US3210347A - Benzothiadiazine-1, 1-dioxides - Google Patents
Benzothiadiazine-1, 1-dioxides Download PDFInfo
- Publication number
- US3210347A US3210347A US123418A US12341861A US3210347A US 3210347 A US3210347 A US 3210347A US 123418 A US123418 A US 123418A US 12341861 A US12341861 A US 12341861A US 3210347 A US3210347 A US 3210347A
- Authority
- US
- United States
- Prior art keywords
- phenyl
- compound
- benzothiadiazine
- chloro
- formula
- 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
- UOCUSOBVEHOMMB-UHFFFAOYSA-N 2h-1$l^{6},2,3-benzothiadiazine 1,1-dioxide Chemical class C1=CC=C2S(=O)(=O)NN=CC2=C1 UOCUSOBVEHOMMB-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 28
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 2
- -1 1,1-ethylene Chemical group 0.000 description 31
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 150000002905 orthoesters Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- DAVOZYNLPXEIEH-UHFFFAOYSA-N aniline;azane Chemical compound N.NC1=CC=CC=C1 DAVOZYNLPXEIEH-UHFFFAOYSA-N 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- SZLZWPPUNLXJEA-UHFFFAOYSA-N 11,17-dimethoxy-18-[3-(3,4,5-trimethoxy-phenyl)-acryloyloxy]-yohimbane-16-carboxylic acid methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(OC)C1OC(=O)C=CC1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 239000005977 Ethylene Substances 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- ZCDNRPPFBQDQHR-SSYATKPKSA-N Syrosingopine 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 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 241000489523 Veratrum Species 0.000 description 1
- 241000339989 Wolffia Species 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 108700025616 angiotensin II amide Proteins 0.000 description 1
- JYPVVOOBQVVUQV-CGHBYZBKSA-N angiotensinamide Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(N)=O)C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 JYPVVOOBQVVUQV-CGHBYZBKSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 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 1
- 229950002565 chlorisondamine Drugs 0.000 description 1
- 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 1
- 229960001993 deserpidine Drugs 0.000 description 1
- 229960002877 dihydralazine Drugs 0.000 description 1
- VQKLRVZQQYVIJW-UHFFFAOYSA-N dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003457 ganglion blocking agent Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 1
- 229960003602 guanethidine Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 201000005857 malignant hypertension Diseases 0.000 description 1
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
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- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- SMSAPZICLFYVJS-QEGASFHISA-N rescinnamine 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)\C=C\C1=CC(OC)=C(OC)C(OC)=C1 SMSAPZICLFYVJS-QEGASFHISA-N 0.000 description 1
- 229960001965 rescinnamine Drugs 0.000 description 1
- 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 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940057613 veratrum Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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
Definitions
- n stands primarily for l, but may also represent one of the numbers 2, 3 and 4.
- the group of the formula -(C H may, therefore, represent lower alkylene having from one to four carbon atoms, primarily methylene, as well as 1,1-ethylene, 1;,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 2,3-propylene, 1,3- propylene, 1,1-butylene, 1,4-butylene and the like.
- the monocyclic carbocyclic aryl portion R represents primarily phenyl; it may also stand for substituted phenyl, such as lower alkyl-phenyl, e.g. 4-methyl-phenyl, 3,4-dimethyl-phenyl, Z-ethyl-ph'enyl, 4-isopropyl-pheny1 and the like, etherified hydroXy-phenyl, particularly lower alkoXy-phenyl, e.g. 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 3-ethoXy-phenyl, 4-secondary butyloxy-phenyl and the like, halogeno-phenyl, e.g.
- the group R which is preferably attached to the 6- position or the 7-position of the 1,2-4-benzothiadiazinel,l-dioxide nucleus may represent hydrogen, nitro or lower alkyl having from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl and the like.
- R represents primarily trifluoromethyl or halogeno, especially halogeno having an atomic weight between 35 and 80, i.e. chloro or bromo, as well as fluoro and the like.
- Salts of the compounds of this invention are primarily alkali metal, e.g. sodium, potassium and the like, or alkaline earth metal, e.g. magnesium, calcium and the like, salts thereof.
- the compounds of this invention counteract'the eifect of physiological pressure agents, such as epinephrine, norepinephrine or hypertensive polypeptides, e.g. angiotensin-II-amide and the like, and thus cause a lowering of the blood pressure. They can, therefore, be used as antihypertensive agents to relieve hypertensive conditions, such as renal hypertension, essential hypertension, malignant hypertension and the like.
- physiological pressure agents such as epinephrine, norepinephrine or hypertensive polypeptides, e.g. angiotensin-II-amide and the like.
- one of the groups R and R represents chloro, bromo or trifluoromethyl, and the other stands for hydrogen or methyl, or the alkali metal, e.g. sodium, potassium and the like, salts thereof.
- the new compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new 3-carbocyclic aryl-lower alkyl-1,2,4-benzothiadiazine-l,l-dioxides or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
- a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
- 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 used for pharmaceutical preparations.
- compositions may be in solid form, for example, as capsules, tablets, dragees and the like or in liquid form, for example, as solutions, suspensions, emulsions and the like.
- these compositions may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, as well as salts for varying the osmotic pressure, butters, etc. They may also contain, in combination, other useful substances, particularly antihypertensive agents, such as Rau'wolfia alkaloids, e.g. reserpine, deserpidine, rescinnamine and the like, semisynthetic Rauwolfia alkaloids, e.g.
- veratrum alkaloids e.g. protoveratine A, protoveratine B and the like
- synthetic antihypertensive drugs e.g. hydralazine, dihydralazine, guanethidine and the like
- ganglionic blockers e.g. chlorisondamine and the like, or any other useful substances, such as potassium chloride and the like.
- the compounds of this invention are prepared according to methods known per se, for example, by cyclizing a 2-sulfamyl-N-(carbocyclic aryl-lower alkanoyl)-aniline, particularly a compound of the formula:
- acyl particularly the acyl radical of the formula Ac, stands for the acyl radical of an organic carboxylic acid, to form the desired 3-(carbocyclic aryl-lower alkyl)- 1,2,4-benzothiadiazine 1,1 dioxide compound, particularly a compound having one of the formulae:
- R and R have the previously-given meaning, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into a salt thereof.
- the acyl radical of an organic carboxylic acid which substitutes the sulfamyl group, and which is represented in the above formula by the radical Ac, is, for example, the acyl radical of a carbocyclic aryl carboxylic acid and has more especially the formula CO(C H )R in which n and R have the previously-given meaning.
- the acyl radical of any other suitable organic carboxylic acid such as a lower alkanoic acid, e.g. acetic, propionic acid and the like.
- Cyclization of the 2-sulfamyl-N-(carbocyclic aryllower alkanoyl) -aniline is carried out at an elevated temperature, preferably at a temperature between 75 and 200.
- the cyclization may take place in the absence or in the presence of an inert solvent, such as, for example, ethanol, propanol, diethyleneglycol dimethyl ether, N,N-dimethylformamide and the like, if necessary,
- the starting materials may be prepared, for example, by reactinga Z-SuIfamyI-aniline, especially a compound of the formula:
- R and Ac have the previously-given meaning, with the halide, particularly chloride, or anhydride of a carbocyclic aryl carboxylic acid, particularly an acid of the formula:
- n and R have the previously-given meaning.
- the acylation of the sulfamyl-nitrogen may take place simultaneously with the desired acylation of the anilinenitrogen.
- the treatment with the acylating reagent is carried out in the presence of an inert, slightly polar to non-polar organic solvent, such as an aromatic hydrocarbon, an ether and the like, the mono-acylated product, in which the aniline-nitrogen is acylated, is obtained.
- Any acid generated during the acylation reaction may be neutralized by adding a suitable reagent, e.g. sodium acetate and the like.
- Di-acylation occurs whenever the acylation is used in an excess amount and in the presence of a base, such as a tertiary amine, e.g. N,N,N-triethylamine and the like, or a heterocyclic base, e.g. pyridine and the like.
- the compounds of this invention may also be prepared by reacting a 2-sulfamyl-aniline compound, particularly a compound of the formula:
- n and R have the previously-given meaning, and R represents lower alkyl, and, if desired, carrying out the optional steps.
- an ortho-ester of a carbocyclic aryl-lower alkanoic acid is preferably a lower alkyl ortho-ester, in which lower alkyl (represented in the above formula by R) has from one to four carbon atoms and stands for methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; ethyl ortho-esters are the preferred reagents.
- the above reaction is preferably carried out at an elevated temperature, and in the presence of an inert organic solvent; if necessaryy, it may be performed in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.
- the resulting product may be obtained in the form of the free compound or as a salt thereof.
- a resulting meal, such as an alkali metal, salt may be converted into the free compound by treatment with an acidic reagent, such as an aqueous mineral acid, e.g. hydrochloric, sulfuric acid and the like.
- a resulting free compound may be converted into a metal, particularly into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, in the presence of a suitable inert solvent, such as in a lower alkanol, e.g.
- methanol, ethanol and the like or in water and evaporating the solvent, or by reacting the free compound, for example, in an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, solution, with a metal, particularly an alkali metal, hydride or a metal, particularly an alkali metal, amide, e.g. sodium hydride, potassium hydride, sodium amide, potassium amide and the like.
- a metal particularly an alkali metal, hydride or a metal, particularly an alkali metal, amide, e.g. sodium hydride, potassium hydride, sodium amide, potassium amide and the like.
- the invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any state of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.
- Example 1 A mixture of 5.0 g. of 4-chloro-Z-sulfamyl-aniline and 3.45 g. of phenyl-acetic acid chloride in benzene contain:
- Example 2 A mixture of 4.0 g. of 5-chloro-Z-sulfamyl-aniline and 2.78 g. of phenyl acetic acid chloride in a benzene solution containing 1.75 g. of sodium acetate, when reacted as shown in Example 1, yields the S-chloro-N-phenylacetyl- 2-sulfamyl-aniline, which is ring-closed to the desired benzyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide having one of the formulae:
- Example 3 An aqueous solution of the sodium salt of 3-benZyl-7- chloro-1,2,4-benzothiadiazine-1,l-dioxide is prepared by dissolving 0.5 g. of 3-benZyl-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide in a solution of an equivalent amount of sodium hydroxide in water.
- R and R represents a member selected from the group consisting of chloro, bromo and trifluoromethyl, and the other stands for hydrogen, and R represents a member selected from the group consisting of hydrogen and methyl.
- R and R represents a member selected from the group consisting of chloro, bromo and trifluoromethyl, and the other stands for hydrogen, and R represents a member selected from the group consisting of hydrogen and methyl.
- a pharmaceutical preparation which contains as the essential ingredient a pharmacologically effective amount of a compound having one of the formulae:
- R represents a member selected from the 2,809,194 10/57 Novello 260-243 group consisting of phenyl, and R represents hydrogen, I 2,910,473 10/59 Novello 260243 halogeno, lower alkyl, trifiuoromethyl and nitro, and an 2,910,476 10/59 Novello 260-243 alkali metal salt thereof, together With an inert carrier. 5 2,986,573 5/61 Topliss et a1. 260-243 OTHER REFERENCES Wertheim; Textbook of Organic Chemistry, pages 763-764.
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Description
United States Patent 3,210,347 BENZOTI-IIADIAZINE-1,1-DIOXIDES Lincoln Harvey Werner, Summit, and George de Stevens, New Providence, N.J., assignors to Ciba Corporation, a corporation of Delaware No Drawing. Filed July 12, 1961, Ser. No. 123,418 Claims. (Cl. 260-243) The present invention concerns S-carbocyclic aryl-lower alkyl-1,2,4-benzothiadiazine-1,1-dioxides. More particularly, it relates to compounds having one of the formulae:
s 7 I IH Rz' g n 2n) Rl 3 and \N R: I l! n 2n) l H in which the letter 11 stands for one of the whole numbers 1, 2, 3 and 4, R represents monocyclic carbocyclic aryl, and R stands for hydrogen, halogeno, lower alkyl, trifiuoromethyl and nitro, or salts of such compounds, as well as process for the preparation thereof.
The letter n stands primarily for l, but may also represent one of the numbers 2, 3 and 4. The group of the formula -(C H may, therefore, represent lower alkylene having from one to four carbon atoms, primarily methylene, as well as 1,1-ethylene, 1;,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 2,3-propylene, 1,3- propylene, 1,1-butylene, 1,4-butylene and the like.
The monocyclic carbocyclic aryl portion R represents primarily phenyl; it may also stand for substituted phenyl, such as lower alkyl-phenyl, e.g. 4-methyl-phenyl, 3,4-dimethyl-phenyl, Z-ethyl-ph'enyl, 4-isopropyl-pheny1 and the like, etherified hydroXy-phenyl, particularly lower alkoXy-phenyl, e.g. 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 3-ethoXy-phenyl, 4-secondary butyloxy-phenyl and the like, halogeno-phenyl, e.g. 4-fluoro-phenyl, 4- chloro-phenyl, 2,5-dichloro-phenyl, 3-bromo-p'henyl and the like, trifluoromethyl-phenyl, e.g. 4-trifluoromethylphenyl and the like, or any other suitably substituted phenyl group.
The group R which is preferably attached to the 6- position or the 7-position of the 1,2-4-benzothiadiazinel,l-dioxide nucleus, may represent hydrogen, nitro or lower alkyl having from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl and the like. However, R represents primarily trifluoromethyl or halogeno, especially halogeno having an atomic weight between 35 and 80, i.e. chloro or bromo, as well as fluoro and the like.
Salts of the compounds of this invention are primarily alkali metal, e.g. sodium, potassium and the like, or alkaline earth metal, e.g. magnesium, calcium and the like, salts thereof.
The compounds of this invention counteract'the eifect of physiological pressure agents, such as epinephrine, norepinephrine or hypertensive polypeptides, e.g. angiotensin-II-amide and the like, and thus cause a lowering of the blood pressure. They can, therefore, be used as antihypertensive agents to relieve hypertensive conditions, such as renal hypertension, essential hypertension, malignant hypertension and the like.
3,210,347 Patented Oct. 5, 1965 Particularly useful are the compounds having one of the formulae:
in which one of the groups R and R represents chloro, bromo or trifluoromethyl, and the other stands for hydrogen or methyl, or the alkali metal, e.g. sodium, potassium and the like, salts thereof.
The new compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new 3-carbocyclic aryl-lower alkyl-1,2,4-benzothiadiazine-l,l-dioxides or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral 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 used for pharmaceutical preparations. The latter may be in solid form, for example, as capsules, tablets, dragees and the like or in liquid form, for example, as solutions, suspensions, emulsions and the like. If necessary, these compositions may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, as well as salts for varying the osmotic pressure, butters, etc. They may also contain, in combination, other useful substances, particularly antihypertensive agents, such as Rau'wolfia alkaloids, e.g. reserpine, deserpidine, rescinnamine and the like, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, veratrum alkaloids, e.g. protoveratine A, protoveratine B and the like, synthetic antihypertensive drugs, e.g. hydralazine, dihydralazine, guanethidine and the like, ganglionic blockers, e.g. chlorisondamine and the like, or any other useful substances, such as potassium chloride and the like.
The compounds of this invention are prepared according to methods known per se, for example, by cyclizing a 2-sulfamyl-N-(carbocyclic aryl-lower alkanoyl)-aniline, particularly a compound of the formula:
or a 2-(N-acyl-sulfamyl) N (carbocyclic aryl-lower alkanoyl)-aniline, particularly a compound of the formula:
in which n, R and R have the previously-given meaning, and acyl, particularly the acyl radical of the formula Ac, stands for the acyl radical of an organic carboxylic acid, to form the desired 3-(carbocyclic aryl-lower alkyl)- 1,2,4-benzothiadiazine 1,1 dioxide compound, particularly a compound having one of the formulae:
in which 11, R and R have the previously-given meaning, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into a salt thereof.
The acyl radical of an organic carboxylic acid, which substitutes the sulfamyl group, and which is represented in the above formula by the radical Ac, is, for example, the acyl radical of a carbocyclic aryl carboxylic acid and has more especially the formula CO(C H )R in which n and R have the previously-given meaning. However, it may also stand for the acyl radical of any other suitable organic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic acid and the like.
Cyclization of the 2-sulfamyl-N-(carbocyclic aryllower alkanoyl) -aniline is carried out at an elevated temperature, preferably at a temperature between 75 and 200. The cyclization may take place in the absence or in the presence of an inert solvent, such as, for example, ethanol, propanol, diethyleneglycol dimethyl ether, N,N-dimethylformamide and the like, if necessary,
in a closed vessel under pressure, and/or in the atmosin which R R and R have the previously-given meaning.
The starting materials may be prepared, for example, by reactinga Z-SuIfamyI-aniline, especially a compound of the formula:
S O ZNHg R2 I or a Z-(N-acyl-sulfarnyl)-aniline, particularly a compound of the formula:
in which R and Ac have the previously-given meaning, with the halide, particularly chloride, or anhydride of a carbocyclic aryl carboxylic acid, particularly an acid of the formula:
in which n and R have the previously-given meaning.
The acylation of the sulfamyl-nitrogen may take place simultaneously with the desired acylation of the anilinenitrogen. Whenever the treatment with the acylating reagent is carried out in the presence of an inert, slightly polar to non-polar organic solvent, such as an aromatic hydrocarbon, an ether and the like, the mono-acylated product, in which the aniline-nitrogen is acylated, is obtained. Any acid generated during the acylation reaction may be neutralized by adding a suitable reagent, e.g. sodium acetate and the like. Di-acylation occurs whenever the acylation is used in an excess amount and in the presence of a base, such as a tertiary amine, e.g. N,N,N-triethylamine and the like, or a heterocyclic base, e.g. pyridine and the like.
The compounds of this invention may also be prepared by reacting a 2-sulfamyl-aniline compound, particularly a compound of the formula:
ASOZNHZ R 1 in which R has the previously-given meaning, with an ortho-ester, especially a lower alkyl ortho-ester, of a carbocyclic aryl-lower alkanoic acid, particularly an orthoester of the formula:
in which n and R have the previously-given meaning, and R represents lower alkyl, and, if desired, carrying out the optional steps.
As mentioned hereinbefore, an ortho-ester of a carbocyclic aryl-lower alkanoic acid is preferably a lower alkyl ortho-ester, in which lower alkyl (represented in the above formula by R) has from one to four carbon atoms and stands for methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; ethyl ortho-esters are the preferred reagents. The above reaction is preferably carried out at an elevated temperature, and in the presence of an inert organic solvent; if necesary, it may be performed in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.
The resulting product may be obtained in the form of the free compound or as a salt thereof. A resulting meal, such as an alkali metal, salt may be converted into the free compound by treatment with an acidic reagent, such as an aqueous mineral acid, e.g. hydrochloric, sulfuric acid and the like. A resulting free compound may be converted into a metal, particularly into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, in the presence of a suitable inert solvent, such as in a lower alkanol, e.g. methanol, ethanol and the like, or in water and evaporating the solvent, or by reacting the free compound, for example, in an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, solution, with a metal, particularly an alkali metal, hydride or a metal, particularly an alkali metal, amide, e.g. sodium hydride, potassium hydride, sodium amide, potassium amide and the like.
The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any state of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.
In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.
The following examples illustrate the invention; they are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade.
Example 1 A mixture of 5.0 g. of 4-chloro-Z-sulfamyl-aniline and 3.45 g. of phenyl-acetic acid chloride in benzene contain:
5. ing 2.2 g. of sodium acetate is heated on the steam bath. The precipitate is filtered off, and the benzene solution is evaporated to yield the desired 4-ch1oro-N-pheny1- acetyl-2-sulfamyl-aniline of the formula:
Cl SOzNHz The latter is dissolved in N,N-dimethylformamide and the solution is refluxed for one hour. Water is added, and, upon chilling, the desired 3-benzyl-7-chl oro-1,2,4-benzothiadiazine-1,1-dioxide having one of the formulae:
N Q H precipitates, is collected and recrystallized from ethanol.
Example 2 A mixture of 4.0 g. of 5-chloro-Z-sulfamyl-aniline and 2.78 g. of phenyl acetic acid chloride in a benzene solution containing 1.75 g. of sodium acetate, when reacted as shown in Example 1, yields the S-chloro-N-phenylacetyl- 2-sulfamyl-aniline, which is ring-closed to the desired benzyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide having one of the formulae:
and
by refluxing an N,N-dimethylformamide solution thereof.
Other compounds, such as, for example, the
6 3- 1, (4-isopropyl-phenyl) -ethyl] -7-trifluoromethyl-1,2,4-
benzothiadiazine-1,1-dioxide, 7-chloro-3-[1-(4-ethoxy-phenyl)-ethyl]-1,2,4-benzothiadiazine-1,1-dioxide and the like,
are prepared according to the previously-outlined procedure illustrated in the above examples.
Example 3 An aqueous solution of the sodium salt of 3-benZyl-7- chloro-1,2,4-benzothiadiazine-1,l-dioxide is prepared by dissolving 0.5 g. of 3-benZyl-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide in a solution of an equivalent amount of sodium hydroxide in water.
What is claimed is:
1. A compound having one of the formulae:
in which one of the groups R and R represents a member selected from the group consisting of chloro, bromo and trifluoromethyl, and the other stands for hydrogen, and R represents a member selected from the group consisting of hydrogen and methyl.
2. An alkali metal salt of a compound having one of the formulae:
in which one of the groups R and R represents a member selected from the group consisting of chloro, bromo and trifluoromethyl, and the other stands for hydrogen, and R represents a member selected from the group consisting of hydrogen and methyl.
3. 3-benzyl-7-chloro-1,2,4-benzothiadiazine-l,l-dioxide. 4. 3-benZyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide. 5. A pharmaceutical preparation, which contains as the essential ingredient a pharmacologically effective amount of a compound having one of the formulae:
NH R2 I l C(OnH2n) Ri and 7 8 in which the letter It stands for an integer from 1 to 4, 2,794,834 6/57 Randall et al. 2 260556 both inclusive R represents a member selected from the 2,809,194 10/57 Novello 260-243 group consisting of phenyl, and R represents hydrogen, I 2,910,473 10/59 Novello 260243 halogeno, lower alkyl, trifiuoromethyl and nitro, and an 2,910,476 10/59 Novello 260-243 alkali metal salt thereof, together With an inert carrier. 5 2,986,573 5/61 Topliss et a1. 260-243 OTHER REFERENCES Wertheim; Textbook of Organic Chemistry, pages 763-764.
References Cited by the Examiner UNITED STATES PATENTS 2,059,903 11/36 Petitcolas 260556 2,388,529 11/45 DAlelio et a1. 260-566 NICHOLAS s. Rlzzo, Primary Examiner. 2,726,264 12/55 Gregory 260-556 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 210,347 October 5, 1965 Lincoln Harvey Werner et a1.
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 7 lines 2 and 3 for "both inclusive R represents a member selected from the group consisting of phenyl, and R represents hydrogen," read both inclusive, R represents phenyl, and R represents a member selected from the group consisting of hydrogen,
Signed and sealed this 19th day of July 1966.
(SEAL) Attest:
ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents
Claims (2)
1. A COMPOUND HAVING ONE OF THE FORMULAE:
5. A PHARMACEUTICAL PREPARATION, WHICH CONTAINS AS THE ESSENTIAL INGREDIENT A PHARMACOLOGICALLY EFFECTIVE AMOUNT OF A COMPOUND HAVING ONE OF THE FORMULAE:
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US4997833A (en) * | 1986-09-25 | 1991-03-05 | Boehringer Ingelheim K G | Aryloxy-aminoalkanes, and antihypertensive use thereof |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2059903A (en) * | 1933-08-10 | 1936-11-03 | Cie Nat Matieres Colorantes | Water insoluble azo dyestuffs and their production |
US2388529A (en) * | 1943-06-07 | 1945-11-06 | Gen Electric | Derivatives of aminobenzenesulphonamides |
US2726264A (en) * | 1954-05-27 | 1955-12-06 | Du Pont | Alpha-halogenosulfamylacetophenones |
US2794834A (en) * | 1954-01-28 | 1957-06-04 | Gen Aniline & Film Corp | Process of preparing nitro-nu-alkyl-sulfonanilides |
US2809194A (en) * | 1957-10-08 | Thiadiazine type natriuretic agents | ||
US2910473A (en) * | 1957-07-16 | 1959-10-27 | Merck & Co Inc | 6-nitro, 7-sulfamyl-benzothiadiazine-1, 1-dioxides |
US2910476A (en) * | 1957-09-13 | 1959-10-27 | Merck & Co Inc | Process for preparing benzothiadiazine-1, 1-dioxides |
US2986573A (en) * | 1961-01-18 | 1961-05-30 | Schering Corp | Method for the treatment of hypertension |
-
1961
- 1961-07-12 US US123418A patent/US3210347A/en not_active Expired - Lifetime
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2809194A (en) * | 1957-10-08 | Thiadiazine type natriuretic agents | ||
US2059903A (en) * | 1933-08-10 | 1936-11-03 | Cie Nat Matieres Colorantes | Water insoluble azo dyestuffs and their production |
US2388529A (en) * | 1943-06-07 | 1945-11-06 | Gen Electric | Derivatives of aminobenzenesulphonamides |
US2794834A (en) * | 1954-01-28 | 1957-06-04 | Gen Aniline & Film Corp | Process of preparing nitro-nu-alkyl-sulfonanilides |
US2726264A (en) * | 1954-05-27 | 1955-12-06 | Du Pont | Alpha-halogenosulfamylacetophenones |
US2910473A (en) * | 1957-07-16 | 1959-10-27 | Merck & Co Inc | 6-nitro, 7-sulfamyl-benzothiadiazine-1, 1-dioxides |
US2910476A (en) * | 1957-09-13 | 1959-10-27 | Merck & Co Inc | Process for preparing benzothiadiazine-1, 1-dioxides |
US2986573A (en) * | 1961-01-18 | 1961-05-30 | Schering Corp | Method for the treatment of hypertension |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4997833A (en) * | 1986-09-25 | 1991-03-05 | Boehringer Ingelheim K G | Aryloxy-aminoalkanes, and antihypertensive use thereof |
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