US3133918A - Derivatives of - Google Patents
Derivatives of Download PDFInfo
- Publication number
- US3133918A US3133918A US3133918DA US3133918A US 3133918 A US3133918 A US 3133918A US 3133918D A US3133918D A US 3133918DA US 3133918 A US3133918 A US 3133918A
- Authority
- US
- United States
- Prior art keywords
- cyclo
- lower alkyl
- dihydro
- benzothiadiazine
- sulfamyl
- 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
- -1 aliphatic hydrocarbon radicals Chemical class 0.000 description 320
- 125000000217 alkyl group Chemical group 0.000 description 126
- 150000001875 compounds Chemical class 0.000 description 106
- 125000004432 carbon atoms Chemical group C* 0.000 description 94
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- 150000003254 radicals Chemical class 0.000 description 52
- 125000001424 substituent group Chemical group 0.000 description 50
- 239000002253 acid Substances 0.000 description 40
- 239000011780 sodium chloride Substances 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- 125000002837 carbocyclic group Chemical group 0.000 description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 34
- 229910052736 halogen Inorganic materials 0.000 description 32
- 150000002367 halogens Chemical class 0.000 description 32
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 30
- 239000000460 chlorine Substances 0.000 description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
- 229910052801 chlorine Inorganic materials 0.000 description 28
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 26
- 125000000753 cycloalkyl group Chemical group 0.000 description 26
- 150000003839 salts Chemical class 0.000 description 26
- 150000001299 aldehydes Chemical class 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 125000003545 alkoxy group Chemical group 0.000 description 22
- 125000003282 alkyl amino group Chemical group 0.000 description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 22
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 22
- 239000011737 fluorine Substances 0.000 description 22
- 229910052731 fluorine Inorganic materials 0.000 description 22
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 229910052760 oxygen Inorganic materials 0.000 description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 20
- 125000002950 monocyclic group Chemical group 0.000 description 18
- 239000001301 oxygen Substances 0.000 description 18
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
- IKHGUXGNUITLKF-UHFFFAOYSA-N acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 16
- 230000001396 anti-anti-diuretic Effects 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- 230000000875 corresponding Effects 0.000 description 16
- 230000001882 diuretic Effects 0.000 description 16
- 230000000894 saliuretic Effects 0.000 description 16
- 125000001302 tertiary amino group Chemical group 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 229910052783 alkali metal Inorganic materials 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 14
- 125000004414 alkyl thio group Chemical group 0.000 description 14
- 125000004429 atoms Chemical group 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 14
- 229910052717 sulfur Inorganic materials 0.000 description 14
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 12
- BUDQDWGNQVEFAC-UHFFFAOYSA-N 3,4-dihydro-2H-pyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 12
- 150000007513 acids Chemical class 0.000 description 12
- 125000005530 alkylenedioxy group Chemical group 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- BVJSHQWNXSXIBK-UHFFFAOYSA-N di(ethyl)azanide Chemical group [CH2]C[N-]C[CH2+] BVJSHQWNXSXIBK-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 description 12
- 239000011707 mineral Substances 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 12
- 239000011593 sulfur Substances 0.000 description 12
- 150000001241 acetals Chemical class 0.000 description 10
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 150000001735 carboxylic acids Chemical class 0.000 description 10
- 229930016911 cinnamic acid Natural products 0.000 description 10
- 235000013985 cinnamic acid Nutrition 0.000 description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 125000004434 sulfur atoms Chemical group 0.000 description 10
- 206010020679 Hypernatraemia Diseases 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 230000003276 anti-hypertensive Effects 0.000 description 8
- 125000002527 bicyclic carbocyclic group Chemical class 0.000 description 8
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 8
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 239000002934 diuretic Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- 239000002841 Lewis acid Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 150000001559 benzoic acids Chemical class 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 150000001925 cycloalkenes Chemical class 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 6
- 239000001530 fumaric acid Substances 0.000 description 6
- 150000007517 lewis acids Chemical class 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- OKXYPUDKVYVJDI-UHFFFAOYSA-N 3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical group C1=CC=C2S(=O)(=O)NCNC2=C1 OKXYPUDKVYVJDI-UHFFFAOYSA-N 0.000 description 4
- AQLGQCKMZPKPBC-UHFFFAOYSA-N 4-methyl-3,4-dihydro-2H-pyran Chemical compound CC1CCOC=C1 AQLGQCKMZPKPBC-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N Boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- JZUFKLXOESDKRF-UHFFFAOYSA-N Dichlothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N Hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 210000003734 Kidney Anatomy 0.000 description 4
- 239000005956 Metaldehyde Substances 0.000 description 4
- 229960004011 Methenamine Drugs 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N Pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 4
- 229940080360 Rauwolfia Alkaloids Drugs 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- 150000004653 carbonic acids Chemical class 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229940083184 centrally acting antiadrenergic Rauwolfia alkaloids Drugs 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- DWYUSIUKGQJEFM-UHFFFAOYSA-N ethoxy hydrogen carbonate Chemical compound CCOOC(O)=O DWYUSIUKGQJEFM-UHFFFAOYSA-N 0.000 description 4
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 4
- 239000004312 hexamethylene tetramine Substances 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 230000001631 hypertensive Effects 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
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 4
- QGCCYBZITYJPJV-UHFFFAOYSA-N methoxy hydrogen carbonate Chemical compound COOC(O)=O QGCCYBZITYJPJV-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 230000001452 natriuretic Effects 0.000 description 4
- 239000002833 natriuretic agent Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000004430 oxygen atoms Chemical group O* 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- HZBCXYOPFGAGJK-UHFFFAOYSA-N phenylmethoxy hydrogen carbonate Chemical compound OC(=O)OOCC1=CC=CC=C1 HZBCXYOPFGAGJK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 159000000001 potassium salts Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- KZDFOVZPOBSHDH-UHFFFAOYSA-N 1,1-diethoxy-2-methylpropane Chemical compound CCOC(C(C)C)OCC KZDFOVZPOBSHDH-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-Dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 2
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- YROIEQHEBPTQKR-UHFFFAOYSA-N 2H-1,2,4-thiadiazine Chemical compound N1SC=CN=C1 YROIEQHEBPTQKR-UHFFFAOYSA-N 0.000 description 2
- ATVJJNGVPSKBGO-UHFFFAOYSA-N 3,4-dihydro-2H-thiopyran Chemical compound C1CSC=CC1 ATVJJNGVPSKBGO-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- BOZSDDFQWJUBNG-UHFFFAOYSA-N 4-aminobenzene-1,3-disulfonamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1S(N)(=O)=O BOZSDDFQWJUBNG-UHFFFAOYSA-N 0.000 description 2
- FWGYRFWKBWPRJD-UHFFFAOYSA-N 4-methyl-2,3-dihydrofuran Chemical compound CC1=COCC1 FWGYRFWKBWPRJD-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- XCHCHGNNHHKGLR-UHFFFAOYSA-N 4H-1,2,4-thiadiazine 1,1-dioxide Chemical group O=S1(=O)NC=NC=C1 XCHCHGNNHHKGLR-UHFFFAOYSA-N 0.000 description 2
- MONCCXUVJLSBQI-UHFFFAOYSA-N 6-ethoxy-3,4-dihydro-2H-pyran Chemical compound CCOC1=CCCCO1 MONCCXUVJLSBQI-UHFFFAOYSA-N 0.000 description 2
- CZBAXSUIRDPNFU-UHFFFAOYSA-N 6-methyl-3,4-dihydro-2H-pyran Chemical compound CC1=CCCCO1 CZBAXSUIRDPNFU-UHFFFAOYSA-N 0.000 description 2
- XSFLOMZKRJOXDO-UHFFFAOYSA-N 6-phenyl-3,4-dihydro-2H-pyran Chemical compound C1CCOC(C=2C=CC=CC=2)=C1 XSFLOMZKRJOXDO-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- JAQGUQBUUALVON-UHFFFAOYSA-N C1(=CC=CC=C1)CCC1NS(C2=C(N1)C=C(C(=C2)S(N)(=O)=O)Cl)(=O)=O Chemical compound C1(=CC=CC=C1)CCC1NS(C2=C(N1)C=C(C(=C2)S(N)(=O)=O)Cl)(=O)=O JAQGUQBUUALVON-UHFFFAOYSA-N 0.000 description 2
- NUIGXSVZZQCRPP-UHFFFAOYSA-N CC1CCOC(=C1)C Chemical compound CC1CCOC(=C1)C NUIGXSVZZQCRPP-UHFFFAOYSA-N 0.000 description 2
- DXXUGBPKQDTBQW-UHFFFAOYSA-L Chlorisondamine Chemical compound [Cl-].[Cl-].ClC1=C(Cl)C(Cl)=C(Cl)C2=C1C[N+](CC[N+](C)(C)C)(C)C2 DXXUGBPKQDTBQW-UHFFFAOYSA-L 0.000 description 2
- 241000416480 Cilea Species 0.000 description 2
- SCPJQKVFTFVKKV-UHFFFAOYSA-N ClC=1C(=CC2=C(NCN(S2(=O)=O)C2OC(CCC2)OCC)C1)S(N)(=O)=O Chemical compound ClC=1C(=CC2=C(NCN(S2(=O)=O)C2OC(CCC2)OCC)C1)S(N)(=O)=O SCPJQKVFTFVKKV-UHFFFAOYSA-N 0.000 description 2
- VGVPLCMVEXSUQO-UHFFFAOYSA-N ClC=1C(=CC2=C(NCN(S2(=O)=O)C2OCCC(C2)C)C1)S(N)(=O)=O Chemical compound ClC=1C(=CC2=C(NCN(S2(=O)=O)C2OCCC(C2)C)C1)S(N)(=O)=O VGVPLCMVEXSUQO-UHFFFAOYSA-N 0.000 description 2
- ISMCNVNDWFIXLM-WCGOZPBSSA-N Deserpidine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ISMCNVNDWFIXLM-WCGOZPBSSA-N 0.000 description 2
- 229960001993 Deserpidine Drugs 0.000 description 2
- CVBMAZKKCSYWQR-BPJCFPRXSA-N Deserpidine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cccc3 CVBMAZKKCSYWQR-BPJCFPRXSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N Diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- VQKLRVZQQYVIJW-UHFFFAOYSA-N Dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- 229960002474 Hydralazine Drugs 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N Pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- HYTGGNIMZXFORS-MGYKWWNKSA-N Protoveratrine A Chemical compound O1[C@@]([C@H](CC[C@]23C)OC(=O)[C@@](C)(O)CC)(O)[C@H]3[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]3[C@@]12C[C@H]1[C@H](CN2[C@@H](CC[C@H](C)C2)[C@@]2(C)O)[C@@H]2[C@@H](O)[C@H](OC(=O)[C@H](C)CC)[C@@]31O HYTGGNIMZXFORS-MGYKWWNKSA-N 0.000 description 2
- SZLZWPPUNLXJEA-FMCDHCOASA-N Rescinnamine Natural products O=C(O[C@H]1[C@@H](OC)[C@@H](C(=O)OC)[C@@H]2[C@H](C1)CN1[C@@H](c3[nH]c4c(c3CC1)ccc(OC)c4)C2)/C=C/c1cc(OC)c(OC)c(OC)c1 SZLZWPPUNLXJEA-FMCDHCOASA-N 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N Reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N Stearyl alcohol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 229950006534 Syrosingopine Drugs 0.000 description 2
- VPAYJEUHKVESSD-UHFFFAOYSA-N Trifluoroiodomethane Chemical group FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 2
- 241000489523 Veratrum Species 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229930013930 alkaloids Natural products 0.000 description 2
- 125000003302 alkenyloxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000012446 aqueous acidic reagent Substances 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000000477 aza group Chemical group 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 150000003938 benzyl alcohols Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 229940023913 cation exchange resins Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229950002565 chlorisondamine Drugs 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- FHEPZBIUHGLJMP-UHFFFAOYSA-N cyclohexene Chemical group [CH]1CCCC=C1 FHEPZBIUHGLJMP-UHFFFAOYSA-N 0.000 description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- DABYZUWMLUGAGP-UHFFFAOYSA-N cyclopentene Chemical group [CH]1CC=CC1 DABYZUWMLUGAGP-UHFFFAOYSA-N 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 2
- 229960002877 dihydralazine Drugs 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 125000000532 dioxanyl group Chemical group 0.000 description 2
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- HZNQVAOLVRFZBE-UHFFFAOYSA-N ethenylcyclohexane Chemical group C=C[C]1CCCCC1 HZNQVAOLVRFZBE-UHFFFAOYSA-N 0.000 description 2
- KONIYTHNVWYBMP-UHFFFAOYSA-N ethylcyclohexane Chemical group [CH2-]C[C+]1CCCCC1 KONIYTHNVWYBMP-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000003948 formamides Chemical class 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000003457 ganglion blocking agent Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- ISOSVXOWIXXPIQ-UHFFFAOYSA-N germine Chemical compound C1=CC=[GeH]C=C1 ISOSVXOWIXXPIQ-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000005842 heteroatoms Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000001282 iso-butane Substances 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- ZCDNRPPFBQDQHR-SSYATKPKSA-N methyl (1R,15S,17R,18R,19S,20S)-17-(4-ethoxycarbonyloxy-3,5-dimethoxybenzoyl)oxy-6,18-dimethoxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate Chemical compound C1=C(OC)C(OC(=O)OCC)=C(OC)C=C1C(=O)O[C@H]1[C@H](OC)[C@@H](C(=O)OC)[C@H]2C[C@@H]3C(NC=4C5=CC=C(OC)C=4)=C5CCN3C[C@H]2C1 ZCDNRPPFBQDQHR-SSYATKPKSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003204 osmotic Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001515 polyalkylene glycol Polymers 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- SZLZWPPUNLXJEA-QEGASFHISA-N rescinnamine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)\C=C\C1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-QEGASFHISA-N 0.000 description 2
- 229960001965 rescinnamine Drugs 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- ODGCEQLVLXJUCC-UHFFFAOYSA-O tetrafluoroboric acid Chemical compound [H+].F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-O 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229940057613 veratrum Drugs 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
- C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
- C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention concerns 2-substituted-3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxides. More particularly, it relates to compounds of the formula (S32 HzNOgS CHE-R1 R3 N/ 1 RBI] in which R represents hydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon, carbocyclic aryl, carbocyclic aryl-lower aliphatic hydrocarbon, heterocyclic aryl or heterocyclic aryl-lower aliphatic hydrocarbon, R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members and advantageously have from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members, R represents hydrogen or lower alkyl, and R stands for halogen, lower alkyl or halogenolower alkyl or salts thereof, as well as process for the
- R may also stand for aliphatic hydrocarbon radicals, for example, lower aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl and the like, lower alkenyl, e.g. vinyl, l-propenyl, allyl and the like, lower alkynyl, e.g.
- lower alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl and the like
- lower alkenyl e.g. vinyl, l-propenyl, allyl and the like
- lower alkynyl
- carbocyclic aliphatic hydrocarbons particularly monocyclic carbocyclic aliphatic hydrocarbons, which contain from three to seven carbon atoms, as ring members and in which the carbocyclic portion may be saturated or may contain from one to two double bonds depending on the number of ring carbon atoms, such as cycloalkyl, which contains from five to six ring carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, or cycloalkenyl, which contains from five to six carbon atoms as ring members, e.g.
- carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon primarily monocyclic carbocyclic aliphatic hydrocarbon-lower alkyl, which contains from three to seven carbon atoms as ring members and in which the carbocyclic portion may be saturated or contain from one to two double bonds depending on the number of ring carbon atoms, and in which lower alkyl represents a lower alkylene radical containing from one to seven, particularly from one to three, carbon atoms, such as cycloalkyl-lower alkyl radicals, which contain from five to six carbon atoms as ring members, e.g.
- cyclopentylmethyl l-cyclopentylethyl, 2 cyclopentylethyl, 1 cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl, 1 cyclohexylethyl, 2 cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals, when con- 3,133,918 Patented May 19, 1964 ice tain from five to six ring carbon atoms, e.g.
- These aliphatic hydrocarbon radicals may contain functional groups as additional substituents.
- substituents are primarily attached to lower alkyl radicals, which may be represented by a lower alkylene radical containing from one to live carbon atoms, such as, for example, methylene, 1,1-ethylene, 1,2-ethylene, l,1-dimethyl-1,2- ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3- propylene, 2,2propylene, 1,1-butylene, 1,2-butylene, 1,3- butylene, 1,4-butylene, 2,2-butylene, 2,3-butylene, 1,5- pentylene, 2,5-pentylene and the like.
- substituents are, for example, one or more than one halogen atom, e.g. fluorine, bromine, or particularly chlorine; halogeno-substituted lower alkyl radicals, representing R are, for example, trifluorornethyl, chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like.
- halogen atom e.g. fluorine, bromine, or particularly chlorine
- halogeno-substituted lower alkyl radicals, representing R are, for example, trifluorornethyl, chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like.
- substituents are amino groups, such as primary amino groups, secondary amino groups, such as N-lower alkyl-amino, e.g. N-methylamino, N-ethylamino and the like, N-carbocyclic arylamino, e.g. N-phenylamino and the like, or N-carbocyclic aryl-lower alkyl-amino, e.g. N-benzylamino and the like, or primarily tertiary amino groups, particularly N,N-di-lower alkylamino, in which lower alkyl contains from one to seven carbon atoms, e.g.
- l-piperazino 4-methyl 1 piperazino, 4 hydroxyethyl-lpiperazino, 4-acetoxyethyl-l-piperazino and the like.
- the teritary amino group and the lower alkyl radical to which the amino group is attached may present together a heterocyclic radical, in which the tertiary amino group is part of the heterocycle and one of the carbon atoms of the heterocyclic ring is connected directly or through a lower alkylene radical, e.g. methylene or 1,2-ethylene, with the 3-position of the 1,2,4-thiadiazine 1,1- dioxide portion.
- Such radicals are, for example, 1-methyl-3-pyrrolidinomethyl, l-methyl 3 piperidinomethyl, 2-(l-methyl-2- piperidino)-ethyl, 1-methyl-4-piperidino and the like.
- radicals are also N-acylamino groups, in which acyl represents the acyl radical of an organic carboxylic acid, for example, a substituted carbonic acid, e.g. methoxy-carbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, a lower aliphatic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, methylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g.
- carbocyclic aryl-carboxylic acids particularly monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, particularly monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g.
- phenylacetic, diphenylacetic, dihydrocinnamic acid and the like which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid or substituted cinnamic acids; substituents attached to these carboxylic acids are, for example, lower alkyl, e.g., methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g.
- N,N-di-lower alkyl-amino e.g. N,N-dimethylamino, N, N-diethylamino and the like
- halogen e.g. fluorine, chlorine, bromine and the like
- halogeno-lower alkyl e.g. trifiuoromethyl.
- Acyl groups are additional substituents of aliphatic hydrocarbon, particularly lower alkyl radicals, primarily acyl radicals of organic carboxylic acids, such as lower alkanoic acid, e.g. acetic, propionic, butyric acid and the like, as well as substituted carbonic acids, e.g. methoxycarbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, lower alkenoic acids, e.g. acrylic, methacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g.
- carbocyclic aryl-carboxylic acids primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g.
- phenylacetic, dihydrocinnamic acid and the like which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnamic acids.
- Additional substituents of these carboxylic acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkylamino, e.g.
- halogen e.g. fluorine, chlorine, bromine and the like, or halogenolower alkyl, e.g. trifiuoromethyl.
- substituents attached to aliphatic hydrocarbon are hydroxyl groups.
- Esterified hydroxyl groups may also be suitable as substituents, especially hydroxyl groups esterified by organic carboxylic acids, for example, substituted carbonic acids, e.g. methoxy-carbonic, ethoxy-carbonic, benzyloxy-carbonic and the like, lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, methylaerylic acid and the like, lower aliphatic dicarboxylic acids, e.g.
- carbocyclic aryl-carboxylic acids primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g.
- phenylacetic, dihydrocinnamic acid and the like which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnarnic acids.
- Substituents of such carboxylic acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g.
- methylenedioxy nitro, amino, particularly tertiary amino, such as di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl.
- di-lower alkyl-amino e.g. N,N-dimethylamino, N,N-diethylamino and the like
- halogen e.g. fluorine, chlorine, bromine and the like
- halogeno-lower alkyl e.g. trifluoromethyl.
- aliphatic hydrocarbon radicals particularly lower alkyl radicals
- etherified hydroxyl groups which may be represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethox n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyioxy and the like, carbocyclic aryloxy, such as monocyclic carbocylic aryloxy, e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclic aryloxy, e.g.
- carbocyclic aryl-aliphatic hydrocarbonoxy such as monocyclic carbocyclic aryl-lower alkoxy, e.g. benzyloxy or substituted benzyloxy.
- the aliphatic hydrocarbon, and particularly the carbocyclic aryl portions of the etherified hydroxyl groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g.
- N,N-di-lower alkyl-amino e.g. N,N-dimethylamino, N,N- diethylamino and the like
- halogen e.g. fluorine, chlorine, bromine and the like
- halogeno-lower alkyl e.g. trlfluoromethyl.
- aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted by an etherified mercapto group, for example, aliphatic hydrocarbon-mercapto, such as lower alkyl-mercapto, e.g. methyl-mercapto, ethyl-mercapto, n-propyl-mercapto, isopropylmercapto, n-butyl-mercapto, isobutyl-mercapto and the like, lower alkenyl-mercapto, e.g. vinyl-mercapto, allylmercapto and the like, carbocyclic aryl-mercapto, such as monocyclic carbocyclic aryl-mercapto, e.g.
- phenylmercapto or substituted phenyl-mercapto or bicyclic carbocyclic aryl-mercapto, e.g. l-naphthyl-mercapto or Z-naphthyl-mercapto or substituted naphthyl-mercapto, or carbocyclic aryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclic aryl-lower alkyl-mercapto, e.g.
- the aliphatic hydrocarbon portions and, particularly, the carbocyclic aryl portions of the etherified mercapto groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g.
- methylenedioxy nitro, amino, such as primary or secondary amines, or, particularly, tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl.
- amino such as primary or secondary amines, or, particularly, tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl.
- R may represent carbocyclic aryl groups, such as monocycle carbocyclic aryl, e.g. phenyl or substituted phenyl, or monocyclic carbocyclic aryl, e.g. l-naplithyl or Z-naphthyl or substituted naphthyl radicals, or carbocyclic arylaliphatic hydrocarbon radicals, particularly monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g.
- substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like,
- lower alkoxy e.g. methoxy, ethoxy and the like
- lower alkylenedioxy e.g. methylenedioxy
- lower alkyl mercapto e.g. methylmercapto and the like
- amino, particularly tertiary amino such as N,N-di-lower alkyl-amino, e.g. dimethylamino and the like
- halogen e.g. fluorine, chlorine, bromine and the like
- halogeno-lower alkyl e.g. trifluoromethyl.
- Substituents attached to carbocyclic aryl, particularly monocyclic carbocyclic aryl portions may be in any of the available positions, whereby one or more than one of the same or of diiferent substituents may be present.
- Additional groups representing R are heterocyclic aryl radicals, particularly monocyclic or bicyclic heterocyclic aryl radicals, which may contain from five to six atoms as ring members in the heterocyclic portion, such as pyridyl, e.g. Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, thienyl, e.g. 2-thienyl and the like, furyl, e.g. 2-furyl and the like, or quinolyl, e.g. 6-quinolyl and the like, or heterocyclic aryl-aliphatic hydrocarbon, such as monocyclic heterocyclic-aryl-lower alkyl, for example, thenyl, e.g.
- radicals may contain additional substituents, particularly lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, or halogen, e.g. fluorine, chlorine, bromine and the like.
- substituents particularly lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, or halogen, e.g. fluorine, chlorine, bromine and the like.
- the radical R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members. These groups have advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members.
- the carbon atoms of the lower cycloalkyl nucleus may be unsubstituted or substituted by lower hydrocarbon, particularly lower alkyl, e.g. ethyl, n-propyl, isopropyl, or especially methyl and the like; other substituents may be, for example, lower cycloalkyl, e.g. cyclopentyl or cyclohexyl and the like, monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl, monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g.
- Two of the carbon atoms of the lower cycloalkyl nucleus may also be part of a second carbocyclic ring system fused onto the lower cycloalkyl nucleus; such carbocyclic ring systems may be represented, for example, by lower cycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl, cyclohexyl or cycloheptyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl.
- the cycloalkyl radical, R may, therefore, be represented primarily by cyclo-oxa-alkyl containing from four to six carbon atoms, such at tetrahydrofuranyl (cyclooxapentyl) radicals, such as Z-tetrahydrofuranyl (2-cyclooxapent-yl) radicals, e.g.
- tetrahydropyranyl (cyclo-oxahexyl) radicals, such as Z-tetrahydropyranyl (Z-cyclo-oxahexyl) radicals, e.g.
- dioxanyl cyclo-dioxahexyl radicals
- 2-( 1,4-dioxanyl) (2-cyclo-dioxahexyl) radicals e.g. 2- (l,4-dioxanyl) (2-cyclo-l,4-dioxahexyl) and the like
- tetrahydro-oxathiinyl cyclo-oxathiahexyl radicals, such as 2 tetrahydro oxathiinyl (2-cyclo-1,4-oxathiahexyl) radicals, e.g.
- Z-tetrahydro-oxathiinyl (2-cyclo-l,4-oxathiahexyl) and the like
- tetrahydrothienyl (cyclo-thiapentyl) radicals such as Z-tetrahydrothienyl (Z-cyclothiapentyl) radicals, e.g. Z-tetrahydrothienyl and the like
- tetrahydro-thiapyranyl (cyclo-thiahexyl) radicals such as 2tetrahydro-thiapyranyl (2 cyclo thiahexyl) radicals, e.g. Z-tetrahydro-thiapyranyl (Z-cyclo-thiahexyl) and the like
- tetrahydro-dithiinyl (cyclo-dithiahexyl) radicals such as Z-tetrahydro-dithiinyl (2-cyclo-1,4-dithiahexyl) radicals, e.g. Z-tetrahydro-dithiinyl (2-cyclo-l,4-dithiahexyl) and the like.
- the radical R attached to the second, aniline-type amino group of the 1,2,4-thiadiazine portion of the compounds of this invention represents primarily hydrogen, but may also stand for lower alkyl, e.g. methyl, ethyl and the like.
- the group R attached to the 6-position of the 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide stands for halogen, e.g. fluorine, bromine, or particularly chlorine and the like, lower alkyl, e.g. methyl and the like, or halogeno-lower alkyl, particularly trifluoromethyl and the like.
- Salts of the compounds of this invention are primarily those with metals, particularly alkali metals, e.g. sodium, potassium and the like; monoor poly-salts may be formed.
- the compounds of the present invention have diuretic and saliuretic, particularly natriuretic properties and are intended to be used as diuretic or saliuretic, particularly natriuretic agents having improved and outstanding properties to relieve conditions of excessive water and salt retention, for example, caused by kidney or heart ailments. Coupled with the diuretic and saliuretic activities of the present compounds is a strong antihypertensive effect, which renders the compounds especially useful as antihypertensive medicaments in hypertensive conditions, which are coupled with water and salt retention, such as, for example, in heart ailments. Particularly outstanding diuretic and saliuretic effects are shown by compounds of the formula in which R represents hydrogen, lower alkyl, e.g.
- R represents cyclo-oxa-alkyl (particularly, 2-cyclo-oxa-alkyl) containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members, R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl, and sodium or potassium salts thereof.
- halogen e.g. fluorine, bromine, or particularly chlorine
- halogeno-lower alkyl e.g. trifluoromethyl, and sodium or potassium salts thereof.
- This group of compounds may be represented by the compounds of the formulae s 2 mNo s R G H- (halogeno-lower alkyl) ⁇ N (/11- (phenyl-lower alkyl) in which compounds R stands for chlorine or trifluoromethyl, and lower alkyl contains from one to four carbon atoms, and R is defined as above.
- Particularly active compounds are, for example,
- each of which is substituted in the 3-position by a lower cyclo-alkyl group containing oxygen and/ or sulfur atoms as ring members and advantageously having from four to six carbon atoms and at most two hetero (S or O) ring members.
- the new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new 2-substituted-3,4-dihydro-2H-l,2, 4-benzothiadiazine-l,l-dioxide compounds or the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration.
- the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments.
- the pharmaceutical preparations may be in solid form, for example, as capsules, tablets or dragees, or in liquid form, for example, as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.
- antihypertensive compounds such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Veratrum alkaloids, e.g. germine, protoveratrine and the like, synthetic antihypertensive compounds, e.g. hydralazine, dihydralazine and the like, or ganglionic blockers, e.g. chlorisondamine and the like.
- antihypertensive compounds such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Veratrum alkaloids, e.g. germine, protoveratrine and the like, synthetic antihypertensive compounds, e
- the compounds of the present invention may be prepared according to methods which are known in themselves.
- compounds of the formula z// in which R R R R and R have the previously-given meaning may be prepared, for example, by treating a 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide of the in which R R and R have the previously-given meaning, or an alkali metal salt thereof, with a cycloalkene containing oxygen and/ or sulfur atoms as ring members, which is capable of introducing the radical R in the presence of a condensing agent, and isolating the desired product, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a free compound into a salt thereof.
- the above-mentioned lower cycloalkene reagents are more particularly Z-cycloalkenes containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members.
- Such compounds are, for example, 2-cyclo-oxaalkenes containing from four to six carbon atoms as ring members, such as dihydrofurans (Z-cyclo-oxapentenes), e.g.
- dihydrofuran Z-cyclo-oxapentene
- 4-methyl-dihydrofuran (4-methyl-2-cyclo-oxapentene)
- S-methyl-dihydrofuran (5-methyl-2cyclo-oxapentene) and the like
- dihydropyrans (2-cyclo-oxahexenes), e.g.
- dihydrodioxines (2-cyclo-dioxahexenes), such as dihydro-1,4- dioxines (2-cyclo-l,4-dioxahexenes), e.g. dihydro-1,4-dioxine (Z-cyclo-1,4-dioxahexene) and the like
- dihydrooxathiins (2-cyclo-oxathiahexenes), such as dihydro-l,4- oxathiins (2-cyclo-1,4-oxathiahexenes), e.g.
- dihydro-1,4- dioxathiin Z-cyclo-l,4-oxathiahexene
- dihydrothiophenes Z-cyClo-thiapentene
- dihydrothiophene (2-cyclo-thiapentene) and the like
- dihydrothiapyrans (2-cyclo-thiahexenes), e.g.
- reagents particularly the 2-cyclo-oxa-alkenes containing from four to six carbon atoms as ring members, such as dihydropyrans, e.g. dihydropyran, are reacted with the deserpidate compound in the presence of a condensing reagent, particularly an acidic condensing reagent represented by a Lewis acid.
- a condensing reagent particularly an acidic condensing reagent represented by a Lewis acid.
- Lewis acids are, for example, mineral acids, e.g.
- hydrochloric, hydrobromic or sulfuric acid used in anhydrous form or as concentrated aqueous solutions
- phosphoric acid for example, in the form of polyphosphoric acid
- phosphorous oxychloride for example, in the form of polyphosphoric acid
- fluoboric acid in the form of a highly concentrated aqueous solution
- borontrifluoride in the form of its etherate, particularly with diethyl ether
- carbocyclic aryl sulfonic acid such as a monocyclic carbocylic acid, especially p-toluene sulfonic acid, or similar reagents having Lewis acid properties, such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resins.
- the reaction may be carried out in the absence of a solvent, whereby an excess of a liquid cycloalkene may serve as the solvent, or in the presence of an inert solvent.
- solvents are, for example, carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene or toluene and the like, others, e.g. diethylether or tetrahydrofuran and the like, lower alkanoncs, e.g. acetone or ethyl methyl ketone and the like, formamides, e.g. formamide or N,N-dimethylformamide and the like.
- the desired product is isolated from the reaction mixture according to usual methods; ordinarily, a resulting precipitate, if necessary after concentration of the reaction mixture, is filtered off and is purified by recrystallization.
- the 3,4-dihydro-2H-1,4-benzothiadiazine-1,l-dioxides used as the starting materials are known or may be prepared according to procedures used for the known analogs.
- an aniline compound of the formula in which R and R have the previously-given meaning is reacted with an aldehyde of the formula R CHO, in which R has the previously-given meaning, or a reactive derivative thereof, to form the desired 3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide, which may then be condensed with the desired cyclo-oxa-alkene or cyclo-azaalkene to yield the R-R '-substituted product, R having the previously-given meaning.
- the disulfamyhaniline compound is preferably treated with approximately an equivalent amount of the aldehyde, particularly when formaldehyde or a reactive derivative, e.g. a polymer thereof is used, an excess of an aldehyde other than formaldehyde or a derivative thereof may be present.
- the reaction may advantageously be carried out in the presence of a small amount of an acid, for example, a mineral acid, e.g. hydrochloric, hydrobrornic acid, sulfuric acid and the like, if desired, in anhydrous form.
- An acid is necessary, if the aldehyde is present in the form of a reactive derivative, such as a polymer or an acetal, thereof.
- aldehyde may also be performed in the absence of a condensing reagent, or in the presence of a base, such as an alkali metal hydroxide, e.g lithium, sodium or potassium hydroxide, whereby the aldehyde is used in its reactive form.
- a base such as an alkali metal hydroxide, e.g lithium, sodium or potassium hydroxide
- the aldehyde may also be given into the reaction medium in a form which yields the desired reactant in situ.
- an acetal of an aldehyde R CHO with lower alkanols may be used in the presence of a mineral acid; such acetals are, for example, 1,1-dimethoxyethane, 1,l-dimethoxy-isobutane, 1,1-diethoxy-isobutane, 2,2-dichloro-1,l-dimethoxyethane, 2,2-dichlorol,l-diethoxy-ethane and the like.
- Formaldehyde may also be employed in the form of a polymer, such as, for example, paraformaldehyde and the like or another formaldehyde furnishing reagent, e.g. hexamethylenetetramine and the like; acetaldehyde may be present in the form of a polymeric substance yielding acetaldehyde under the condition of the reaction, e.g. metaldehyde and the like.
- the reaction is preferably carried out in the presence of a solvent, for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.g. methanol, ethanol and the like, a formamide, e.g. dirnethylformamide and the like, or an aqueous mixture of such solvents or water.
- a solvent for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.g. methanol, ethanol and the like, a formamide, e.g. dirnethylformamide and the like, or an aqueous mixture of such solvents or water.
- a solvent for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.
- the 5-R -2,4-disulfamyl-anilines, used as the intermediates in the above reaction are known or, if new, may be prepared according to known procedures.
- the compounds of the present invention may also be prepared by reacting a 2,4-disulfamyl-aniline of the formula in which R R and R have the previously-given meaning, with an aldehyde of the formula R CHO, in which R has the above-given meaning, or a reactive derivative thereof, and, if desired, carrying out the optional steps.
- the above reaction may be performed according to the previously-described method for the preparation of 2-unsubstituted 3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxides used as the starting materials in the first modifimtion of the process of this invention.
- the two reactants may be heated in a solution using one of the previously-described diluents, if desired, in the pres ence of a base as a condensing reagent.
- the aldehyde may also be used in the form of an appropriate reactive derivative.
- the 2 (N-R '-sulfamyl) 4 sulfamyl-5-R -N-R analine compounds used as the starting materials, are new and are intended to be included within the scope of the invention.
- the compounds of the formula in which R R and R have the previously-given meaning may be obtained by reacting an aniline-2,4-disulfonyl halide of the formula in which R and R have the previously-given meaning, and Hal stands for halogen, particularly chlorine, with approximately two molar equivalents of an amine of the formula R '--NH in which R has the above-given meaning, and reacting the resulting compound of the formula in which R R R and Hal have the previously-given meaning, with ammonia.
- the first step in the above procedure may be carried out in a solvent; halogenated alkanes, particularly chloroform, methylene chloride and the like, or lower alkanones, e.g. acetone and the like, may be used as diluents.
- Amines of the formula R -NH are those in which the term R has the meaning given above.
- the resulting 2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound may be separated from any 2,4-di-(N- R '-sulfamyl)-aniline formed in the reaction, for example, on the basis of their different solubilities in a given solvent, e.g. the diluent used in the reaction.
- the 2,4-bis-(N-R '-sulfamyl)-aniline compound may precipitate from the reaction mixture and be removed by filtration, whereas the desired 2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound may be recovered from the filtrate.
- the resulting 2-(N-R '-sulfamyl)aniline-4-sulfonyl halide derivative is then reacted with ammonia.
- Liquid ammonia may be used and may simultaneously serve as a diluent, or the compound may be dissolved in an organic solvent, e.g. acetone and the like, or less favorably, in water, and be treated with concentrated aqueous ammonia, to give the desired 2-(N-R -sulfamyl)-4-sulfamylaniline compound.
- R R R and R have the previously-given meaning, and R stands for aliphatic hydrocarbon, substituted aliphatic hydrocarbon or carbocyclic aryl-lower aliphatic hydrocarbon, or metal, particularly alkali metal, salts thereof.
- the compounds of the above-given formula have diuretic and saliuretic, particularly natriuretic properties and are intended to be used as diuretic or saliuretic, particularly natriuretic agents having improved and outstanding properties to relieve conditions of excessive water and salt retention, for example, those connected with kidney or heart ailments. Coupled with the diuretic and saliuretic activities of these compounds is a strong antihypertensive effect, which renders the compounds especially useful as antihypertensive medicaments in hypertensive conditions, which are coupled with water and salt retention, such as, for example, in heart ailments. Particularly outstanding diuretic and saliuretic effects are shown by compounds of the formula in which R represents hydrogen, lower alkyl, e.g.
- R stands for lower cycloalkyl containing oxygen and/ or sulfur atoms as ring members and advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members and R stands for lower alkyl containing from one to four carbon atoms, e.g.
- allylic lower alkenyl containmg allyl, 3-methyl-allyl and the like, or phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the from three to five carbon atoms, e.g. allyl, Z-methyl- 13 like, and R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g.
- This group of compounds may be represented by the compounds of the formula aza eyeloalkyl in which formulae R represents chlorine or trifluoromethyl, lower alkyl contains from one to four and lower alkenyl from three to five carbon atoms, as well as compounds of the above formulae, which contain in the 3- position a lower alkyl radical containing from one to four carbon atoms, particularly methyl, ethyl, isobutyl and the like, halogeno-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g.
- the compounds of the above formula may be formulated into pharmaceutical compositions for enteral, e.g. oral, or parenteral application; such compositions may be prepared according to known procedures, using standard vehicles and fillers.
- the above-described compounds may be prepared, for example, by treating a compound of the formula in which R R R and R have the previously-given meaning, with a reactive ester of an alcohol of the formula R "'OH, in which R has the above-given meaning, or treating a compound of the formula in which R R R and R have the previouslygiven meaning, with an aldehyde of the formula R CHO, in which R has the above-given meaning, or a reactive derivative thereof and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a free compound into a salt thereof.
- an ester of a reactive alcohol of the formula R "OH is particularly an ester with a strong acid, particularly a mineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and the like, or an organic sulfonic acid, e.g. methane sulfonic, ethane sulfonic, Z-hydrOXy-ethane sulfonic, p-tolu- 14 ene sulfonic acid and the like; such esters are preferably reacted with a salt, particularly an alkali metal salt of the starting material.
- an aldehyde of the formula R CHO may also be used in the form of an acetal with a lower alkanol, e.g. methanol, ethanol and the like.
- a lower alkanol e.g. methanol, ethanol and the like.
- Formaldehyde or acetaldehyde may be present as a polymeric form thereof, e.g. paraformaldehyde, metaldehyde and the like; other reactive forms furnishing formaldehyde are, for example, hexamethylenetetramine and the like. Reactions with such acetals and polymeric forms of aldehydes are carried out in the presence of an acid, for example, a mineral acid, e.g. hydrochloric acid and the like.
- the reaction may be performed as previously shown; the desired product is separated from any simultaneously formed 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide containing an unsubstituted sulfamyl group in the 7-position, on the basis of differing solubilities in solvents, for example, by recrystallization and the like.
- the resulting product may be obtained in the form of the free compound or as a salt thereof.
- An alkali metal salt may be converted into the free compound by treatment with an aqueous acidic reagent, such as a mineral acid, e.g. hydrochloric, sulfuric acid and the like.
- a free compound may be converted into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent, such as in a lower alkanol, e.g. methanol, ethanol and the like, or in water and evaporating the solvent.
- Monoor poly-salts may be obtained.
- Any resulting racemate may be converted into the antipodes thereof according to methods used for resolving racemates.
- Example 1 To 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamy1-l,2,4- benzothiadiazine-l,l-dioxide in 35-40 cc. of warm acetone is added 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight, then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals are obtained, yielding, when recrystallized from acetone, 600 mg.
- Example 2 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in 40 cc. of warm acetone is treated with 0.9 g. 4-methyl-dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight and then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals of the product, 6-chloro-3,4-dihydro 7 sulfamyl 2 (4 methyl-tetrahydro-2-pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide, are obtained.
- 6-ethoxy-dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight at room temperature, the solution is concentrated to dryness in vacuo.
- Example 6 3.2 g. of 6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfarnyl-l,2,4-benzothiadiazine-l,l-dioxide in cc. of warm acetone is treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain overnight at room temperature and then concentrated to dryness in vacuo. The residue thus obtained is recrystallized from ethanol-water to produce the pure 6-chloro-3-dichloromethyl 7 sulfamyl-Z-(tetrahydro-Z-pyranyl)-l,2,4-benzothiadiazine-1,l-dioxide.
- R represents a member of the group consisting of hydrogen, lower alkyl, lower alkyl substituted by halo gen, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-rnercapto-lower alkyl, phenyl-lower alkyl-mercaptolower alkyl, lower alkenyl, cycloalkyl having from five to six ring carbon atoms and phenyl-lower alkyl, R stands for 2-cycloalkyl having four to six carbon atoms and at least one and at most two atoms of the group consisting of oxygen and sulfur as ring members, and R represents a member of the group consisting of halogen and halogen-lower alkyl, and alkali metal salts thereof.
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Description
United States Patent 015 3,1l33fi18 DERIVATEVES F 3, l-DKHYDRQ-Zfi-1,2,4-BENZO- THIADIAZINE 1,1-Dl0XlDES Harold Balding Maelhillamy, Madison, and Geargc dc Stevens, Willow Kncll, New Providence, NJ, assignors to Cilea (forporation, a corporation of Delaware No Drawing. Filed Apr. 20, 1960, Ser. No. 23,373
Claims. (Cl. 260-243) The present invention concerns 2-substituted-3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxides. More particularly, it relates to compounds of the formula (S32 HzNOgS CHE-R1 R3 N/ 1 RBI] in which R represents hydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon, carbocyclic aryl, carbocyclic aryl-lower aliphatic hydrocarbon, heterocyclic aryl or heterocyclic aryl-lower aliphatic hydrocarbon, R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members and advantageously have from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members, R represents hydrogen or lower alkyl, and R stands for halogen, lower alkyl or halogenolower alkyl or salts thereof, as well as process for the preparation of such compounds.
Apart from being hydrogen, R may also stand for aliphatic hydrocarbon radicals, for example, lower aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl and the like, lower alkenyl, e.g. vinyl, l-propenyl, allyl and the like, lower alkynyl, e.g. ethynyl and the like carbocyclic aliphatic hydrocarbons, particularly monocyclic carbocyclic aliphatic hydrocarbons, which contain from three to seven carbon atoms, as ring members and in which the carbocyclic portion may be saturated or may contain from one to two double bonds depending on the number of ring carbon atoms, such as cycloalkyl, which contains from five to six ring carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, or cycloalkenyl, which contains from five to six carbon atoms as ring members, e.g. 2 cyclopentenyl, 3 cyclopentenyl, 2 cyclohexenyl, 3- cyclohexenyl and the lke, or carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon, primarily monocyclic carbocyclic aliphatic hydrocarbon-lower alkyl, which contains from three to seven carbon atoms as ring members and in which the carbocyclic portion may be saturated or contain from one to two double bonds depending on the number of ring carbon atoms, and in which lower alkyl represents a lower alkylene radical containing from one to seven, particularly from one to three, carbon atoms, such as cycloalkyl-lower alkyl radicals, which contain from five to six carbon atoms as ring members, e.g. cyclopentylmethyl, l-cyclopentylethyl, 2 cyclopentylethyl, 1 cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl, 1 cyclohexylethyl, 2 cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals, when con- 3,133,918 Patented May 19, 1964 ice tain from five to six ring carbon atoms, e.g. 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 2 (2 cyclopentenyl) ethyl, 2 cyclohexenylmethyl, 3 cyclohexenylmethyl, 1-(3-cyclol1exenyl) ethyl, 2 (2 cyclohexenyl)- ethyl, 3-(2-cyclohexenyl)-propyl and the like.
These aliphatic hydrocarbon radicals may contain functional groups as additional substituents. Such substituents are primarily attached to lower alkyl radicals, which may be represented by a lower alkylene radical containing from one to live carbon atoms, such as, for example, methylene, 1,1-ethylene, 1,2-ethylene, l,1-dimethyl-1,2- ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3- propylene, 2,2propylene, 1,1-butylene, 1,2-butylene, 1,3- butylene, 1,4-butylene, 2,2-butylene, 2,3-butylene, 1,5- pentylene, 2,5-pentylene and the like.
substituents are, for example, one or more than one halogen atom, e.g. fluorine, bromine, or particularly chlorine; halogeno-substituted lower alkyl radicals, representing R are, for example, trifluorornethyl, chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like.
Other substituents are amino groups, such as primary amino groups, secondary amino groups, such as N-lower alkyl-amino, e.g. N-methylamino, N-ethylamino and the like, N-carbocyclic arylamino, e.g. N-phenylamino and the like, or N-carbocyclic aryl-lower alkyl-amino, e.g. N-benzylamino and the like, or primarily tertiary amino groups, particularly N,N-di-lower alkylamino, in which lower alkyl contains from one to seven carbon atoms, e.g. N,N-dimethylamino, N-ethyl-N-methyl-amino, N,N- diethylamino, N,N dipropylamino, N,N di isopropylamino, N,N-dibutylamino and the like, N-cycloalkyl-N- lower alkyl amino, e.g. N-cyclopentyl-N-methyl-amino, N-cyclohexyl-N-methyl-amino and the like, N carbocyclic aryl lower alkyl N lower alkyl amino, e.g. N- benzyl-N-rnethyl-amino, N-methy N (2 phenylethyl)- amino and the like, 1-N,N-lower alkylene-imino group, in which the lower alkylene radical contains from four to six carbon atoms, such as l-pyrrolidino, e.g. l-pyrrolidino, Z-methyl-l-pyrrolidino and the like, l-piperidino, e.g. 1 piperidino, 2 methyl 1 piperidino, 3-methyl-1- piperidino, 4 methyl 1 piperidino, 3 hydroxy 1- piperidino, 3-acetoxy 1 piperidino, 3-hydroxymethyl-1 piperidino and the like, or l-N,N-hexamethylene-imi11o, l-N,N-lower oxa-a1kylene-imino, in which oxa-alkylene contains preferably four carbon atoms, e.g. l-morpholino and the like, or l-N,N-lower aza-alkylene-imino, in which aza-alkylene contains preferably four carbon atoms, e.g. l-piperazino, 4-methyl 1 piperazino, 4 hydroxyethyl-lpiperazino, 4-acetoxyethyl-l-piperazino and the like. The teritary amino group and the lower alkyl radical to which the amino group is attached may present together a heterocyclic radical, in which the tertiary amino group is part of the heterocycle and one of the carbon atoms of the heterocyclic ring is connected directly or through a lower alkylene radical, e.g. methylene or 1,2-ethylene, with the 3-position of the 1,2,4-thiadiazine 1,1- dioxide portion. Such radicals are, for example, 1-methyl-3-pyrrolidinomethyl, l-methyl 3 piperidinomethyl, 2-(l-methyl-2- piperidino)-ethyl, 1-methyl-4-piperidino and the like.
Other substituents attached to aliphatic hydrocarbon,
particularly lower alkyl, radicals are also N-acylamino groups, in which acyl represents the acyl radical of an organic carboxylic acid, for example, a substituted carbonic acid, e.g. methoxy-carbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, a lower aliphatic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, methylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, particularly monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, particularly monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, diphenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid or substituted cinnamic acids; substituents attached to these carboxylic acids are, for example, lower alkyl, e.g., methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N, N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifiuoromethyl.
Acyl groups are additional substituents of aliphatic hydrocarbon, particularly lower alkyl radicals, primarily acyl radicals of organic carboxylic acids, such as lower alkanoic acid, e.g. acetic, propionic, butyric acid and the like, as well as substituted carbonic acids, e.g. methoxycarbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, lower alkenoic acids, e.g. acrylic, methacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnamic acids. Additional substituents of these carboxylic acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogenolower alkyl, e.g. trifiuoromethyl.
Other substituents attached to aliphatic hydrocarbon, particularly lower alkyl radicals, are hydroxyl groups. Esterified hydroxyl groups may also be suitable as substituents, especially hydroxyl groups esterified by organic carboxylic acids, for example, substituted carbonic acids, e.g. methoxy-carbonic, ethoxy-carbonic, benzyloxy-carbonic and the like, lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, methylaerylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their haltesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnarnic acids. Substituents of such carboxylic acids, are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl.
Further substituents of aliphatic hydrocarbon radicals, particularly lower alkyl radicals, are etherified hydroxyl groups, which may be represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethox n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyioxy and the like, carbocyclic aryloxy, such as monocyclic carbocylic aryloxy, e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclic aryloxy, e.g. l-naphthyloxy or Z-naphthyloxy or substituted naphthyloxy, or carbocyclic aryl-aliphatic hydrocarbonoxy, such as monocyclic carbocyclic aryl-lower alkoxy, e.g. benzyloxy or substituted benzyloxy. The aliphatic hydrocarbon, and particularly the carbocyclic aryl portions of the etherified hydroxyl groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N- diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trlfluoromethyl.
in addition, aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted by an etherified mercapto group, for example, aliphatic hydrocarbon-mercapto, such as lower alkyl-mercapto, e.g. methyl-mercapto, ethyl-mercapto, n-propyl-mercapto, isopropylmercapto, n-butyl-mercapto, isobutyl-mercapto and the like, lower alkenyl-mercapto, e.g. vinyl-mercapto, allylmercapto and the like, carbocyclic aryl-mercapto, such as monocyclic carbocyclic aryl-mercapto, e.g. phenylmercapto or substituted phenyl-mercapto, or bicyclic carbocyclic aryl-mercapto, e.g. l-naphthyl-mercapto or Z-naphthyl-mercapto or substituted naphthyl-mercapto, or carbocyclic aryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclic aryl-lower alkyl-mercapto, e.g. benzyl-mercapto, l-phenylethyl-mercapto, 2-phenylethyl-mercapto and the like, or substituted benZyl-mercapto, substituted l-phenylethyl-mercapto, substituted 2- phenylethyl-mercapto and the like. The aliphatic hydrocarbon portions and, particularly, the carbocyclic aryl portions of the etherified mercapto groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, such as primary or secondary amines, or, particularly, tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl.
Apart from aliphatic hydrocarbon radicals R may represent carbocyclic aryl groups, such as monocycle carbocyclic aryl, e.g. phenyl or substituted phenyl, or monocyclic carbocyclic aryl, e.g. l-naplithyl or Z-naphthyl or substituted naphthyl radicals, or carbocyclic arylaliphatic hydrocarbon radicals, particularly monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, lphenylethyl, Z-phenylethyl, 3-pl1enylpropyl, l-naphylmethyl and the like, or these radicals substituted in the carbocyclic aryl portion, or monocyclic or bicyclic carbocyclic aryl-lower alkenyl, e.g. 2-phenyl-ethenyl and the like, as well as such radicals containing in the carbocyclic portion additional substituents. Such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like,
lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, lower alkyl mercapto, e.g. methylmercapto and the like, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. dimethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl. Substituents attached to carbocyclic aryl, particularly monocyclic carbocyclic aryl portions may be in any of the available positions, whereby one or more than one of the same or of diiferent substituents may be present.
Additional groups representing R are heterocyclic aryl radicals, particularly monocyclic or bicyclic heterocyclic aryl radicals, which may contain from five to six atoms as ring members in the heterocyclic portion, such as pyridyl, e.g. Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, thienyl, e.g. 2-thienyl and the like, furyl, e.g. 2-furyl and the like, or quinolyl, e.g. 6-quinolyl and the like, or heterocyclic aryl-aliphatic hydrocarbon, such as monocyclic heterocyclic-aryl-lower alkyl, for example, thenyl, e.g. Z-thenyl and the like. These radicals may contain additional substituents, particularly lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, or halogen, e.g. fluorine, chlorine, bromine and the like.
The radical R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members. These groups have advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members.
The carbon atoms of the lower cycloalkyl nucleus may be unsubstituted or substituted by lower hydrocarbon, particularly lower alkyl, e.g. ethyl, n-propyl, isopropyl, or especially methyl and the like; other substituents may be, for example, lower cycloalkyl, e.g. cyclopentyl or cyclohexyl and the like, monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl, monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenylethyl or Z-phenylethyl and the like. Two of the carbon atoms of the lower cycloalkyl nucleus may also be part of a second carbocyclic ring system fused onto the lower cycloalkyl nucleus; such carbocyclic ring systems may be represented, for example, by lower cycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl, cyclohexyl or cycloheptyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl.
The cycloalkyl radical, R may, therefore, be represented primarily by cyclo-oxa-alkyl containing from four to six carbon atoms, such at tetrahydrofuranyl (cyclooxapentyl) radicals, such as Z-tetrahydrofuranyl (2-cyclooxapent-yl) radicals, e.g. 2-tetrahydrofuranyl (2-cyclo oxapentyl), 4-methyI-Z-tetrahydrofuranyl (4 methyl 2- cyclo-oxapentyl) or S-methyl-Z-tetrahydrofuranyl (5- methyl-2-cyclo-oxapentyl) and the like, tetrahydropyranyl (cyclo-oxahexyl) radicals, such as Z-tetrahydropyranyl (Z-cyclo-oxahexyl) radicals, e.g. Z-tetrahydropyranyl (2- cyclo-oxahexyl), 2-methyl-2-tetrahydropyranyl (2-methyl 2-cyclo-oxahexyl), 4 methyl 2 tetrahydropyranyl (4- methyl-Z-cyclo-oxahexyl), 6-rnethyl-2-tetrahydropyranyl (6-methyl-2-cyclo-oxahexyl), 6 phenyl 2 tetrahydro pyranyl (6 phenyl 2 cyclo oxahexyl), 2-hexahydrobenz [e] tetrahydropyranyl (bicyclo [4,4,0] -2-oxa-3-decyl or 2 benz[e]tetrahydropyranyl (2 benz[e]cyclo oxahexyl) and the like, cyclo-oxaheptyl radicals, such as 2-cyclo-oxaheptyl radicals, e.g. Z-cyclo-oxaheptyl, and the like, dioxanyl (cyclo-dioxahexyl) radicals, such as 2-( 1,4-dioxanyl) (2-cyclo-dioxahexyl) radicals, e.g. 2- (l,4-dioxanyl) (2-cyclo-l,4-dioxahexyl) and the like, tetrahydro-oxathiinyl (cyclo-oxathiahexyl) radicals, such as 2 tetrahydro oxathiinyl (2-cyclo-1,4-oxathiahexyl) radicals, e.g. Z-tetrahydro-oxathiinyl (2-cyclo-l,4-oxathiahexyl) and the like, tetrahydrothienyl (cyclo-thiapentyl) radicals, such as Z-tetrahydrothienyl (Z-cyclothiapentyl) radicals, e.g. Z-tetrahydrothienyl and the like,
tetrahydro-thiapyranyl (cyclo-thiahexyl) radicals, such as 2tetrahydro-thiapyranyl (2 cyclo thiahexyl) radicals, e.g. Z-tetrahydro-thiapyranyl (Z-cyclo-thiahexyl) and the like, or tetrahydro-dithiinyl (cyclo-dithiahexyl) radicals, such as Z-tetrahydro-dithiinyl (2-cyclo-1,4-dithiahexyl) radicals, e.g. Z-tetrahydro-dithiinyl (2-cyclo-l,4-dithiahexyl) and the like.
The radical R attached to the second, aniline-type amino group of the 1,2,4-thiadiazine portion of the compounds of this invention, represents primarily hydrogen, but may also stand for lower alkyl, e.g. methyl, ethyl and the like.
The group R attached to the 6-position of the 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, stands for halogen, e.g. fluorine, bromine, or particularly chlorine and the like, lower alkyl, e.g. methyl and the like, or halogeno-lower alkyl, particularly trifluoromethyl and the like.
Salts of the compounds of this invention are primarily those with metals, particularly alkali metals, e.g. sodium, potassium and the like; monoor poly-salts may be formed.
The compounds of the present invention have diuretic and saliuretic, particularly natriuretic properties and are intended to be used as diuretic or saliuretic, particularly natriuretic agents having improved and outstanding properties to relieve conditions of excessive water and salt retention, for example, caused by kidney or heart ailments. Coupled with the diuretic and saliuretic activities of the present compounds is a strong antihypertensive effect, which renders the compounds especially useful as antihypertensive medicaments in hypertensive conditions, which are coupled with water and salt retention, such as, for example, in heart ailments. Particularly outstanding diuretic and saliuretic effects are shown by compounds of the formula in which R represents hydrogen, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, or lower alkyl substituted by halogen, lower alkoxy, lower alkyl-mercapto, phenyl-lower alkyl-mercapto and the like, e.g. chloromethyl, dichloromethyl, ethoxymethyl, ethylmercaptoethyl, benzylmercaptoethyl and the like, lower alkenyl, e.g. l-propenyl and the like, cycloalkyl containing from five to six ring carbon atoms, e.g. cyclo pentyl and the like, or phenyl-lower alkyl, e.g. benzyl, Z-phenylethyl and the like, R represents cyclo-oxa-alkyl (particularly, 2-cyclo-oxa-alkyl) containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members, R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl, and sodium or potassium salts thereof. This group of compounds may be represented by the compounds of the formulae s 2 mNo s R G H- (halogeno-lower alkyl) \N (/11- (phenyl-lower alkyl) in which compounds R stands for chlorine or trifluoromethyl, and lower alkyl contains from one to four carbon atoms, and R is defined as above. Particularly active compounds are, for example,
6-chloro-2- (2-cyclo-oxapentyl) -3-methyl-7-sulfamyl-3 ,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-trifluoromethyl-2- (4-methyl-2-cyclo-oxapentyl -3- methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1 l-dioxide,
6-chloro-2- (Z-cyclo-oxapentyl -3-methyl-7-sulfamyl-3 ,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-trifluoromethyl-2- (4-methyl-2-cyclo-oxapentyl) -3 -methyl-7-sulfarnyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide,
6-chloro-2- 5-methyl-2-cyclo-oxapentyl) -3-isobutyl-2- methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiaZine-1,1-dioxide,
6-trifiuoromethyl-2- (2-cyclo-oxahexyl) -3-isobutyl-2- methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1 l-dioxide,
6-chloro-2- (2-methyl-Z-cyclo-oxahexyl) -3-dichloromethyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,1-dioxide,
3-dichloromethyl-6-trifluoromethyl-2- (4-methyl-2-cyclooxahexyl) -7-sulfamyl-3,4-dihydro-2H-l ,2,4-benzothiadiazine-l,1-dioxide,
3-benzyl-6-chloro-2- 6-methyl-2-cyclo-oxahexyl) -7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide,
3-benzyl-2- 6-phenyl-2-cyclo-oxahexyl) -6-trifluoromethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,
2- (bicyclo [4,4,0] -2-oxa-3-decyl) -6-chloro-7-sulfamyl-3,4-
dihydro-ZH-l,2,4-benZothiadiaZine-1,l-dioxide,
2- (Z-benz [e] -cyclo-oxahexyl -3-ethyl-6-trifluoromethyl- 7-sulfamyl-3 ,4-dihydro-2H-l,2,4-benZothiadiaZine-1,1- dioxide,
6-chloro-3-ethyl-2- (2-cyclo-oxaheptyl -7-sulfamyl-3,4-
dihydro-2H-1,2,4-benzothiadiaZine-l,l-dioxide,
6-trifiuoromethyl-2-(2-cyclo-1,4-dioxahexyl)-7-sulfamyl- 3 ,4-dihydro-2I-I-1,2,4-benzothiadiaZine-1, l-dioxide,
6-chloro-3-ethyl-2-(Z-cyclo-1,4-oxathiahexyl) -7-sulfamyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide,
6-trifluoromethyl-2- (Z-cyclo-thiapentyl) -3-isobutyl-7- sulfamyl-3,4-dihydro-2H-l,2,4-benZothiadiaZine-1,1- dioxide,
6-chloro-2- (Z-cycIo-thiahexyl) -3-ethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,
2- Z-cyclol ,4-dithiahexyl) -3-ethyl-6-trifluoromethyl-7- sulfamyl-3 ,4-dihydro-2H-l,2,4-benZothiadiazine-1,1- dioxide,
6-ehloro-2- (2-cyclo-oxapentyl) -7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide,
2- (4-methyl-2-cyclo-oxapentyl) -6-trifluoromethyl-7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide,
6-chloro-2- (2-cyclo-oxahexyl) -7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-trifluoromethyl-2- Z-cyclo-oxahexyl -7-sulfamyl-3,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-chloro-2- (2-cyclo-oxaheptyl -7-sulfamyl-3,4-dihydro- ZH-l,2,4-benzothiadiazine-1,l-dioxide,
-trifluoromethyl-Z- (Z-cyclo-oxaheptyl -7-sulfamyl-3,4-
dihydro-ZH-1,2,4-benzothiadiazi ne-1,1-dioxide,
2-(2-cyclo-1,4-dioxapentyl)-6-chloro-7-sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide,
2- (Z-cyclo-1,4-oxathiahexyl) -6-trifluoromethyl-7-sulfamyl-B'A-dihydro-ZH-l,2,4,-benzothiadiazine-l,l-dioxide and the like,
each of which is substituted in the 3-position by a lower cyclo-alkyl group containing oxygen and/ or sulfur atoms as ring members and advantageously having from four to six carbon atoms and at most two hetero (S or O) ring members.
The new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new 2-substituted-3,4-dihydro-2H-l,2, 4-benzothiadiazine-l,l-dioxide compounds or the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets or dragees, or in liquid form, for example, as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances; particularly useful are antihypertensive compounds, such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Veratrum alkaloids, e.g. germine, protoveratrine and the like, synthetic antihypertensive compounds, e.g. hydralazine, dihydralazine and the like, or ganglionic blockers, e.g. chlorisondamine and the like.
The compounds of the present invention may be prepared according to methods which are known in themselves.
Thus, compounds of the formula z// in which R R R and R have the previously-given meaning may be prepared, for example, by treating a 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide of the in which R R and R have the previously-given meaning, or an alkali metal salt thereof, with a cycloalkene containing oxygen and/ or sulfur atoms as ring members, which is capable of introducing the radical R in the presence of a condensing agent, and isolating the desired product, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a free compound into a salt thereof.
The above-mentioned lower cycloalkene reagents are more particularly Z-cycloalkenes containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members. Such compounds are, for example, 2-cyclo-oxaalkenes containing from four to six carbon atoms as ring members, such as dihydrofurans (Z-cyclo-oxapentenes), e.g. dihydrofuran (Z-cyclo-oxapentene), 4-methyl-dihydrofuran (4-methyl-2-cyclo-oxapentene), or S-methyl-dihydrofuran (5-methyl-2cyclo-oxapentene) and the like, dihydropyrans (2-cyclo-oxahexenes), e.g. dihydropyran (2-cyclo-oxahexene), Z-methyl-dihydropyran (Z-methyl- 2-cyclo oxahexene), 4-methyl-dihydropyran (4-methyl-2- cyclo-oxahexene), 6-methyl-dihydropyran (6-methyl-2- cyclo-oxahexene), 6-phenyl-dihydropyran (6 phenyl 2- cyclo-oxahexene), hexahydro-benz[eJdihydropyran (bicyclo[4,4,0]-2-oxa-3-decene) or 2-benz[e]dihydr0pyran (2-benz[e]cyclo-oxahexene) and the like, 2-cyclo-oxaheptenes, e.g. 2-cyclo-oxaheptene and the like, dihydrodioxines (2-cyclo-dioxahexenes), such as dihydro-1,4- dioxines (2-cyclo-l,4-dioxahexenes), e.g. dihydro-1,4-dioxine (Z-cyclo-1,4-dioxahexene) and the like, dihydrooxathiins (2-cyclo-oxathiahexenes), such as dihydro-l,4- oxathiins (2-cyclo-1,4-oxathiahexenes), e.g. dihydro-1,4- dioxathiin (Z-cyclo-l,4-oxathiahexene) and the like, dihydrothiophenes (Z-cyClo-thiapentene), e.g. dihydrothiophene (2-cyclo-thiapentene) and the like, dihydrothiapyrans (2-cyclo-thiahexenes), e.g. dihydrothiapyran (2- cyclo-thiahexene) and the like, or dihydro-dithiins (2- cyclo-dithiahexenes), such as dihydro-l,4-dithiins (2- cyclo-l,4-dithi&exenes), e.g. dihydro-l,4-dithiin (2-eyclo- 1,4-dithiahexene) and the like.
These reagents, particularly the 2-cyclo-oxa-alkenes containing from four to six carbon atoms as ring members, such as dihydropyrans, e.g. dihydropyran, are reacted with the deserpidate compound in the presence of a condensing reagent, particularly an acidic condensing reagent represented by a Lewis acid. Such Lewis acids are, for example, mineral acids, e.g. hydrochloric, hydrobromic or sulfuric acid (used in anhydrous form or as concentrated aqueous solutions), phosphoric acid (for example, in the form of polyphosphoric acid), phosphorous oxychloride, fluoboric acid (in the form of a highly concentrated aqueous solution), borontrifluoride (in the form of its etherate, particularly with diethyl ether), or a carbocyclic aryl sulfonic acid, such as a monocyclic carbocylic acid, especially p-toluene sulfonic acid, or similar reagents having Lewis acid properties, such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resins.
The reaction may be carried out in the absence of a solvent, whereby an excess of a liquid cycloalkene may serve as the solvent, or in the presence of an inert solvent. Such solvents are, for example, carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene or toluene and the like, others, e.g. diethylether or tetrahydrofuran and the like, lower alkanoncs, e.g. acetone or ethyl methyl ketone and the like, formamides, e.g. formamide or N,N-dimethylformamide and the like.
The desired product is isolated from the reaction mixture according to usual methods; ordinarily, a resulting precipitate, if necessary after concentration of the reaction mixture, is filtered off and is purified by recrystallization.
The 3,4-dihydro-2H-1,4-benzothiadiazine-1,l-dioxides used as the starting materials are known or may be prepared according to procedures used for the known analogs. For example, an aniline compound of the formula in which R and R have the previously-given meaning is reacted with an aldehyde of the formula R CHO, in which R has the previously-given meaning, or a reactive derivative thereof, to form the desired 3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide, which may then be condensed with the desired cyclo-oxa-alkene or cyclo-azaalkene to yield the R-R '-substituted product, R having the previously-given meaning.
Although the disulfamyhaniline compound is preferably treated with approximately an equivalent amount of the aldehyde, particularly when formaldehyde or a reactive derivative, e.g. a polymer thereof is used, an excess of an aldehyde other than formaldehyde or a derivative thereof may be present. The reaction may advantageously be carried out in the presence of a small amount of an acid, for example, a mineral acid, e.g. hydrochloric, hydrobrornic acid, sulfuric acid and the like, if desired, in anhydrous form. An acid is necessary, if the aldehyde is present in the form of a reactive derivative, such as a polymer or an acetal, thereof. It may also be performed in the absence of a condensing reagent, or in the presence of a base, such as an alkali metal hydroxide, e.g lithium, sodium or potassium hydroxide, whereby the aldehyde is used in its reactive form. As mentioned above, the aldehyde may also be given into the reaction medium in a form which yields the desired reactant in situ. Thus, f r example, an acetal of an aldehyde R CHO with lower alkanols, for example, with methanol or ethanol, may be used in the presence of a mineral acid; such acetals are, for example, 1,1-dimethoxyethane, 1,l-dimethoxy-isobutane, 1,1-diethoxy-isobutane, 2,2-dichloro-1,l-dimethoxyethane, 2,2-dichlorol,l-diethoxy-ethane and the like. Formaldehyde may also be employed in the form of a polymer, such as, for example, paraformaldehyde and the like or another formaldehyde furnishing reagent, e.g. hexamethylenetetramine and the like; acetaldehyde may be present in the form of a polymeric substance yielding acetaldehyde under the condition of the reaction, e.g. metaldehyde and the like.
The reaction is preferably carried out in the presence of a solvent, for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.g. methanol, ethanol and the like, a formamide, e.g. dirnethylformamide and the like, or an aqueous mixture of such solvents or water. If desired, it may be completed at an elevated temperature, for example, on the steam bath or at the boiling temperature of the sol vent and, if necessary, the reaction may be performed under increased pressure or in the atmosphere of an inert gas, e.g, nitrogen.
The 5-R -2,4-disulfamyl-anilines, used as the intermediates in the above reaction are known or, if new, may be prepared according to known procedures.
The compounds of the present invention may also be prepared by reacting a 2,4-disulfamyl-aniline of the formula in which R R and R have the previously-given meaning, with an aldehyde of the formula R CHO, in which R has the above-given meaning, or a reactive derivative thereof, and, if desired, carrying out the optional steps.
The above reaction may be performed according to the previously-described method for the preparation of 2-unsubstituted 3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxides used as the starting materials in the first modifimtion of the process of this invention. For example, the two reactants may be heated in a solution using one of the previously-described diluents, if desired, in the pres ence of a base as a condensing reagent. As pointed out, the aldehyde may also be used in the form of an appropriate reactive derivative.
The 2 (N-R '-sulfamyl) 4 sulfamyl-5-R -N-R analine compounds used as the starting materials, are new and are intended to be included within the scope of the invention. The compounds of the formula in which R R and R have the previously-given meaning, may be obtained by reacting an aniline-2,4-disulfonyl halide of the formula in which R and R have the previously-given meaning, and Hal stands for halogen, particularly chlorine, with approximately two molar equivalents of an amine of the formula R '--NH in which R has the above-given meaning, and reacting the resulting compound of the formula in which R R R and Hal have the previously-given meaning, with ammonia.
The first step in the above procedure may be carried out in a solvent; halogenated alkanes, particularly chloroform, methylene chloride and the like, or lower alkanones, e.g. acetone and the like, may be used as diluents. Amines of the formula R -NH are those in which the term R has the meaning given above.
The resulting 2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound may be separated from any 2,4-di-(N- R '-sulfamyl)-aniline formed in the reaction, for example, on the basis of their different solubilities in a given solvent, e.g. the diluent used in the reaction. Thus, the 2,4-bis-(N-R '-sulfamyl)-aniline compound may precipitate from the reaction mixture and be removed by filtration, whereas the desired 2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound may be recovered from the filtrate.
The resulting 2-(N-R '-sulfamyl)aniline-4-sulfonyl halide derivative is then reacted with ammonia. Liquid ammonia may be used and may simultaneously serve as a diluent, or the compound may be dissolved in an organic solvent, e.g. acetone and the like, or less favorably, in water, and be treated with concentrated aqueous ammonia, to give the desired 2-(N-R -sulfamyl)-4-sulfamylaniline compound.
It may also be possible to omit the separation of the desired 2-(N-R '-sulfamyl)-aniline-4-sulfonyl halide from any 2,4-bis-(N-R '-sulfamyl)-aniline compound simultaneously formed as a by-product; a resulting mixture may be reacted directly with ammonia directly and separation of the two products may be achieved after such treatment.
Especially useful as intermediates are the compounds of the formula R3 NH:
members, as enumerated above.
Also new and valuable as intermediates are the compounds of the formula in which R R R and Hal have the previously-given meaning, which are formed in the two-step synthesis for the preparation of the starting materials. A preferred group of such new intermediate compounds are those of the formula in which R and R have the meaning given above.
Also included within the scope of the present invention are the compounds of the formula in which R R R and R have the previously-given meaning, and R stands for aliphatic hydrocarbon, substituted aliphatic hydrocarbon or carbocyclic aryl-lower aliphatic hydrocarbon, or metal, particularly alkali metal, salts thereof.
The compounds of the above-given formula have diuretic and saliuretic, particularly natriuretic properties and are intended to be used as diuretic or saliuretic, particularly natriuretic agents having improved and outstanding properties to relieve conditions of excessive water and salt retention, for example, those connected with kidney or heart ailments. Coupled with the diuretic and saliuretic activities of these compounds is a strong antihypertensive effect, which renders the compounds especially useful as antihypertensive medicaments in hypertensive conditions, which are coupled with water and salt retention, such as, for example, in heart ailments. Particularly outstanding diuretic and saliuretic effects are shown by compounds of the formula in which R represents hydrogen, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, or lower alkyl substituted by halogen, lower alkoxy, lower alkyl-mercapto, phenyl-lower alkyl-mercapto and the like, e.g. chloromethyl, dichloromethyl, ethoxymethyl, ethylmercaptoethyl, benzylmercaptoethyl and the like, lower alkenyl, e.g. l-propenyl and the like, cycloalkyl containing from five to six carbon atoms as ring members, e.g. cyclopentyl and the like, or phenyl-lower alkyl, e.g. benzyl, 2- phenylethyl and the like, the radical R stands for lower cycloalkyl containing oxygen and/ or sulfur atoms as ring members and advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members and R stands for lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isoproyl, nbutyl, isobutyl and the like, allylic lower alkenyl containmg allyl, 3-methyl-allyl and the like, or phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the from three to five carbon atoms, e.g. allyl, Z-methyl- 13 like, and R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl, and sodium or potassium salts thereof. This group of compounds may be represented by the compounds of the formula aza eyeloalkyl in which formulae R represents chlorine or trifluoromethyl, lower alkyl contains from one to four and lower alkenyl from three to five carbon atoms, as well as compounds of the above formulae, which contain in the 3- position a lower alkyl radical containing from one to four carbon atoms, particularly methyl, ethyl, isobutyl and the like, halogeno-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. chloromethyl, dichloromethyl and the like, or phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like.
Similarly, as with the previously-described compounds containing an N-unsubstituted sulfamyl group in the 7- position, the compounds of the above formula may be formulated into pharmaceutical compositions for enteral, e.g. oral, or parenteral application; such compositions may be prepared according to known procedures, using standard vehicles and fillers.
The above-described compounds may be prepared, for example, by treating a compound of the formula in which R R R and R have the previously-given meaning, with a reactive ester of an alcohol of the formula R "'OH, in which R has the above-given meaning, or treating a compound of the formula in which R R R and R have the previouslygiven meaning, with an aldehyde of the formula R CHO, in which R has the above-given meaning, or a reactive derivative thereof and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a free compound into a salt thereof.
The above reactions are carried out according to the previously-described procedures. For example, an ester of a reactive alcohol of the formula R "OH is particularly an ester with a strong acid, particularly a mineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and the like, or an organic sulfonic acid, e.g. methane sulfonic, ethane sulfonic, Z-hydrOXy-ethane sulfonic, p-tolu- 14 ene sulfonic acid and the like; such esters are preferably reacted with a salt, particularly an alkali metal salt of the starting material. Or, an aldehyde of the formula R CHO may also be used in the form of an acetal with a lower alkanol, e.g. methanol, ethanol and the like. Formaldehyde or acetaldehyde may be present as a polymeric form thereof, e.g. paraformaldehyde, metaldehyde and the like; other reactive forms furnishing formaldehyde are, for example, hexamethylenetetramine and the like. Reactions with such acetals and polymeric forms of aldehydes are carried out in the presence of an acid, for example, a mineral acid, e.g. hydrochloric acid and the like.
Compounds of the formula in which R R R R and R have the previouslygiven meaning, and R and R stand for the identical group, may also be prepared by reacting a compound of the formula in which R R and R have the above-given meaning with an excess of a reactive ester of an alcohol of the formula R 'OH, in which R has the previously-given meaning, and isolating the desired compound, and, if desired, carrying out the optional steps.
The reaction may be performed as previously shown; the desired product is separated from any simultaneously formed 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide containing an unsubstituted sulfamyl group in the 7-position, on the basis of differing solubilities in solvents, for example, by recrystallization and the like.
The resulting product may be obtained in the form of the free compound or as a salt thereof. An alkali metal salt may be converted into the free compound by treatment with an aqueous acidic reagent, such as a mineral acid, e.g. hydrochloric, sulfuric acid and the like. A free compound may be converted into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent, such as in a lower alkanol, e.g. methanol, ethanol and the like, or in water and evaporating the solvent. Monoor poly-salts may be obtained.
Any resulting racemate may be converted into the antipodes thereof according to methods used for resolving racemates.
The following examples illustrate the invention; they are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.
Example 1 To 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamy1-l,2,4- benzothiadiazine-l,l-dioxide in 35-40 cc. of warm acetone is added 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight, then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals are obtained, yielding, when recrystallized from acetone, 600 mg. 6-chloro-3,4-dihydro- 7 sulfamyl Z-(tetrahydro-Z-pyranyl)-1,2,4-benzothiadizine-1,1-dioxide; M.P. 23 l232d.
[By substituting an equivalent amount of 6-trifluor0- methyl-3,4-dihydro 7 sulfamyl-l,2,4-be11zothiadiazine- 1,1-dioxide for the 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-l,l-dioxide and following the procedure 15 given above, the corresponding 6-trifluoromethyl compound may be obtained. Using the identical procedure and any of the other cyclooxa-alkyl or cyclo-aza-alkyl reactants named above, corresponding products may be obtained, as is evident below.]
Example 2 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in 40 cc. of warm acetone is treated with 0.9 g. 4-methyl-dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight and then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals of the product, 6-chloro-3,4-dihydro 7 sulfamyl 2 (4 methyl-tetrahydro-2-pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide, are obtained.
[By substituting an equivalent amount of 6-trifluoromethyl-3,4-dihydro 7 sulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide for the 6-chloro-3,4-dihydro-7-sultamyl-l,2,4- benzothiadiazine-1,1-dioxide and following the procedure given above, the corresponding 6-trifluoromethyl compound may be obtained] Example 3 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide in 35 cc. of warm acetone is treated with 1 g. 6-ethoxy-dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight at room temperature, the solution is concentrated to dryness in vacuo. The product, 6-chloro-3,4-dihydro- 2-(6-ethoxy-tetrahydro 2 pyranyl) 7 sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide, is collected and recrystallized from acetone.
[By substituting an equivalent amount of 6-trifiuoromethyl-3,4-dihydro 7 sulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide for the 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide and following the procedure given above, the corresponding 6-trifluoromethyl compound may be obtained] Example 4 3.2 g. of 6-chloro-3-cyclopentylmethyl-3,4-dihydro-7- sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide in 40 cc. of warm acetone is treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight. The product is then collected and recrystallized from ethanol-Water to produce the pure 6-chloro-3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl-2 (tetrahydro-2-pyranyl)- 1 ,2,4-benzothiadiazine-1,l-dioxide.
[By substituting 6-trifluoromethyl-3-cyclopentylmeth yl-3,4-dihydro 7 sulfamyl 1,2,4 benzothiadiazine-l,1- dioxide for the 6-chloro-3-cyclopentylmethyl-3,4-dihydro- 7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide reactant used in this example, the corresponding trifluoromethyl product may be obtained] Example 3.8 g. of 3-benzylmethyl-6-chloro-3,4-dihydro-7-sulfamyl-l,2,4-benzothiadiazine-l,l-dioxide is dissolved in 50 cc. of warm acetone. This is treated with 1 g. 4,6-dimethyl-dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight at room temperature, the solution is concentrated to dryness in vacuo. The residue is recrystallized from ethanol to produce the pure 3-benzylmethyl-6-chloro 3,4 dihydro-7-sulfamyl-2- (4,6-dimethyl 2 pyranyl) 1,2,4 benzothiadiazine-1,ldioxide.
[By substituting 3-benzylmethyl-6-trifiuoromethyl-3,4- dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide for the 3-benzylmethyl-6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide used in this example, the corresponding trifluoromethyl compound may be obtained.]
15 Example 6 3.2 g. of 6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfarnyl-l,2,4-benzothiadiazine-l,l-dioxide in cc. of warm acetone is treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain overnight at room temperature and then concentrated to dryness in vacuo. The residue thus obtained is recrystallized from ethanol-water to produce the pure 6-chloro-3-dichloromethyl 7 sulfamyl-Z-(tetrahydro-Z-pyranyl)-l,2,4-benzothiadiazine-1,l-dioxide.
[By substituting 6-trifluor0methy1-3-monochlorometl1 yl-3,4-dihydro 7 sulfamyl 1,2,4 benzothiadiazine-l,1- dioxide for the 6-chloro-3-dichloromethyl-3,4-dihydro-7- sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide used in this example, the corresponding 3-monochloromethyl compound may be obtained. Substitution of the 6-chloro-3- monochloromethyl (or 3-dichloromethyl) reactants for the one used in this example, will yield the corresponding trifluoromethyl derivatives] Example 7 2.75 g. of 3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl- 6-trilluoromethyl-1,2,4-benzothiadiazine-1,l-dioxide is dissolved in cc. of warm acetone and then treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight the solution is evaporated to one-half its volume, the crystals collected and recrystallized from ethanol-water to produce the pure 3-cyclopentylmethyl 3,4 dihydro-7-sulfamyl-6-trifiuoromethyl-2-(tetrahydro 2 pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide.
1 What is claimed is:
l. A member of the group consisting of 3,4-dihydro- ZH-l,2,4-benzothiadiazine-1,l-dioxides of the formula in which R represents a member of the group consisting of hydrogen, lower alkyl, lower alkyl substituted by halo gen, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-rnercapto-lower alkyl, phenyl-lower alkyl-mercaptolower alkyl, lower alkenyl, cycloalkyl having from five to six ring carbon atoms and phenyl-lower alkyl, R stands for 2-cycloalkyl having four to six carbon atoms and at least one and at most two atoms of the group consisting of oxygen and sulfur as ring members, and R represents a member of the group consisting of halogen and halogen-lower alkyl, and alkali metal salts thereof.
2. 6 chloro 2-R-7 sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine-l,l-dioxide, wherein R is 2-tetrahydro-2- pyranyl.
3. 6 chloro 2-R-7 sulfamyl-3,4-dihydro-2H-l,2,4- benzothiadiazine-1,1-dioxide, wherein R is 4-methyl-tetrahydro-Z-pyranyl.
4. 6 trifluoromethyl 2-R-7 sulfamyl-3,4-dihydro- ZH-1,2,4-benzothiadiazine-l,l-dioxide, in which R is 2- cyclo-oxaalkyl having from four to six carbon atoms.
5. -chloro-3-halogeno-lower alkyl-2-R-7-sulfamyl-3,4- dihydro-ZH-1,2,4-benzothiadiazine-l,l-dioxide, in which lower alkyl has from one to four carbon atoms and R is 2-cyclooxaalkyl having from four to six carbon atoms.
6. 6 trifiuoromethyl-3-halogeno-lower alkyl 2-R-7- sulfamyl 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide, in which lower alkyl has from one to four carbon atoms and R is 2-cyclo-oxaalkyl having from four to six carbon atoms.
7. 6-chloro-2-R-3-phenyl-lower alkyl-7-sulfamy hydro-2H-1,2,4-benzothiadiazine-l,l-dioxide, in which lower alkyl has from one to four carbon atoms and R is y -oxaalkyl having from four to six carbon atoms.
3,133,918 17 18 8. 6 trifiuoromethy1-2-R-3-phenyl-10wer alkyl 7 suI- References Cited in the file of this patent famyI-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 diOX- UNITED STATES PATENTS ide, in which lower alkyl has from one to four carbon atoms and R is zmrmhydmpyranyli 1,911,719 Schwefzer et a1 May 30, 1933 9. 6 chl0ro-2,3-bis-(tetrahydro-Z-pyranyl)-7-su1famy1- 5 g g et a 3,4- dihydro-2H-1,2,4-benzothiadiazine-1, 2809194 n i 5 10. 6 n-ifluoromethy1-2,3-bis-(tetrahydr -py y 2910475 oveno c 7 1959 7-sulfamyl 3,4 dihydm-ZH-l,2,4-benzothiadiazinel,1- Nove 2 dioxidi 2,910,4588 Novello Oct. 27, 1959
Claims (1)
1. A MEMBER OF THE GROUP CONSISTING OF 3,4-DIHYDRO2H-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDES OF THE FORMULA
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3356692A (en) * | 1963-11-30 | 1967-12-05 | Bayer Ag | Tetrahydrofuryl-benzene sulfonamides |
US3452020A (en) * | 1967-11-09 | 1969-06-24 | Wallace & Tiernan Inc | 2-alkenyl and 2-alkynyl substituted - tetrahydro - halo-sulfamyl-quinazolinones |
US3458513A (en) * | 1967-11-02 | 1969-07-29 | Wallace & Tiernan Inc | 2-substituted-tetrahydro-halosulfamyl-quinazolinones |
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US20040167123A1 (en) * | 2002-11-01 | 2004-08-26 | Pratt John K | Anti-infective agents |
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US2338106A (en) * | 1937-02-13 | 1944-01-04 | Foldi Zoltan | Process for the production of new efficacious p-amino-benzene-sulphamide derivativessuitable for injection purposes |
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US3356692A (en) * | 1963-11-30 | 1967-12-05 | Bayer Ag | Tetrahydrofuryl-benzene sulfonamides |
US3458513A (en) * | 1967-11-02 | 1969-07-29 | Wallace & Tiernan Inc | 2-substituted-tetrahydro-halosulfamyl-quinazolinones |
US3452020A (en) * | 1967-11-09 | 1969-06-24 | Wallace & Tiernan Inc | 2-alkenyl and 2-alkynyl substituted - tetrahydro - halo-sulfamyl-quinazolinones |
US3868379A (en) * | 1972-04-28 | 1975-02-25 | Warner Lambert Co | Heterocyclic amides of 4-hydroxy-2H-1-benzothiopyran-3-carboxylic acid 1,1-dioxide |
US3957769A (en) * | 1973-11-23 | 1976-05-18 | E. R. Squibb & Sons, Inc. | 1,2,4-benzothiadiazines |
US4029780A (en) * | 1974-10-29 | 1977-06-14 | Dainippon Pharmaceutical Co., Ltd. | 3-Piperazinyl 1,2,4-benzothiadiazine 1,1-dioxide derivatives their compositions and method of use |
US20040087577A1 (en) * | 2002-11-01 | 2004-05-06 | Pratt John K | Anti-infective agents |
US20040097492A1 (en) * | 2002-11-01 | 2004-05-20 | Pratt John K | Anti-infective agents |
US20040162285A1 (en) * | 2002-11-01 | 2004-08-19 | Pratt John K. | Anti-infective agents |
US20040167123A1 (en) * | 2002-11-01 | 2004-08-26 | Pratt John K | Anti-infective agents |
US7902203B2 (en) | 2002-11-01 | 2011-03-08 | Abbott Laboratories, Inc. | Anti-infective agents |
US20050075331A1 (en) * | 2003-10-06 | 2005-04-07 | Pratt John K. | Anti-infective agents |
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