric acid employed in the above example by zinc amalgam and sulfuric acid, zinc dust and sulfuric acid, or tin and concentrated hydrochloric acid the same product is obtained.
Step B Preparation of 6-Chloro-7-isopropylthiol ,2,4-benzothiadiazine-l ,1-
dioxide A suspension of 6-chloro-7-mercapto-l ,2,4- benzothiadiazine-l,l-dioxide (49.7 g., 0.02 mole), prepared as described in Step A, in dimethylformamide (300 ml.) is heated with anhydrous potassium carbonate (27.6 g., 0.02 mole) with stirring. A solution results within 30 minutes whereupon isopropyl chloride (0.022 mole) is added with stirring over a 30-minute period. The reaction mixture is heated on a steam bath for one hour, poured onto a mixture of ice (2 liters) and water (2 liters) and acidified with concentrated hydrochloric acid. The solid is collected, stirred with 5% sodium hydroxide solution 1500 ml.) at room temperature and filtered. The filtrate is acidified with concentrated hydrochloric acid and the product collected and recrystallized from a mixture of methanol and water to provide 6-chloro-7-isopropylthio-l ,2,4-benzothiadiazine-1,1-dioxide, m.p. 23l232 C.
Analysis calculated for lhHllClNgOgS- I C. 41.301H. 3.81; N. 9.64; Found: C. 41.48; H. 3.88; N. 9.65.
Step C Preparation of 6-chloro-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel l -dioxide A solution of potassium premanganate (0.003 mole) in water ml.) is added dropwise to a solution of 6- chloro-7-isopropylthio-l ,2,4'benzothiadiazine-l ,1- dioxide (0.002 mole) in acetic acid (30 ml.) and water (10 ml.). The mixture is stirred at 30 C. for 1 hour, treated with sodium bisulfite and diluted with water. The product, following recrystallization from acetone, melts at 280282 C.
Analysis calculated for CWH CIN OS C, 37.21; H. 3.44; N 8.68; Found: C. 37.37; H, 3.14 N 8.73.
Following the procedure of Example 1, Step B, but replacing the isopropyl chloride by an equivalent quantity of benzyl chloride, n-propyl chloride and lethylpropyl chloride, respectively, followed by oxidation by the process described in Step C of Example 1, there is obtained, sequentially:
EXAMPLE 2 Step B Process 6-Chloro-7-benzylthio-l ,2,4-benzothiadiazine-l ,1- dioxide, m.p. 26827l C.
Analysis calculated for C H CIMO S C. 49.62; H, 3.27; N, 8.27;
Found: C, 50.14; H, 3.43; N, 8.24.
6 Step C Process 6-Chloro-7-benzylsulfonyl-l ,2,4-benzothiadia2inel,l-dioxide, m.p. 287-290 C.
Analysis calculated for C H CIN O S C, 45.34; H, 2.99; Found: C, 45.25; H, 3.07;
EXAMPLE 3 Step B Process 6-Chloro-7-n-pr0pylthio-l ,2,4-benzothiadiazinel l dioxide, m.p. l93-l94 C.
Analysis calculated for C,..H ClN:O- S- C. 41.30111. 3.8] N 9 Found: C, 41.55; H. 3.87; N. 9.
Step C Process 6-Chloro-7-n-propylsulfonyl-l ,2,4-benzothiadiazine- 1,1-dioxide, m.p. 246-248 C.
Analysis calculated for C mH ClN o S C, 37.21; H. 3.44; N. 8 Found: C, 37.35; H, 3.40; N, 8
Analysis calculated for C,-;H,,-,ClN- O S C. 45.20: H, 4.74; N, 8.79; Found: C, 45.32; H, 4.54; N. 8.83.
Step C Process 6-Chloro-7-( l-ethylpropylsulfonyl)-l ,2,4- benzothiadiazine-l,l-dioxide, m.p. 263-265 C.
EXAMPLE 5 6-Trifluoromethyl-7-isopropylsulfonyl-1,2,4- benzothiadiazinel l -dioxide Step A Preparation of 6-Trifluoromethyl-7-chlorosulfonyl-l ,2,4- benzothiadiazinel l -dioxide 6-Trifluoromethyl-7-sulfamoyl-1 ,2,4-benzothiadiazine-1,1-dioxide (0.2 mole) is added portionwise with irring to chlorosulfonic acid (300 ml.) cooled in an e-bath over 30 minutes. The mixture is then heated r two hours on the steam bath, cooled and poured no a mixture of ice and water. The solid product is llected on the filter, washed with cold water and air- 'ied at room temperature and recrystallized from acene-hexane.
Step B Preparation of 6-Trifluoromethyl-7-isopropylsulfonyl-l ,2,4- benzothiadiazine-l l -dioxide 6-Trifluoromethyl-7-mercapto-l ,2,4-benzothiadiane-l ,l-dioxide is prepared by reducing ifluoromethyl-7-chlorosulf0nyl-l ,2,4-benzothiadiane-l,l-dioxide with stannous chloride dihydrate by bstantially the same procedure described in Example Step A, employing equivalent quantities of all reacnts and reagents. Alkylation of this product by reac- Jn with isopropyl chloride as described in Example 1, ep B, to give the 7-isopropylthio derivative followed I oxidation with potassium permanganate by the pro- :dure of Step C of Example 1 provides 6- ifluoromethyl-7-isopropylsulfonyll ,2,4- :nzothiadiazine-l .l-dioxide.
Example 6 -Methyl-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel 1 -dioxide By replacing the 6-triflu0romethyl-7-sulfamoyl- 2,4-benzothiadiazinel l dioxide employed in Step A 'Example 5 by an equivalent quantity of 6-methyl-7- lfamoyl-l,2,4-benzothiadiazine-l,1-dioxide and then llowing substantially the same procedure described in eps A and B of Example 5, there is obtained 6- ethyl-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel-dioxide.
The products identified in Table I are prepared by e process of Example 1 employing equivalent quantias of the 7-mercapto-benzothiadiazine, B, an alkylatg agent, R-chloride (R being the radical identified in e table) in the process of Step B followed by oxidam as described in Step C:
EXAMPLE l0 3-(4-Pyridyl)-6-chloro-7-isopropylsulfonyll ,2,4- benzothiadiazinel l -dioxide Step A Preparation of 2-sulfamoyl-4-isopropylthio-5-chloroaniline 6-Chloro-7-isopropylthiol ,2,4-benzothiadiazinel,l-dioxide'(0.03 mole), prepared as described in Ex-.
ample 1, Step B, is dissolved in 10% aqueous sodium hydroxide ml.) and heated on the steam bath for one hour. The solution is chilled, acidified with hydrochloric acid and the product upon recrystallization from a mixture of ethanol and water melts at l37-l 38 Analysis calculated for c HmclNgo-gsgi C. 38.50; H, 4.66; N. 9.98; Found: C. 38.71: H. 4.60; N. 9.81.
Step B Preparation of 3-(4-Pyridyl)-6-chloro-7-isopropylthio-1,2,4- benzothiadiazinel l -dioxide An intimate mixture of the orthanilamide derivative prepared as described in Step A (0.01 mole) and 4- pyridine carboxylic acid (0.01 mole) is heated with 20 ml. of phosphorus oxychloride for l5 minutes at 50 C. and 45 minutes on the steam bath. The solution is cooled, poured onto ice and the product heated on the steam bath with ethanol (50 ml.) and concentrated ammonia hydroxide (50 ml.) for two hours. After concentration in vacuo, the residue is treated with 50 ml. of water acidified with hydrochloric acid yielding 3-(4- pyridyl )-6-chloro-7-isopropylthio-l ,2,4-benzothiadiazine-1,1-dioxide which following recrystallization from a mixture of dimethylformamide and water, melts at 254256 C.
lrExt 1, Step C *U R0 5 ENH TABLE I x K X RC1 Ex. 1 a 3 ENH Step B RS Ex. No. X R
7 CE; Cl' 2);!"' 8 CH CH.1(CH 9 CH3 (C2H3)2 CH"' Analysis calculated for c H ClN o S C, 48.97; H, 3.84; N, 11.42; Found: C, 49.14; H. 3.82; N, 1142.
Step C 9 v 10 Preparation of chloro-7-methylthio-l ,2,4-benzothiadiazine-l ,1- 3-(4-Pyridy1)-6-chloro-7-isopropylsulfonyl-l .2,4- dioxide. This compound then is converted to the corre benzothiadiazine-1,l-dioxide sponding orthanilamide by the process of Example 10,
Oxidation of the 6 Step A, the orthanilamide reacted with 4-pyridine carisopropylthio-l,2,4-ber1zothiadiazine-l ,l-dioxide by 5 boxyhcacld by the pmcedur? i g m.step B of the process described in Step C of Example 1 provides Example followed by Oxldatlon accordmg to the the 7 isopropylsulfonyl derivative, o o method described in Example 1, Step C, to provide 3- 4-pyridyl )-6-chloro-7-methylsulfonyl-l ,2,4-
benzothiadiazine-l ,l-dioxide, m.p. '346347 C.
Analysis calculated for C -H CIN QS- 10 C. 45.05; H. 3.53, N. 10.51; Found: C 45.20; H N 1039' Analysis calculated for C HmCIN O S c.41.99;11.2.71;1-1. 11.30; 7 Found: C. 4l.9l', H, 2.73; N. 11.24. EXAMPLE H Th d 'd 'f' d T bl ll d b h 15 epro uctslentiie 1n a e aremae yte $553 7 a a z i fg process described in Example 10, Steps A-C, except enzo lazme' e that the benzothiadiazine in Step A and the 4-pyridine By replacing the isopropyl chloride employed in Excarboxylic acid employed in Step B are replaced by the ample I, Step B, by an equivalent quantity of methyl reactants identified in the table. The X, R and R iodide and following substantially the same procedure 20 groups in the reactants are retained unchanged in the described in Step B of Example 1, there is obtained 6- end product, I:
i TABLE II Ex- R -COOH Ex- RS ,NH Step A RS 50 N31 Step B X fi-R X R Ex. 10 U T R0 5 51m tep C RS 11111 I :1. Ex. No. 3 5 n 12 Cl. i-propyl 1.3 C]. n-propyl 14 C1. n-propyl 15 C1 n-propyl 16 Cl n-propy].
17 c1 n-propyl 18 C1 n-propy].
19 CF i-propyl 20 -CH i-propyl 21 -CF n-propy1 22 -CH 1 n-propyl I 23 -61 i-propyl N 1 ["8 24 -cr i-pmpyl EXAMPLE 25 3-Methyl-6-chloro-7-isopropylsulfonyl-l ,2,4-
benzothiadiazine-l 1 -dioxide A mixture of 2-sulfamoyl-4-isopropylthio-5- 5 hloroaniline (0.02 mole), (prepared as described in vxample 10, Step A) and acetyl chloride (0.022 mole) idioxane (75 ml.) is heated under reflux for 24 hours. he solution is concentrated to dryness in vacuo and 1e residue dissolved in 75 ml. of ethanol and treated ith 75 ml. of concentrated ammonium hydroxide in ie cold. Thereafter the solution is heated under reflux )r three hours and concentrated to dryness in vacuo roviding enzothiadiazine-l,l-dioxide. Oxidation of this comsund by the process described in Step C of Example gives 3-methyl-6-chloro-7-isopropylsulfonyl-l ,2,4-' :nzothiadiazine-l,l-dioxide, m.p. 282-283 C.
3-methyl-6-chloro-7-isopropylthio-l ,2,4- l 5 This product, also prepared by the process described in Example except methyl oxalyl chloride and methanol are employed in place of acetyl chloride and dioxane,and trimethylamine is used instead of ammonium hydroxide, melts at 262264 C.
Analysis calculated for C H mClN- O.;S
C, 37.84; H, 3.43; N. 7.36; Found: C. 38.07; H. 3.65; N. 7.43.
The products identified in Table III are prepared following substantially the same procedure described in Example 25 but replacing the orthanilamide derivative, the acid chloride, and ammonium hydroxide by the reactants and reagents identified in the following table:
w c1 NH 1 c1 \l-R R -COC1 base RS SO NH Examp e 5 R0 5 iNH 28 i-propyl C H CH NH OH 29 n-propyl C H O C- (CH N 31 i-propyl ca rmoc- CH NH 32 n-propyl HO(CH HNOC- NR (CH 0H plu dioxane Ex. No. R R base Analysis Calculated for cuHmclNgoqs-gi 28 I CIH CH NH OH I 5 8-32; 29 5.212%] c- .'Ho2cciinun Fmmd- Q 3o Lpropyl (CHuhNOC- tcunt 3 l i-propyl CHttHNOC-- CHHNHQ 32 n-propyl H0(CH2)2HNOC NHACHMOH EXAMPLE 26 di it. Ethoxycarbonyl--chloro-7-isopropylsulfonyl-l ,2,4-
benzothiadiazinel l -dioxide EXAMPLE 33 ["his product, prepared by replacing the acetyl chloe and the ammonium hydroxide employed in Exam- 2 25 by equivalent quantities of ethyl oxalyl chloride 55 Analysis calculated for CmH CIN-Q S C. 39.54; H. 3.83; N. 7.10; Found: C. 39.71; H, 3.78; N. 7.3
EXAMPLE 27 3-Methoxycarbonyl-6-chlor0-7-isopropylsulfonyll ,2,4-benzothiadiazine-1,l-dioxide 3-Carbamoyl-6-chloro-7-n-propylsulfonyll ,2,4- benzothiadiazinel l -dioxide A mixture of 2-sulfamoyl-4-n-propylthio-S- chloroaniline 0.02 mole), [made by the procedure described in Example 1. Step B, using n-propyl chloride instead of isopropyl chloride followed by treatment with sodium hydroxide by the method described in Example 10, Step A] and ethyl oxalyl chloride (0.022 mole) in dioxane (40 ml.) is heated under reflux for 18 hours and then concentrated to dryness in vacuo. The residue is dissolved in a mixture of ethanol (30 ml.) and concentrated ammonium hydroxide (30 ml.) and stirred at room temperature for 2-3 days. The solution is concentrated to dryness in vacuo and the residue stirred in sodium bicarbonate solution and filtered. The filtrate is acidified and the product recrystallized from dimethylformamide-water providing 3-carbamoyl-6- chloro-7-n-propylthio-l ,2,4-benzothiadiazine-l .1- dioxide. Oxidation of this compound by the process described in Example 1. Step C, gives 3-carbamoyl-6- chloro-7-n-propylsulfonyl-l ,2,4-benzothiadiazine-l .1- dioxide, m.p. 29930l C.
Analysis calculated for C H N.=O -,S.
N. Found: C. 36.29; H. 3.52; N.
EXAMPLE 34 3-Carbamoyl-6-chloro-7-isopropylsulfonyl-1 ,2,4- benzothiadiazine-l l -dioxide By replacing the orthanilamide employed in Example 33 by an equivalent quantity of 2-sulfamoyl-4-isopropylthio-S-chloroaniline and following substantially the same procedure described in Example 33, there is obtained 3-carbamoyl-6-chloro-7-isopropylsulfonyll,2.4-benzothiadiazine-l,l-dioxide. m.p. 228230 C.
Analysis calculated for C,,H,. .ClN;.O -,S. C. 36.1]; H. 3.31; N. 11.49; Found: C. 36.04: H. 3.43; N. 11.27.
EXAMPLE 35 3-Carbamoyl-6-chloro-7-( l-ethylpropylsulfonyl)- 1 ,2,4-benzothiadiazine-l .l-dioxide Analysis calculated for C|.tHu=ClN=.O,-,S C. 39.64. H. 4.09; N. 10.67; Found: C. 39.83; H. 4.00; N. 10.69.
EXAMPLE 36 3-Chloromethyl-6-chloro-7-isopropylsulfonyl-l ,2,4- benzothiadiazine l l -dioxide Step A Preparation of 3-chloromethyl-6-chloro-7-isopropylthio-l ,2,4- benzothiadiaZine-l l -dioxide A mixture of 2-sulfamoyl-4-isopropylthio-5- chloroaniline (0.02 mole) and chloroacetyl chloride (0.022 mole) in dioxane (75 ml.) is heated under reflux for 24 hours. The solution then is concentrated to dryness in vacuo, the residue dissolved in ethanol ml.) and heated under reflux with potassium acetate (0.022 mole) and water 10 ml.) for two hours. The alcohol is removed in vacuo and the solution then acidified with hydrochloric acid. The precipitated product is recrystallized from a mixture of methanol and water to provide 3-chloromethyl-6-chloro-7-isopropylthio-l ,2,4- benzothiadiazine-l .l-dioxide, m.p. 248250 C.
Analysis calculated for c HmclgNgogsgi C. 38.94; H. 3.57: N. 8.26. Found: C. 39.16; H. 3.65; N. 8.28.
Step B Preparation of 3-Chloromethyl-6-chloro-7-isopropylsulfonyll ,2,4- benzothiadiazine- 1 l -dioxide Oxidation of the 7-isopropylthio compound of Step A by the process described in Example I, Step C, gives 3-chloromethyl-o-chloro-7isopropylsulfonyll ,2,4- benzothiadiazine-l,l-dioxide, m.p. 284287 C.
Analysis calculated for c H Cl N o S z C. 35.58; H. 3.26; N. 7.55: Found: C. 35.95; H. 3.20; N. 7.59.
EXAMPLE 37 3-Chloromethyl-6-chloro-7-n-propylsulfonyl-l ,2,4- benzothiadiazine-l l -dioxide This product, prepared following substantially the same procedure described in Example 36 with the exception that an equivalent quantity of 2-sulfamoyl-4-npropylthio-S-chloroaniline is employed in place of the aniline reactant used in Example 36, melts at 268-269 C.
Analysis calculated for C H 2Cl-3NgO Sg:
C. 35.58; H. 3.26; N. 7.55; Found: C. 35.34; H. 3.33; N. 7.69.
EXAMPLE 38 3-Dichloromethyl-6-chloro-7-isopropylsulfonyl-1 ,2,4- benzothiadiazine-l 1 -dioxide Step A Preparation of 3-Dichloromethyl-6-chloro-7-isopropylthio-1.2.4- benzothiadiazine-l l-dioxide By replacing the acid chloride employed in Example 36 by an equimolecular quantity of dichloroacetyl chloride and following substantially the same procedure described in Example 36, Step A. there is obtained 3-dich1oromethyl-6-chloro-7-isopropylthiol,2,4-benzothiadiazine-l.l-dioxide. m.p. 287-289 C.
Analysis calculated for C H Cl N O sz C. 35.35; H, 2.97; N. 7.50; Found: C. 35.41; H. 3.11; N. 7.54.
Step B Preparation of -Dichloromethyl-6-chloro-7-isopropylsulfonyl-l ,2,4- benzothiadiazine- 1 1 -dioxide Oxidation of the 7-isopropyl compound of Step A by e process described in Example 1, Step C, gives 3- chloromethyl-6-chloro-7-isopropylsulfonyll ,2,4-
enzothiadiazine-l ,l-dioxide, m.p. 287290 C.
Analysis calculated for C HH||CI;|N3O.|SQZ
C. 32.56; H, 2.73; N, 6.91;
Found: C, 32.96; H. 2.99; N. 6.97.
EXAMPLE 39 i-Dichloromethyl-6-chloro-7-n-propylsulfonyl-1,2,4- benzothiadiazinel l-dioxide Analysis calculated for C ,,H,,C|,,N. 0,s,;
C, 32.56; H, 2.73; N, 6.91;
Found: C. 32.63; H. 2.87; N. 6.90.
EXAMPLE 4O -Trichloromethyl-6-chloro-7-isopropylsulfonyl-1 ,2,4- benzothiadiazine-l l -dioxide By replacing the acid chloride employed in Example 3 by an equivalent quantity of trichloroacetyl chloride ld following substantially the same procedure deribed in Step A of Example 36 followed by the oxida- )n procedure described in Step C of Example I, there obtained 3-trichloromethyl-6-chloro-7- apropylsulfonyl-l ,2,4-benzothiadiazine-l l -dioxide, .p. 298300 C.
Analysis calculated for C,,HmCl. N O.S::
C, 30.01; H, 2.29; N, 6.36; Found: C, 30.25; H. 2.40; N. 6.46.
EXAMPLE 41 3-Trichloromethyl-6-chloro-7-n-propylsulfonyl-l ,2,4-
benzothiadiazine-l 1 -dioxide By replacing the orthanilamide and the acid chloride employed in Example 36, Step A, by equivalent quantities of 2-sulfamoyl-4-n-propylthio-S-chloroaniline and trichloroacetyl chloride, respectively, and then following substantially the same procedure described in Example 36, Step A, followed by the oxidation procedure described in Example 1, Step C, there is obtained 3- trichloromethyl-6-chloro-7-n-propylsulfonyl-1,2,4- benzothiadiaZine-l,ldioxide, m.p. 304-305 C.
Analysis calculated for C HmCl N O.S::
C, 30.01; H, 2.29; N. 6.36; Found; C. 30.32; H. 2.41; N. 6.71.
EXAMPLE 42 3-Carboxy-6-chloro-7-isopropylsulfonyl-l ,2,4- benzothiadiazinel l -dioxide.H O
A mixture of 2-sulfamoyl-4-isopropylthio-S- chloroaniline (0.02 mole) and ethyl oxalyl chloride (0.022 mole) in dioxane (40 ml.) is heated under reflux for 18 hours and then concentrated to dryness in vacuo. The residue is dissolved in 25% trimethylamine (40 ml.) and stirred at ambient temperature for about 3 days. The solution is concentrated to dryness in vacuo and the residue dissolved in sodium bicarbonate solution, filtered and the filtrate acidified to precipitate 3-carboxy-6-chloro-7-isopropylthio-l ,2,4- benzothiadiazineJ,l-dioxide. Treatment of this compound with potassium permanganate by the process described in Example 1, Step C, gives 3-carboxy-6- chloro-7-isopropylsulfonyl-l ,2,4-benzothiadiazinel ,l
dioxidel-l O, m.p. 28l283 C.
Analysis calculated for CnHlzt lNgOyS-zl C, 34.33; H. 3.40; N, 7.28; Found: C, 34.62; H. 3.45; N, 7.27.
Representative 7-alkylsulfonylbenzothiadiazines were found to be effective when tested by an art recognized procedure designed to evaluate xanthine oxidase inhibiting properties of compounds. The procedure used employed the principals described in J. Pharm. Sci. 56:955 (1967), Baker et al, and was carried out in the following manner:
A reference cuvette is filled with 0.05M pH 7.4 buffer. For the control, mix quickly in a cuvette 2 ml. hy-
' AA control AA test AA control X where AA is the change in absorbance in one minute. If the inhibition is I percent. the test solution is serially diluted to determine the concentration required for 50 percent inhibition.
The percent inhibition effected by certain representative products employed in the method of this invention is provided in the following table. The concentration of the test compound was 2 X ""M unless otherwise noted. For comparison 3.2 X 10"M of allopurinol, a known xanthine oxidase inhibiting agent, effects 50 percent inhibition of xanthine oxidase by this protocol.
TABLE IV T R0 5 5m 5 g3; Inhibition (C 11 CH H 22 (I iC H N 5].
ic n CH 78 iC H -CO C H 4 0 16 8 "CO CH 4 9 nC H -OONH 5 9 3 7 2 Q ic n -cotm 8 iC H -CH C1. 6 p
M2 11 -CB Cl 77 iC2 H -CHC1 43 110 11 --t2HCLI. 5
1.6 8., -CCl 3 4 9 :LC H -OO H 24 TABLE IV (continued) c1 NTRI R0 5 ENH Concentration of test compound:
2 x 10' 2 x 10 2 x 10' I claim:
1. A method which comprises orally administering to a mammal having an elevated blood uric acid level a dose sufficient to lower the blood uric acid level to normal for that species a 3'R"6-X-7-ROgS-1,2,4- benzothiadiazine-l ,l-dioxide or a pharmacologically acceptable salt thereof wherein X represents C alkyl, chloro and trifluoromethyl; R represents hydrogen. lower alkyl, halo-lower alkyl. phenyl-lower alkyl, carboxy, CO lower alkyl and -CONH- and R represents lower alkyl and phenyl lower alkyl.
2. A method of claim 1 wherein X is trifluoromethyl.
3. A method of claim 1 wherein X is chloro.
4. A method as claimed in claim 1 wherein in the active agent X is chloro, and R is lower alkyl.
5. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R is methyl.
6. A method as claimed in claim 1 wherein in the active agent X is chloro and R is -CO lower alkyl.
7. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R is ethoxycarbonyl.
8. A method as claimed in claim 1 wherein in the active agent X is chloro, and R is CONRR.
9. A method as claimed in claim 1 wherein in the active agent X is chloro, and R is carbamoyl.
10. A method as claimed in claim 1 wherein in the active agent X is chloro, R is l-ethylpropyl and R is carbamoyl.
l l. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R is carbamoyl.
12. A method as claimed in claim 1 wherein in the active agent X is chloro, R is n-propyl and R is carbamoyl.
tive agent X is chloro, and R is halo-lower alkyl.
14. A method as claimed in claim 1 wherein in the active agent X is chloro and R is chloromethyl.
15. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R is chloromethyl.
16. A method as claimed in claim 1 wherein in the active agent X is chloro, R is n-propyl and R is chloromethyl.
13. A method as claimed in claim 1 wherein in the ac-
Claims (16)
1. A METHOD WHICH COMPRISES ORALLY ADMINISTERING TO A MAMMAL HAVING AN ELEVATED BLOOD URIC ACID LEVEL A DOSE SUFFICIENT TO LOWER THE BLOOD URIC ACID LEVEL TO NORMAL FOR THAT SPECIES A 3-R1-6-X-7-RO2S-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE OR A PHARMACOLOGICALLY ACCEPTABLE SALT THEREOF WHEREIN X REPRESENTS C1-C3 ALKYL, CHLORO AND TRIFLUOROMETHYL, R1 REPRESENTS HYDROGEN, LOWER ALKYL, HALO-LOWER ALKYL, PHENYL-LOWER ALKYL, CARBOXY, -CO2 LOWER ALKYL AND -CONH2, AND R REPRESENTS LOWER ALKYL AND PHENYL LOWER ALKYL.
2. A method of claim 1 wherein X is trifluoromethyl.
3. A method of claim 1 wherein X is chloro.
4. A method as claimed in claim 1 wherein in the active agent X is chloro, and R1 is lower alkyl.
5. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R1 is methyl.
6. A method as claimed in claim 1 wherein in the active agent X is chloro and R1 is -CO2lower alkyl.
7. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R1 is ethoxycarbonyl.
8. A method as claimed in claim 1 wheRein in the active agent X is chloro, and R1 is -CONR3R4.
9. A method as claimed in claim 1 wherein in the active agent X is chloro, and R1 is carbamoyl.
10. A method as claimed in claim 1 wherein in the active agent X is chloro, R is 1-ethylpropyl and R1 is carbamoyl.
11. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R1 is carbamoyl.
12. A method as claimed in claim 1 wherein in the active agent X is chloro, R is n-propyl and R1 is carbamoyl.
13. A method as claimed in claim 1 wherein in the active agent X is chloro, and R1 is halo-lower alkyl.
14. A method as claimed in claim 1 wherein in the active agent X is chloro and R1 is chloromethyl.
15. A method as claimed in claim 1 wherein in the active agent X is chloro, R is isopropyl and R1 is chloromethyl.
16. A method as claimed in claim 1 wherein in the active agent X is chloro, R is n-propyl and R1 is chloromethyl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US456947A US3892858A (en) | 1972-06-22 | 1974-04-01 | Method for lowering uric acid levels using 7-alkylsufonyl substituted benzothiadiazine-1,1-dioxides |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US00265132A US3816625A (en) | 1972-06-22 | 1972-06-22 | Method for lowering uric acid levels using 7-alkyl-sulfonyl substituted benzothiadiazine-1,1-dioxides |
US456947A US3892858A (en) | 1972-06-22 | 1974-04-01 | Method for lowering uric acid levels using 7-alkylsufonyl substituted benzothiadiazine-1,1-dioxides |
Publications (1)
Publication Number | Publication Date |
---|---|
US3892858A true US3892858A (en) | 1975-07-01 |
Family
ID=26951000
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US456947A Expired - Lifetime US3892858A (en) | 1972-06-22 | 1974-04-01 | Method for lowering uric acid levels using 7-alkylsufonyl substituted benzothiadiazine-1,1-dioxides |
Country Status (1)
Country | Link |
---|---|
US (1) | US3892858A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6191136B1 (en) | 1997-11-07 | 2001-02-20 | Johns Hopkins University | Methods for treatment of disorders of cardiac contractility |
US20050107365A1 (en) * | 2001-01-02 | 2005-05-19 | Becker Cyrus K. | Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists |
-
1974
- 1974-04-01 US US456947A patent/US3892858A/en not_active Expired - Lifetime
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6191136B1 (en) | 1997-11-07 | 2001-02-20 | Johns Hopkins University | Methods for treatment of disorders of cardiac contractility |
US6569862B1 (en) | 1997-11-07 | 2003-05-27 | Johns Hopkins University | Methods for treatment of disorders of cardiac contractility |
US20030186998A1 (en) * | 1997-11-07 | 2003-10-02 | John Hopkins University | Methods for treatment of disorders of cardiac contractility |
US20050107365A1 (en) * | 2001-01-02 | 2005-05-19 | Becker Cyrus K. | Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists |
US7091200B2 (en) * | 2001-01-02 | 2006-08-15 | Syntex U.S.A. Llc | Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0163324B1 (en) | Aminoalkylphenoxy derivatives | |
US3669968A (en) | Trialkoxy quinazolines | |
EP0288973B1 (en) | Benzothiazolinone derivatives, their production and pharmaceutical composition | |
JPS62161763A (en) | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro- naphthylidine or - quinoline-3-carboxylic acids or salts and manufacture | |
US3419575A (en) | Novel 2-amino-5-aminoalkyl-thiadiazoles | |
US4021556A (en) | Xanthine oxidase inhibitors | |
JPS59155381A (en) | Benzoquinolizinecarboxylic acid derivative and its preparation | |
SE431985B (en) | ANALOGY PROCEDURE FOR PREPARATION OF IMIDAZO / 1,2-A / QUINOLINES | |
US3892858A (en) | Method for lowering uric acid levels using 7-alkylsufonyl substituted benzothiadiazine-1,1-dioxides | |
US3459756A (en) | N-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl-4-chloro-benzoic acid amide | |
US3960854A (en) | 7-Mercapto(or thio)-benzothiadiazine products | |
US3111517A (en) | Derivatives of 3, 4-dihydrobenzo-thiadiazine dioxides | |
CA2049490A1 (en) | Pyrrolobenzimidazoles, imidazobenzoxazinones and imidazoquinolones, process for their preparation and their use and preparations containing the compounds | |
US3969518A (en) | Inhibiting xanthine oxidase with 3-haloalkyl substituted benzothiadiazine-1,1-dioxides | |
US3816625A (en) | Method for lowering uric acid levels using 7-alkyl-sulfonyl substituted benzothiadiazine-1,1-dioxides | |
US4029780A (en) | 3-Piperazinyl 1,2,4-benzothiadiazine 1,1-dioxide derivatives their compositions and method of use | |
US3951967A (en) | 7-Mercapto(or thio)-benzothiadiazine products | |
SE434944B (en) | 5- (chlorophenyl) -6H-1,3,4-thiadiazine-2-AMINES | |
US3551483A (en) | 2,4-disulfonyl halide substituted acylanilides | |
US3892738A (en) | 7-Thiasubstituted-1,2,4-benzothiadiazine-1,1-dioxides and their salts | |
US3816631A (en) | 6-sulfamoyl-7-substituted-4(3h)-quinazolinones for decreasing uric acid concentration | |
US3816626A (en) | 3-pyridyl-1,2,4-benzothiadiazine-1,1-dioxide for lowering uric acid levels | |
US5446152A (en) | Heterocyclic compounds active in gastro-intestinal pathologies | |
CZ278281B6 (en) | ENOL ETHER OF 1,1-DIOXIDE OF 6-CHLORO-4-HYDROXY-2-METHYL-N- (2-PYRIDYL-2H-THIENO(2,3-c)-1,2-THIAZINECARBOXYLIC ACID AMIDE, PROCESS OF ITS PREPARATION AND ITS USE | |
US4344946A (en) | 2,6-Diamino-benzo[1,2-d:5,4-d']bisthiazoles and salts thereof |