CN1137035A - 碱性基取代的苯甲酰胍,其制备方法,其作为药物或诊断试剂的用途,以及含有它们的药物 - Google Patents
碱性基取代的苯甲酰胍,其制备方法,其作为药物或诊断试剂的用途,以及含有它们的药物 Download PDFInfo
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- CN1137035A CN1137035A CN96101243A CN96101243A CN1137035A CN 1137035 A CN1137035 A CN 1137035A CN 96101243 A CN96101243 A CN 96101243A CN 96101243 A CN96101243 A CN 96101243A CN 1137035 A CN1137035 A CN 1137035A
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- phenoxy
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- 238000000034 method Methods 0.000 title claims description 62
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 title abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 title description 3
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- 238000002360 preparation method Methods 0.000 claims abstract description 24
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 67
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- -1 hetero atom radical Chemical class 0.000 claims description 60
- 125000004432 carbon atom Chemical group C* 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 150000002431 hydrogen Chemical class 0.000 claims description 38
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 38
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- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 150000003254 radicals Chemical class 0.000 claims description 25
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- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 15
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 13
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
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- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
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- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
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- UYBRHOIBBAJWHJ-UHFFFAOYSA-N n-(diaminomethylidene)-3-methylsulfonyl-4-[4-(1-pyrrolidin-1-ylpropan-2-ylsulfamoyl)phenoxy]benzamide;dihydrochloride Chemical compound Cl.Cl.C=1C=C(OC=2C(=CC(=CC=2)C(=O)NC(N)=N)S(C)(=O)=O)C=CC=1S(=O)(=O)NC(C)CN1CCCC1 UYBRHOIBBAJWHJ-UHFFFAOYSA-N 0.000 claims description 3
- UDFFGMSOASTRHM-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethylsulfonylmethyl]phenoxy]-3-(trifluoromethyl)benzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(CS(=O)(=O)CCN(C)C)=CC=C1OC1=CC=C(C(=O)NC(N)=N)C=C1C(F)(F)F UDFFGMSOASTRHM-UHFFFAOYSA-N 0.000 claims description 3
- BIVYFVIMFQZEIN-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethylsulfonylmethyl]phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(CS(=O)(=O)CCN(C)C)=CC=C1OC1=CC=C(C(=O)N=C(N)N)C=C1S(C)(=O)=O BIVYFVIMFQZEIN-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
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- KHABPRMUUQCJLV-ODZAUARKSA-N (z)-but-2-enedioic acid;guanidine Chemical compound NC(N)=N.OC(=O)\C=C/C(O)=O KHABPRMUUQCJLV-ODZAUARKSA-N 0.000 claims description 2
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- IDXLGKYKEPDVIJ-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-(3-imidazol-1-ylpropylsulfamoyl)phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)NC(N)=N)=CC=C1OC1=CC=C(S(=O)(=O)NCCCN2C=NC=C2)C=C1 IDXLGKYKEPDVIJ-UHFFFAOYSA-N 0.000 claims description 2
- BHYNHWQZAABXIS-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-(4-methylpiperazin-1-yl)sulfonylphenoxy]-3-(trifluoromethyl)benzamide;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(C(=O)NC(N)=N)C=C1C(F)(F)F BHYNHWQZAABXIS-UHFFFAOYSA-N 0.000 claims description 2
- IVDPDMCZJKRLBA-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(1h-imidazol-2-yl)ethanethioyl]phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)N=C(N)N)=CC=C1OC1=CC=C(C(=S)CC=2NC=CN=2)C=C1 IVDPDMCZJKRLBA-UHFFFAOYSA-N 0.000 claims description 2
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- KXLGNRLHNRLKND-UHFFFAOYSA-N methyl 3,4-dichloro-5-methylsulfonylbenzoate Chemical compound COC(=O)C1=CC(Cl)=C(Cl)C(S(C)(=O)=O)=C1 KXLGNRLHNRLKND-UHFFFAOYSA-N 0.000 description 1
- QCUVEYBGBFFUOT-UHFFFAOYSA-N methyl 3-chloro-4-[4-[2-(dimethylamino)ethyl]phenoxy]-5-methylsulfonylbenzoate Chemical compound CS(=O)(=O)C1=CC(C(=O)OC)=CC(Cl)=C1OC1=CC=C(CCN(C)C)C=C1 QCUVEYBGBFFUOT-UHFFFAOYSA-N 0.000 description 1
- CKYDZVKKBMMCTG-UHFFFAOYSA-N methyl 3-methyl-4-phenoxybenzoate Chemical compound CC1=CC(C(=O)OC)=CC=C1OC1=CC=CC=C1 CKYDZVKKBMMCTG-UHFFFAOYSA-N 0.000 description 1
- LOQLLANJWRQRCR-UHFFFAOYSA-N methyl 4-(4-ethoxycarbonylphenoxy)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OC1=CC=C(C(=O)OC)C=C1 LOQLLANJWRQRCR-UHFFFAOYSA-N 0.000 description 1
- CEJOIKLXHJMQJM-UHFFFAOYSA-N methyl 4-[4-[2-(dimethylamino)ethyl]phenoxy]-3-methylsulfonylbenzoate Chemical compound CS(=O)(=O)C1=CC(C(=O)OC)=CC=C1OC1=CC=C(CCN(C)C)C=C1 CEJOIKLXHJMQJM-UHFFFAOYSA-N 0.000 description 1
- TUDIYILNAFRSPU-UHFFFAOYSA-N methyl 4-[4-[2-(dimethylamino)ethyl]phenoxy]-3-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC=C1OC1=CC=C(CCN(C)C)C=C1 TUDIYILNAFRSPU-UHFFFAOYSA-N 0.000 description 1
- YFTOYWCQCUSTMO-UHFFFAOYSA-N methyl 4-[4-[2-(dimethylamino)ethylsulfanyl]phenoxy]-3-(trifluoromethyl)benzoate Chemical compound FC(F)(F)C1=CC(C(=O)OC)=CC=C1OC1=CC=C(SCCN(C)C)C=C1 YFTOYWCQCUSTMO-UHFFFAOYSA-N 0.000 description 1
- SNLRFWLXOFRFDJ-UHFFFAOYSA-N methyl 4-[4-[2-(dimethylamino)ethylsulfanyl]phenoxy]-3-methylsulfonylbenzoate Chemical compound CS(=O)(=O)C1=CC(C(=O)OC)=CC=C1OC1=CC=C(SCCN(C)C)C=C1 SNLRFWLXOFRFDJ-UHFFFAOYSA-N 0.000 description 1
- OCDIFIYFPFLAOU-UHFFFAOYSA-N methyl 4-fluoro-3-methylbenzoate Chemical compound COC(=O)C1=CC=C(F)C(C)=C1 OCDIFIYFPFLAOU-UHFFFAOYSA-N 0.000 description 1
- YQNWDVLPPUEESQ-UHFFFAOYSA-N methyl 4-fluoro-3-sulfamoylbenzoate Chemical compound COC(=O)C1=CC=C(F)C(S(N)(=O)=O)=C1 YQNWDVLPPUEESQ-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- YPLIFKZBNCNJJN-UHFFFAOYSA-N n,n-bis(ethylamino)ethanamine Chemical compound CCNN(CC)NCC YPLIFKZBNCNJJN-UHFFFAOYSA-N 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- JYSMLUKHTVYTPN-UHFFFAOYSA-N n-(diaminomethylidene)-3-methylsulfonyl-4-[4-(2-pyridin-2-ylethylsulfamoyl)phenoxy]benzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)NC(N)=N)=CC=C1OC1=CC=C(S(=O)(=O)NCCC=2N=CC=CC=2)C=C1 JYSMLUKHTVYTPN-UHFFFAOYSA-N 0.000 description 1
- DCQUZLPJDNNCPA-UHFFFAOYSA-N n-(diaminomethylidene)-3-methylsulfonyl-4-[4-(2-quinolin-2-ylethanethioyl)phenoxy]benzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)N=C(N)N)=CC=C1OC1=CC=C(C(=S)CC=2N=C3C=CC=CC3=CC=2)C=C1 DCQUZLPJDNNCPA-UHFFFAOYSA-N 0.000 description 1
- FKOLJQUYUVBLMH-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-(1-hydroxy-2-pyridin-2-ylsulfanylethyl)phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)N=C(N)N)=CC=C1OC1=CC=C(C(O)CSC=2N=CC=CC=2)C=C1 FKOLJQUYUVBLMH-UHFFFAOYSA-N 0.000 description 1
- KDXCKXOYWGNCQY-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-(1-hydroxy-2-quinolin-2-ylsulfanylethyl)phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)N=C(N)N)=CC=C1OC1=CC=C(C(O)CSC=2N=C3C=CC=CC3=CC=2)C=C1 KDXCKXOYWGNCQY-UHFFFAOYSA-N 0.000 description 1
- UDYAJKNBBHUKJW-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(4,5-dihydro-1h-imidazol-2-yl)ethanethioyl]phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.CS(=O)(=O)C1=CC(C(=O)N=C(N)N)=CC=C1OC1=CC=C(C(=S)CC=2NCCN=2)C=C1 UDYAJKNBBHUKJW-UHFFFAOYSA-N 0.000 description 1
- FPLLMAFICJTNSF-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethyl]phenoxy]-3-(trifluoromethyl)benzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(CCN(C)C)=CC=C1OC1=CC=C(C(=O)N=C(N)N)C=C1C(F)(F)F FPLLMAFICJTNSF-UHFFFAOYSA-N 0.000 description 1
- ROWRMLYVYMXVNR-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethylsulfanyl]phenoxy]-3-(trifluoromethyl)benzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(SCCN(C)C)=CC=C1OC1=CC=C(C(=O)NC(N)=N)C=C1C(F)(F)F ROWRMLYVYMXVNR-UHFFFAOYSA-N 0.000 description 1
- AORHZUUCBZCEET-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethylsulfanyl]phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(SCCN(C)C)=CC=C1OC1=CC=C(C(=O)NC(N)=N)C=C1S(C)(=O)=O AORHZUUCBZCEET-UHFFFAOYSA-N 0.000 description 1
- JOSBUTKUHFDVSM-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethylsulfanylmethyl]phenoxy]-3-(trifluoromethyl)benzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(CSCCN(C)C)=CC=C1OC1=CC=C(C(=O)NC(N)=N)C=C1C(F)(F)F JOSBUTKUHFDVSM-UHFFFAOYSA-N 0.000 description 1
- IEAUGSFMUZYQAX-UHFFFAOYSA-N n-(diaminomethylidene)-4-[4-[2-(dimethylamino)ethylsulfonyl]phenoxy]-3-methylsulfonylbenzamide;dihydrochloride Chemical compound Cl.Cl.C1=CC(S(=O)(=O)CCN(C)C)=CC=C1OC1=CC=C(C(=O)NC(N)=N)C=C1S(C)(=O)=O IEAUGSFMUZYQAX-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000001282 organosilanes Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 239000011251 protective drug Substances 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/64—X and Y being nitrogen atoms, e.g. N-sulfonylguanidine
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
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- C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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Abstract
本发明涉及碱性基取代的苯甲酰胍、制备方法、以及含有它们的药物,描述了式I化合物及其药理可接受盐,其中R1-R6如权利要求书所定义。并描述其制备方法及其用脏循环疾病的治疗药物。
Description
R(6)-A-B-D-;
R(7)、R(8)、R(9)和R(10)彼此独立地为氢或具有1、2、3或4个碳原子的烷基;或
R(7)和R(8)一起为CaH2a;
a为4,5,6或7;
其中,当a=5,6或7时,基团CaH2a的一个亚甲基基团可被杂原子基团O、SOm或NR(11)代替,或者
R(8)和R(9)或R(9)和R(10)或R(7)和R(10)为基团CaH2a;
a为2、3、4或5;
其中,当a=3、4或5时,基团CaH2a的一个亚甲基基
团可被杂原子基团O、SOm或NR(11)代替;
m为零、1或2;
R(11)为氢或甲基;或者
R(6)为具有1-9个碳原子的碱性芳香杂环体系;
A为CbH2b;
b为1、2、3、4、5、6、7、8、9或10;
其中,在基团CbH2b中,一个或两个亚甲基基团可被选自下
列基团中的一个所取代,包括-O-、-CO-、-CH〔OR(20)〕-
、-SOm、-NR(20)-、-NR(20)-CO-、
-NR(20)-CO-NH-、-NR(20)-CO-NH-SO2-
和-SOaa〔NR(19)〕bb-;
并且其中在基团CbH2b的一个亚甲基基团可被-CH-R(99)
代替,其中R(99)与R(7)一起形成一个吡咯烷或
哌啶环;
aa为1或2;
bb为0或1;
aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的烷基,
R(20)为氢或甲基;B为亚苯基或亚萘基残基
R(12)和R(13)彼此独立地为氢、甲基、F、Cl、Br、I、
CF3或-SOW-R(14);
R(14)为甲基或NR(15)R(16);
R(15)和R(16)彼此独立地为氢或具有1、2、3或4个
碳原子的烷基;
W为零、1或2;
D为-CdH2d-Xf-;
d为零、1、2、3或4;
X为-O-、-CO-或、-CH〔OR(21)〕-、-SOm-或
-NR(21)-;
f为零或1;
R(21)为氢或甲基;
m为零、1或2;并且在每种情况下,取代基R(1)和R(2)和R(3)中的另外两个彼此独立地为氢、F、Cl、Br、I、-CN-、-(C1-C8)-烷基、-(C2-C8)-链烯基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
g为零、1、2、3或4;
h为零或1;
R(35)和R(36)彼此独立地为氢或具有1、2、3、4、5或6个碳原子的烷基;
或者
R(35)和R(36)一起为4-7个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-、-NCH3或-N-苄基所代替;
Z为-O-、-CO、-SOV-、-NR(18)-、-NR(18)-CO-、-NR(18)-CO-NH-或-NR(18)-SO2-;
R(18)为氢或甲基;
V为零、1或2;
R(17)为氢、具有3、5或6个碳原子的环烷基、或CkF2k+1-;
k为1、2或3,
或者
R(17)为吡咯-1-基、吡咯-2-基或吡咯-3-基,其不被取代或被选自下列基团的1-4个取代基取代,取代基包括F、Cl、Br、I、-CN、(C2-C8)-链烷酰基、(C2-C8)-烷氧羰基、甲酰基、羧基、-CF3、甲基和甲氧基;
或者
R(17)为-(C3-C8)-环烷基或苯基,其不被取代或被选自下列基团的1-3个取代基取代,包括F和Cl、-CF3、甲基、羟基、甲氧基、-NR(37)R(38)、CH3SO2-和H2NO2S-;
R(37)和R(38)为氢或-CH3;
R(4)和R(5)彼引独立地为氢、具有1、2、3或4个碳原子的烷基、F、Cl、OR(32)、-NR(33)R(34)或-CrF2r+1;
R(32)、R(33)和R(34)彼此独立地为氢或具有1、2或
3个碳原子的烷基;
r为1、2、3或4;
具有式I的化合物中优选其中R(1)为氢、F、Cl、-(C1-C4)-烷基、-(C2-C4)-链烯基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
R(35)和R(36)彼此独立地为氢、甲基或乙基;
或者
R(35)和R(36)一起为4-5个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-或-NCH3代替;
R(17)为氢、具有5或6个碳原子的环烷基、或CkF2k+1-;
k为1、2或3,
g为零、1、2、3或4;
h为零或1;
Z为-O-,-CO-,-SOV-、-NR(18)-、-NR(18)-CO-、-NR(18)-CO-NH-或-NR(18)-SO2-;
R(18)为氢或甲基;
V为零、1或2;
或者,如果g和h为零,
R(17)为吡咯-1-基、吡咯-2-基或吡咯-3-基,其不被取代或被选自下列基团的1-2个取代基取代,包括F、Cl、(C2-C5)-链烷酰基、(C2-C5)-烷氧羰基、甲酰基、羧基、-CF3、甲基和甲氧基;
或者
R(17)为-(C3-C8)-环烷基或苯基,其不被取代或被选自下列基团的1-2个取代基取代,包括F和Cl、-CF3、甲基、甲氧基、-NR(37)R(38)、CH3SO2-和H2NO2S-;
R(37)和R(38)彼此独立地为氢或-CH3;
取代基R(2)和R(3)之一为R(6)-A-B-D;
R(7)、R(8)、R(9)和R(10)彼此独立地为氢或具有1、2、3或4个碳原子的烷基;或者
R(7)和R(8)一起为CaH2a;
a为4、5、6或7;
其中,当a=5、6或7时,基团CaH2a中的一个亚甲基
基团可被杂原子基团O、SOm或NR(11)代替
R(11)为氢或甲基;或者
R(8)和R(9)一起为CaH2a;
a为2、3、4或5;
其中,当a=3、4或5时,基团CaH2a中的一个亚甲基基团
可被杂原子基团O、SOm或NR(11)代替;
m为零、1或2;或者R(6)为咪唑基、吡啶基、喹啉基或异喹啉基;A为CbH2b
b为1、2、3、4或5,
其中,在基团CbH2b中,一个或两个亚甲基基团可被选自下
列一组基团中的一个所代替,包括-O-、-CO-、
和-SOaa〔NR(19)〕bb-;
并且其中在基团CbH2b中,一个亚甲基基团可被-CH-R(99)
代替,其中R(99)与R(7)一起形成一个吡咯烷或
哌啶环;
aa为1或2;
bb为0或1;
aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的烷基,
R(20)为氢或甲基;B为亚苯基或亚萘基残基
R(12)和R(13)彼此独立地为氢、甲基、F、Cl、CF3或
-SO2-R(14);
R(14)为甲基或NR(15)R(16);
R(15)和R(16)彼此独立地为氢或具有1、2、3或4个
碳原子的烷基;
D为-CdH2d-Xf-;
d为零、1、2、3或4;
X为-O-、-CO-、-CH〔OR(21)〕-、-SOm-或
-NR(21)-;
f为零或1;
R(21)为氢或甲基;
m为零、1或2;并且在每种情况下,基团R(2)和R(3)的另一个为氢、具有1、2、3或4个碳原子的烷基、F、Cl或CF3;
R(4)和R(5)彼此独立地为氢、具有1、2或3个碳原子的烷基、F、Cl或-CF3;及其药理上可接受的盐。
具有式I的化合物中特别优选其中R(1)为氢、F、Cl、具有1、2、3、或4个碳原子的烷基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
g为零、1、2、3或4;
h为零或1;
Z为-O-、-CO-、-SOV-、-NR(18)-、-NR(18)-CO-、-NR(18)-CO-NH或-NR(18)-SO2-;
R(18)为氢或甲基;
V为零、1或2;
R(17)为氢、含有5或6个碳原子的环烷基、或CF3-
或者,如果g和h为零,
R(17)为吡咯-1-基,其不被取代或被选自下列基团的
1-2个取代基取代,包括F、Cl、(C2-C5)-链烷酰基、(C2-
C5)-烷氧羰基、-CF3和甲基;
或者
R(17)为-(C5-C6)-环烷基或苯基,其不被取代或被选自下列基团的一个取代基取代,包括F和Cl、-CF3、甲基、CH3SO2-和H2NO2S-;
R(35)和R(36)彼此独立地为氢、甲基或乙基;
或者
R(35)和R(36)一起为4-5个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-或-NCH3代替;取代基R(2)和R(3)之一为R(6)-A-B-D-;
R(7)为氢或具有1、2、3或4个碳原子的烷基;
R(8)、R(9)和R(10)彼此独立地为氢、甲基或乙基;
或者
R(7)和R(8)一起为CaH2a;a为4或5;其中当a=5时,
基团CaH2a中的一个亚甲基基团可被NR(11)代替,R
(11)为氢或甲基;
或者
R(6)为咪唑基或吡啶基;A为CbH2b;
b为1、2、3、4或5,其中,在基团CbH2b中,一个或两个亚甲
基基团可被选自下列一组基团中的一个所代替,包括-CO-、
-SOaa〔NR(19)〕bb和-SO2-;
并且其中,在基团C2bH2b中,一个亚甲基基团可被
-CH-R(99)取代,其中R(99)与R(7)一起形成一个吡咯烷或哌啶
环;
aa为1或2,
bb为0或1;
aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的烷基,
R(20)为氢或甲基;
或者,如果b为2、3、4或5,CbH2b中的一个碳原子可被-O-、
-S-、-NR(20)-、-NR(20)-CO-或-NR(20)-CO-NH-
代替;B为亚苯基残基,
R(12)和R(13)彼此独立地为氢、甲基、F、Cl、CF3或
-SO2R(14);
R(14)为甲基或NH2;D为-CH2-、-O-、-CO-、-SOm-或-NR(21);
m为零或2
R(21)为氢或甲基;并且在每种情况下基团R(2)和R(3)的另一个为氢;R(4)和R(5)彼此独立地为氢、具有1、2或3个碳原子的烷基、F、Cl或-CF3;及其药学上可接受的盐。
具有式(I)的化合物中更尤其优选其中R(1)为氢、F、Cl具有1、2、3或4个碳原子的烷基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
g为零或1;
h为零或1;
Z为-O-、-CO-、-NR(18)-CO-、-NR(18)-CO-NH-
或-NR(18)-SO2-;
R(18)为氢或甲基;
或者,如果g为1;
Z为-SO2-;
R(17)为氢或CF3-;
R(35)为R(36)彼此独立地为氢、甲基或乙基;
或者
R(35)和R(36)一起为4-5个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-或-NCH3代替;取代基R(2)和R(3)之一为R(6)-A-B-O-;
R(6)为-NR(7)R(8)或胍基基团
R(7)为氢或具有1、2、3或4个碳原子的烷基;
R(8)、R(9)和R(10)彼此独立地为氢、甲基或乙基;
或者
R(7)和R(8)一起为CaH2a;a为4或5;其中,当a=
5时,基团CaH2a或的一个亚甲基基团可被-NH-或
-NCH3-取代,或者R(6)为咪唑基;A为CbH2b
b为1、2、3或4;其中,基团CbH2b中的一个或两个亚甲
基基团可被选自下列的一组基团中的一个所代替,包括
-CO,
-SOaa〔NR(19)〕bb和-SO2-,
并且在基团CbH2b中,一个亚甲基基团可被-CH-R(99)
代替,其中R(99)与R(7)一起可形成吡咯烷或哌啶环
;或者如果b为2、3或4,基团CbH2b中的一个亚甲基基可
被原子团-O-或-S-代替;
aa为1或2;
bb为0至1;
aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的烷基;
R(12)和R(13)为氢;并且在每种情况下残基R(2)和R(3)中的另一个为氢;R(4)和R(5)为氢;及其药理上可接受的盐。
特别优选的是选自下列的化合物,包括4-〔4-N-(二甲基氨基乙基)甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍二盐酸化物;4〔4-(4-甲基哌嗪磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物;4-〔4-(2-吡咯烷乙基氨基磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍马来酸氢酯;4-〔4-(2-哌啶乙基氨基磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍马来酸氢酯;4-〔4-(N-二甲基氨基-正丙基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍;4-〔4-(N-二甲基氨基乙基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍;4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酰胍;3-三氟甲基-4-(4-N-甲基亚氨基氨磺酰)苯氧基-苯甲酰胍;3-甲基-4-(4-(1-甲基哌嗪-4-基磺酰基)苯氧基)-苯甲酰胍;4-(4-胍基磺酰基)苯氧基-3-三氟甲基苯甲酰胍;4-〔4-(2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基-苯甲酰胍二盐酸化物;4-〔4-(N,N’-二甲基-S-异硫脲基(insothiuronyl)-乙酰基)苯氧基〕-3-甲基磺-酰基苯甲酰胍二盐酸化物;4-〔4-(2-苯并咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基-苯甲酰胍二盐酸化物;4-〔4-(2-N-咪唑基-1-羟乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸盐;4-〔4-(N,N-二甲基甘氨酰氨基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(N,N-二乙基氨基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(4-咪唑基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(3-N-咪唑基-1-丙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(1-甲基-2-吡咯烷基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物4-〔4-(N-哌啶子基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(2-二甲基氨基乙基)磺酰基甲基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(2-二甲基氨基乙基)磺酰基甲基-苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物。
所述烷基残基可为直链或支链。
具有1-9个碳原子的碱性芳香杂环体系可被理解为是指,特别是,从环戊基、苯基或萘基衍生的残基,并且其中一个或多个CH基团被N代替。杂芳基是,特别是,咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、喹啉基和异喹啉基。卤素是F、Cl、Br或I。
如果具有式I的化合物含有不对称中心,则式l代表单一的光学对映体以及它们可能的对映异构混合物。
本发明进一步涉及制备化合物I的方法,其包括将具有式II的化合物与胍反应其中R(1)至R(5)具有上述含义并且L为可被轻易亲核取代的离去基团,并且,如需要,将产物转化成药理上可接受的盐。
最好用已知方法从其羧酰氯(式II,L=Cl)获得活化的式II酸衍生物(其中L为烷氧基,优选甲氧基、苯氧基、苯基硫、甲基硫、或者3-吡啶基氧或2-吡啶基硫,或氮杂环,优选1-咪唑基)。其中,其羧酰氯又可用已知方法从其羧酸(式II,L=OH)制得,例如用亚硫酰氯。
除式II的羧酰氯(L=Cl)以外,也可以用已知方法直接从其苯甲酸衍生物(式II,L=OH)制备活化的式II羧酸衍生物,例如通过在甲醇中用气体HCl处理获得其中L=OCH3的式II的甲基酸,通过用羰基二咪唑〔L=1-咪唑,Staab,Angew.Chem.Int.Ed.Engl.1,351-367(1962)〕处理获得式II的咪唑化物,在惰性溶剂中在三乙胺的存在下用ClCOOC2H5或甲苯磺酰氯获得混合酸酐II,也可用二环己基碳化二亚胺(DCC)或者用O〔(氰(乙氧羰基)-亚甲基)氨基〕-1,1,3,3-四甲基脲翁四氟硼酸盐(“TOTU”)活化苯甲酸〔Proocedings of the 21.European Peptide Symposium,Peptides1990.作者E.Giralt和D.Andren,Escom,Leiden,1991)。可从J.March,Advanced Organic Chemistry,第三版(John Wiley & Sons,1985),350页中发现一系列适于制备活化的式II羧酸衍生物的方法,其中列出了原始文献。
在质子或非质子的传递的极性的、但是惰性的有机溶剂中用已知方法将式II活化的羧酸衍生物与胍反应。已证实,在苯甲酸甲酯(II,L=OME)与胍于从20℃至溶剂沸点的温度下的反应中,甲醇、异丙醇或THF证明是合适的。化合物II与游离胍的大多数反应最好在非质子传递的惰性的溶剂中进行,例如THF、二甲氧乙烷、二噁烷或异丙醇。但是,当使用碱时也可以用水作为II和III的反应中的溶剂。
如果L=Cl,最好加入吸收酸的试剂进行反应,例如可用过量胍的形式,来结合氢卤酸。
已知一些其苯甲酸衍生物。其通过从文献中得知的方法进行制备,例如,通过卤素交换将已得到的残基R(6)-A-B-CdH2d-Xf或其前体转化成式III的苯甲酸衍生物其中取代基R’是低级烷基残基,例如甲基或乙基,并且R”为卤素。文献中描述了该反应,例如亲核取代反应、自由基Ullmann反应或钯催化反应。
用从文献中得知的在芳香部分进行亲核取代的方法在苯基部分进行硫—、氧—或氮亲核取代获得了苯磺酰胺衍生物。已证实,在该取代反应中,作为苯甲酸衍生物上的离去基团,卤化物和三氟甲烷磺酸酯是合适的。反应最好是在偶极质子惰性溶剂中进行,例如DMF或TMU,反应温度为从0℃至溶剂的沸点,优选从80℃至溶剂的沸点。最好用具有一个碱性较高且亲核能力较低的阴离子的碱金属盐或碱土金属盐,例如K2CO3或CsCO3,作为吸收酸的试剂。
已知许多作为前体的R(6)-A-B-CdH2d-Xf-化合物,它们中的一部分可作为试剂买到。它们可按照从文献中得知的方法制备,这些方法是本领域技术人员所熟知的。
按照从文献中得知的方法可成功地将一些取代基引入4和5位,即,以钯为媒介的芳基卤化物与下列化合物的交叉—偶联反应,例如,有机锡烷、有机硼酸或有机硼烷或有机铜或有机锌化合物。
通常,苯甲酰胍I为弱碱,并且可与酸结合形成盐。适宜的酸加成盐是所有药理上可接受的酸的加成盐,例如卤化物,特别是盐酸化物、乳酸盐、硫酸盐、柠檬酸盐、酒石酸盐、抗坏血酸盐、乙酸盐、磷酸盐、甲磺酸盐和对—甲苯磺酸盐。
化合物I为被取代的酰基胍。最熟知的酰基胍的代表物是吡嗪衍生物氨氯吡脒,其可作为保钾(Kaliumsparendes)利尿剂用于治疗。文献中描述了许多其它氨氯吡脒型化合物,例如二甲基氨氯吡脒或乙基异丙基氨氯吡脒。氨氯吡脒:R’,R”=H二甲基氨氯吡脒:R’,R”=CH3乙基异丙基氨氯吡脒:R’=C2H5,以及R”=CH(CH3)2
另外,已知有试验表明氨氯吡脒具有抗心律失常的作用(Circu-lation79,1257至1263(1989))。但是,妨碍其作为抗心律失常药广泛使用的原因在于该作用表现得非常微弱,并且伴随有降血压和促尿食盐排泄作用,而这些副作用是治疗心律失常时所不希望的。
动物离体心脏的实验也已经表明氨氯吡脒具有抗心律失常的作用(Eur.Heart J.9(suppl.1):167(1988)(book of abstracts)。
已发现氨氯吡咪可以完全抑制人工诱导的大鼠心脏的心室纤颤。在该模型中,上述氨氯吡脒衍生物乙基异丙基氨氯吡脒比氨氯吡脒自自更为有效。
美国专利5091394(HOE 89/F 288)描述了苯甲酰胍,其在相对于残基R(1)的位置上仅携带一个氢原子,并且其中没有一个取代基具有R(5)-A-B-D-的含义。欧洲公开申请0556 674A(HOE92/F 034)提出了3,5-取代的苯甲酰胍,但是其中取代基R(2)不具有本发明已要求的R(5)-A-B-D-的含义。
美国专利3 780 027要求了酰基胍,其在结构上与具有式I的化合物类似,并且是从市售的袢性利尿药(Schleifendiuretika)衍生的,例如从丁苯氧酸。因此据报道这些化合物具有很强的袢性利尿(Sa-lidiuretische)活性。
令人惊奇的是,这些新化合物没有任何不希望的、不利的袢性利尿药的性质,但是,当例如在缺氧时出现心律失常时,其具有良好的抗心律失常活性。由于其药理性质,这些化合物非常适于用作含有心脏保护性成分的抗心律失常药,用于预防和治疗梗塞的形成并且用于治疗的心绞痛,在此,这些化合物还预防性地抑制或显著降低与局部缺血导致的损伤的产生有关的病理生理过程,特别是当局部缺血导致的心脏心律失常触发时。由于它们对于病理性缺氧和局部缺血状态的保护性作用,这些式I的新化合物基于对细胞Na+/H+交换机制的抑制作用,其用作治疗局部缺血引起的所有急性或慢性损伤、或者治疗由此原发性或继发性导致的疾病的药物。这使它们适于作为外科手术用药,例如在器官移植时,其中当移植前和移植过程中用该化合物保护移植体器官,例如将其用生理浴液进行处理或保存在生理浴液中以保护移植的器官,以及应用在器官移植到受体生物体的过程中。同样,这些化合物是很有价值的保护性药物,用于血管成形的外科手术,例如心脏或外周血管手术。与它们对局部缺血导致的损伤的保护性活性相关,这些化合物也适于用作治疗神经系统局部缺血的药物,特别是中枢神经系统,其中例如适于治疗中风或脑水肿。另外,根据本发明的具有式I的化合物也适于治疗多种形式的休克,例如过敏性、心原性、血容量减少性和细菌性休克。
另外,根据本发明的具有式I的化合物对细胞增生有很强的抑制作用,例如成纤维细胞增生和血管平滑肌细胞增生。因此具有式I的化合物是很有价值的治疗由细胞增生原发性或继发性引起的疾病的药物,并且因此它们可以用作抗动脉粥样硬化剂、治疗糖尿病晚期并发症、癌症、纤维变性疾病,例如肺纤维化、肝纤维化或肾纤维化,器官肥大和增生,特别是前列腺增生或前列腺肥大。
根据本发明的化合物是很有价值的细胞钠/质子抗搬运器(An-tiporters)(Na+/H+交换器)的抑制剂,该交换器在许多病症中(特别是高血压、动脉粥样硬化、糖尿病等等)甚至在那些易于接受测量的细胞中,例如红细胞、血小板或白细胞中有所增加。因此根据本发明的化合物适于作为出色而简单的科学工具,例如用作诊断剂来测定以及区别高血压的特定形式,还有动脉粥样硬化、糖尿病、增生性疾病等等。另外,具有式I的化合物适用于避免高血压产生的预防性冶疗,例如原发性高血压。
除了对Na+/H+交换器的强烈抑制作用之外,根据本发明的化合物在水中的溶解度与已知化合物相比显著增加。因此这些化合物更适于静脉给药。
含有化合物I的药物可由口服、肠胃外、静脉、直肠或吸入给药,优选的给药方式取决于疾病的特定症状。化合物I可单独使用或与盖伦氏助剂一起使用,并且它们可用于兽用药及人体用药。
本领域熟练技术人员基于他的专业知识知道哪些助剂适用于所需的药物剂型。除了溶剂、胶凝剂、栓剂基质、片剂助剂以及其它活性物质载体以外,可使用的助剂是,例如,抗氧化剂、分散剂、乳化剂、消沫剂、调味剂、防腐剂、助溶剂或着色剂。
对于口服剂型,将活性化合物与载体、稳定剂或惰性稀释剂之类的添加剂混合并按通常的方法配制成适宜剂型,例如片剂、糖衣片、硬胶囊、或者水、醇或油的溶液。可使用的惰性载体例如为阿拉伯树胶、氧化镁、碳酸镁、磷酸钾、乳糖、葡萄糖或淀粉,特别是玉米淀粉。可用干粒或湿粒制备。油状载体的例子或溶剂的例子是,植物或动物油,例如葵花子油或鱼肝油。
对于皮下或静脉给药,将活性化合物如需要的话与通常所用的用于该目的的物质如助溶剂、乳化剂或其它助剂一起,溶解、悬浮或乳化。适宜的溶剂的例子是:水、生理盐溶液或醇,例如乙醇、丙醇、甘油,还有糖溶液,例如葡萄糖或甘露糖醇溶液,或者含有上述多种溶剂的混合物。
适于以气雾剂或喷雾剂给药的药物剂型例如为溶液、悬浮液或乳液,其中将具有式I的活性物质置于药学上可接受的溶剂中,例如,特别是乙醇或水,或者这些溶剂的混合物。
如需要,剂型中还可含有其它药用助剂,例如表面活性剂、乳化剂或稳定剂、以及抛射气体(TreTbgas)。在这样的制备中活性物质的浓度一般在约0.1至10,特别是从约0.3至3%重量。
具有式I的活性物质的给药剂量和给药频率决定于所用化合物的作用强度和作用时间;另外还决定于所治疗的疾病的种类和严重程度、以及性别、年龄、体重以及所治疗的动物的个体反应。
一般来说,对于约75kg的病人,式I的化合物的每日剂量为至少0.001mg/kg,优选0.01mg/kg,最高至10mg/kg,优选1mg/kg(按体重重计算)。如果是急性疾病,例如患心肌梗塞后马上使用,会需要较高剂量,特别是更多的给药次数,例如多至每天4次单剂量。特别是对于静脉给药,例如对于监护阶段的(Intensivstation)患梗塞的病人可需要每天多至200mg。缩写表AIBN α,α-偶氮二异丁腈Bn 苯基盐水 NaCl饱和水溶液CH2Cl2 二氯甲烷DCl 解吸化学电离DIP 二异丙基醚DMA 二甲基乙酰胺DME 二甲氧乙烷DMF N,N-二甲基甲酰胺EE 乙酸乙酯(EtOAc)EI 电子冲击cq 当量ES 电子喷雾电离Et 乙基FAB 快原子轰击HEP 正庚烷HOAc 乙酸Me 甲基MeOH 甲醇mp 熔点MTB 甲基叔丁基醚NBS N-溴琥珀酰亚胺NMP N-甲基吡咯烷酮RT 室温THF 氢呋喃TMU N,N,N’,N’-四甲基脲ZNS 中枢神经系统制备苯甲酰胍(I)的一般步骤
方案A:从苯甲酸(II,L=OH)
将0.01摩尔具有式II的苯甲酸衍生物溶解或悬浮于60ml无水THF中,然后加入1.78g(0.011摩尔)羰基二咪唑。将混合物于RT搅拌2小时后,向反应液中加入2.95克(0.05摩尔)胍。将混合物搅拌过夜,在减压下(旋转蒸发仪)蒸去THF,加入水,用2N HCl调节PH至6-7,并且滤出相应的苯甲酰胍(式I)。用水、甲醇或醚的盐酸溶液或其它药理上可接受的酸进行处理,可将如此获得的苯甲酰胍转化成相应的盐。制备苯甲酰胍(I)的一般步骤
方案B:从苯甲酸烷基酯(II,L=O-烷基)
将5毫摩尔具有式II的苯甲酸烷基酯和25毫摩尔胍(游离碱)溶于15ml异丙醇中或悬浮于15mlTHF中,回流加热混合物至反应完全(用薄层色谱法监测)(通常反应时间为2-5小时)。在减压下(旋转蒸发仪)蒸去溶剂,将残余物溶于300mlEE中,用50ml NaHCO3溶液洗涤3次。通过Na2SO4干燥并且真空蒸去溶剂,在硅胶上用适宜洗脱液例如EE/MeOH,5∶1层析残余物,(盐的形成,参见方案A)
实施例1:4-(4-氨基磺酰基)-苯氧基-3-三氟甲基-苯甲酰胍
a)4-氟-3-三氟甲基苯甲酸甲酯
将5g 4-氟-3-三氟甲基苯甲酸和9ml SOCl2于60℃在50mlMeOH中搅拌8小时。然后真空除去挥发性成分得到5.1g无色油状物,不需纯化而应用于下一步骤。Rf(EE/MeOH 10∶1)=0.74 MS(DCI)223(M+H)+b)4-(4-氨基磺酰基)苯氧基-3-三氟甲基苯甲酸甲酯
将890mg氟化物a)、690mg4-羟基苯磺酰胺和1.1gK2CO3于120℃在5ml DMF中搅拌2小时。将混合物冷却至RT,加入100ml盐水,且每次用50mlEE萃取3次,将有机相通过Na2SO4干燥,真空除去溶剂。得到1.2g无色油状物。Rf(MTB)=0.45 MS(DCI)376(M+H)+c)4-(4-氨基磺酰基)苯氧基-3-三氟甲基苯甲酰胍
按照方案B,将500mg甲酯1b脒基化。得到170mg无定形粉末,Rf(EE/MeOH10∶1)=0.50 MS(ES)403(M+H)+
转化成盐酸盐。mp>270℃
实施例2:4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕-3-三氟甲基苯甲酰胍二盐酸化物
a)4-氟苯磺酸-N,N’-二-叔丁基-亚氨基酰胺
于-30℃下将10.3ml溴加入900ml叔丁基胺中。将混合物加热至-5℃,加入6.6ml4-氟苯硫酚。将混合物加热至RT并在该温度搅拌4小时。随后倾至600g冰上,并加入500mlEE;将该混合物洗涤3次,每次用100ml Na2SO3饱和水溶液。真空浓缩有机相,再将残余物溶于500mlEE中;洗涤该溶液3次,每次用200ml 0.6MKH2PO4水溶液。然后将有机相与100ml 2N HCl水溶液一起搅拌1小时,然后分离掉EE相。用Na2CO3将水相调至PH=9,萃取3次,每次用200mlEE。经Na2SO4干燥并且真空除去溶剂。得到6.4g无色油状物。Rf(DIP)=0.46 MS(DCI):287(M+H)+b)4-羟基-苯磺酸-N,N’-二-叔丁基-亚氨基酰胺
将2.9g 4-氟苯磺酸-N,N’-二叔丁基-亚氨基酰胺和3.4g CsOH(-水合物)于160-170℃在25mlTMU中搅拌8小时。然后将混合物冷却至RT,加入100ml水和50ml NaHCO3饱和水溶液。且萃取3次,每次用100mlEE。经Na2SO4干燥有机相并真空除去溶液。用EE/HEP 1∶1在硅胶上层析,得到700mg无色油状物。Rf(MTB/DIP 1∶1)=0.27MS(EI):285(M+H)+c)4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕苯氧基-3-三氟甲基苯甲酸甲酯
将600mg 4-羟基-苯磺酸-N,N’-二-叔丁基-亚氨基酰胺、468mg 4-氟-3-三氟甲基苯甲酸甲酯和2.1g Cs2CO3于160℃在10ml TMU中搅拌1.5小时。将混合物冷却至RT,加入100mlNaHCO3饱和水溶液,然后将所有混合物萃取3次,每次用100mlEE.经Na2SO4干燥有机相并真空除去溶剂。用DIP在硅胶上层析,得到400mg无色油状物。Rf(DIP)=0.28MS(ES):487(M+H)+d)4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍
按照制备苯甲酰胍的一般步骤方案B将300mg4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕-3-三氟甲基苯甲酸甲酯和182mg胍于10ml异丙醇中反应。得到120mg无色油状物。Rf(EE)=0.24MS(FAB):587(M+H)+mp(二盐酸化物)=165-168℃
实施例3:4-〔4-N-(二甲基氨基乙基)-甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍二盐酸化物
将15g4-氯-3-三氟甲基苯甲酸甲酯、5.9g苯酚和17.4gK2CO3于110℃在100ml DMF中搅拌14小时。将混合物冷却至RT,用1升EE稀释,然后洗涤2次,每次用200ml水,再用0.1NNaOH水溶液洗涤2次,每次用200ml,然后用NaCl饱和水溶液洗涤2次,每次用300ml。经Na2SO4干燥有机相并真空除去溶剂。用EE/HEP1∶8在硅胶上层析,得到11g无色油状物。Rf(EE/HEP1∶8)=0.24MS(DCI):297(M+H)+b)4-苯氧基-3-三氟甲基苯甲酸
将11g 4-苯氧基-3-三氟甲基苯甲酸甲酯溶于200ml MeOH中,加入41ml 1N NaOH水溶液并将混合物于RT搅拌24小时。真空除去MeOH,然后用1升水稀释余下的混合物,用HCl水溶液调节至PH=2;滤出沉淀。将沉淀在空气中干燥48小时,得到9.2g无定形固体。Rf(EE)=0.10MS(DCI):283(M+H)+c)4-(4-氯磺酰基)苯氧基-3-三氟甲基苯甲酸
将1g4-苯氧基-3-三氟甲基苯甲酸溶于15mlCHCl3,逐滴加入710μl氯磺酸。于RT搅拌混合物3小时接着真空除去溶剂。然后加入50g冰和50ml水,搅拌混合物10分钟,滤出沉淀。得到0.96g无定形固体。Rf(DIP 2%HOAc)=0.38MS(EI):381(M+H)+
d)4-〔4-N-(二甲基氨基乙基)-甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酸
将475mg4-(4-氯磺酰基)苯氧基-3-三氟甲基苯甲酸溶于10ml丙酮中,然后加入160微升三甲基亚乙基二胺和350微升三乙胺。将混合物于RT搅拌2小时,然后用100ml水稀释并真空除去丙酮。将余下的混合物用0.1N HCl水溶液调节至PH=6-7,然后用EE萃取6次,每次用100ml。经Na2SO4干燥有机相并真空除去溶剂。得到330mg无定形固体。Rf(CH2Cl2/MeOH/HOAc/H2O8∶4∶1∶1)=0.42
ML(S(EI):447(M+H)+e)4-〔4-N-(二甲基氨基乙基)-甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酸甲酯
将330mg 4-〔4-N-(二甲基氨基乙基)-甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酸和1ml SOCl2于10ml MeOH中回流加热8小时。真空除去混合物中的挥发性成分,将残余物加入100mlNa2CO3饱和水溶液和100mlEE中,用EE萃取3次,每次用EE100ml。经Na2SO4上干燥有机相,真空除去溶剂。用EE/MeOH2∶1在硅胶上层析残余物,得到150mg无色树脂。Rf(EE/MeOH1∶1)=0.30MS(EI)∶461(M+H)+f)4-〔4-N-(二甲基氨基乙基)-甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍
按照制备苯甲酰胍的一般步骤方案B使140mg 4-〔4-N-(二甲基氨基乙基)-甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酸甲酯和90mg胍于3ml异丙醇中进行反应,得到130mg无定形固体。Rf(EE/MeOH1∶1)=0.12MS(EI):488(M+H)+mp(二盐酸化物)=203℃
按照与实施例3类似的方法合成实施例4-8的标题化合物
实施例4:4-〔4-(4-甲基哌嗪磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物
实施例5:4-〔4-(2-吡咯烷乙基氨基磺酰基)-苯氧基〕-3-三氟甲基苯甲酰胍氢马来酸盐
MS(FAB):500(M+H)+
实施例6:4-〔4-(2-哌啶乙基氨基磺酰基)苯氧基〕-3-三氟甲基苯胍二马来酸盐
实施例7:4-〔4-(N-二甲基氨基-正丙基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍
Rf(EA/MeOH1∶1)=0.06 MS(EI):488(M+H)+
实施例8:4-〔4-(N-二甲基氨基乙基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍
实施例9:4-(4-亚氨基氨磺酰)苯氨基-3-三氟甲基苯甲酰胍
a)4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕苯氧基-3-三氟甲基苯甲酸
将7.9g 4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕苯氧基-3-三氟甲基苯甲酸甲酯(实施例2c)溶于100mlMeOH中,加入40ml 2N NaOH水溶液。将混合物回流加热3小时,真空除去MeOH,将残余物加入含100ml水和100mlEE的混合物中。加入500ml NaH2PO4的饱和水溶液,将全部混合物萃取3次,每次用200mlEE。经Na2SO4干燥有机相并真空除去溶剂。得到7.2g白色结晶。Rf(MTB)=0.25 MS(ES):473(M+H)+mp=200℃b)4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酸。
将6.6g 4-〔4-(N-叔丁基亚氨基-N’-叔丁基)氨磺酰〕苯甲基-3-三氟甲基苯甲酸溶于140ml无水CH2Cl2中,加入3.7ml三氟甲烷磺酸,将混合物于RT搅拌24小时,然后将混合物搅拌加入1升0.66MKH2PO4水溶液中,分离二氯甲烷相并用EE萃取3次,每次用300ml。将合并的有机相经Na2SO4干燥并真空除去溶剂。得到6.7g粘稠油状物,不经进一步纯化便可使用。Rf(EE/MeOH5∶1)=0.21 MS(ES):361(M+H)+c)4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酸,以及d)4-(4-N-甲基-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酸甲酯
将6.7g 4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酸溶于100ml MeOH中,逐滴加入(三甲基甲硅烷基)重氮甲烷于HEP中的2N溶液20ml,将混合物于RT搅拌6小时。然后加入200ml20%。醋酸水溶液,将所有混合物搅拌30分钟。然后加入200mlEE,将该混合物萃取9次,每次用100ml 1NHCl水溶液。用Na2CO3调节水相的PH至10,再萃取3次,每次用200ml EE。经Na2SO4干燥有机相并真空除去溶剂。用EE/HEP1∶1在硅胶上层析残余物,除了890mg产物d)以外获得1.2g产物c),两种产物均为油状物。c)Rf(EE)=0.32 MS(ES):375(M+H)+d)Rf(EE)=0.38 MS(ES):389(M+H)+e)4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酰胍
按照制备苯甲酰胍的一般步骤方案B将220mg 4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酸甲酯与174mg胍于10mlTHF中进行反应。然后用EE/MeOH5∶1在硅胶上层析,获得80mg无色晶体。Rf(EE/MeOH5∶1)=0.22 MS(ES):402(M+H)+mp=156℃
实施例10:3-三氟甲基-4-(4-N-甲基亚氨基氨磺酰)苯氧基-苯甲酰胍
按照制备苯甲酰胍的一般步骤方案B将490mg 4-(4-N-甲基亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酸甲酯(实施例9d)与373mg胍于20mlTHF中进行反应。用EE/MeOH5∶1在硅胶上层析后获得370mg无色晶体。Rf(EE/MeOH5∶1)=0.33 MS(ES):416(M+H)+mp(二盐酸化物)=233℃用与实施例3类似的方法从3-甲基-4-苯氧基-苯甲酸甲酯合成实施例11的标题化合物。
实施例11:3-甲基-4-(4-(1-甲基哌嗪-4-基-磺酰基)苯氧基)-苯甲酰胍
a)3-甲基-4-苯氧基苯甲酸甲酯
将3.4g 4-氟-3-甲基苯甲酸甲酯、2.4g苯酚和19.5gCS2CO3于160℃在100mlNMP中搅拌20分钟。将混合物倾入400ml NaHCO3饱和水溶液中,将所有混合物用400ml水稀释,再萃取3次,每次用200ml MTB。经Na2SO4干燥有机相并真空除去溶剂。用EE/HEP1∶4在硅胶上层析残余物,获得2.0g无色油状物。Rf(EE/HEP1∶4)=0.33 MS(EI):243(M+H)+用与实施例9类似的方法合成实施例12的标题化合物:
实施例12:3-甲基磺酰基-4-(4-亚氨基氨磺酰)苯氧基-苯甲酰胍
实施例13:4-(4-胍基磺酰基)苯氧基-3-三氟甲基苯甲酰胍
将13.5g 4-苯氧基-3-三氟甲基苯甲酸(实施例3b)溶于150ml CHCl3中,在RT下逐滴加入3.3ml氯磺酸,然后搅拌混合物3小时。真空除去溶剂,加入300g冰和100ml水,搅拌混合物10分钟。然后加入冷却至0℃的NaCl饱和水溶液400ml,然后将混合物于0℃再搅拌15分钟,抽滤出沉淀。于40℃真空干燥,得到16.5g白色固体,不经纯化便可进一步使用。b)4-(4-氯磺酰基)苯氧基-3-三氟甲基苯甲酰氯
将14.0g 4-(4-羟基磺酰基)苯氧基-3-三氟甲基苯甲酸和1ml DMF溶于250ml SOCl2中,将该溶液在回流下加热8小时。真空除去约一半量的过量SOCl2,然后将该溶液逐滴加入1kg冰中。萃取该混合物3次,每次用500ml CH2Cl2,经MgSO4干燥有机相并真空除去溶剂。得到18.0g油状物,不经进一步纯化便可使用。Rf(DIP/2%HOAc)=0.51c)4-〔4-(3-吡啶基氧)磺酰基〕苯氧基-3-三氟甲基苯甲酸三羟基吡啶基酯。
将18.0g4-(4-氯磺酰基)苯氧基-3-三氟甲基-苯甲酰氯溶于150ml丙酮中,加入3.7g3-羟基吡啶和11.0g K2CO3,并将反应混合物于RT搅拌3小时。然后将其倾八500ml水中,并将所有混合物萃取3次,每次用300ml EE。经Na2SO4干燥有机相,真空除去溶剂,并用MTB/2%HOAc在硅胶上层析残余物。得到8.0g淡黄色油状物。Rf(MTB/2%HOAc)=0.29 MS(FAB):517(M+H)+d)4-(4-胍基磺酰基)苯氧基-3-三氟甲基苯甲酰胍
将3.0g 4-〔4-(3-吡啶基氧)磺酰基〕苯氧基-3-三氟甲基苯甲酸3-羟基吡啶基酯和3.4g胍溶于10ml异丙醇中,将该溶液回流加热3小时。真空除去溶剂,将残余物溶于400ml水中;用HCl水溶液调节该溶液至PH=8并于RT搅拌2小时。滤出沉淀物并用EE/MeOH5∶1在硅胶上层析。获得272mg无定形固体。Rf(EE/MeOH5∶1)=0.33 MS(ES):445(M+H)+
实施例14:3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕苯甲酰胍二甲磺酸盐
14a)5-羧基-2-氟苯亚磺酸
在70℃将15.6g(0.124mol)亚硫酸钠溶于120ml水中。在保持同样温度下同时分次加入23.8g(0.1mol)4-氟-3-氯磺酰基苯甲酸和10N NaOH,从而保持PH于9-10之间(放热反应)。将混合物于70℃再搅拌3小时,然后再与活性炭一起搅拌15分钟,过滤。用浓盐酸调节滤液至PH0-1,同时从外部冷却,滤出结晶性5-羧基-2-氟苯亚磺酸。为无色结晶。mp:167-170℃14b)5-羧基-2-氟苯亚磺酸二钠盐
将6.72g(0.168mol)NaOH加入含有150ml甲醇和30ml水的混合物中,在该搅拌的溶液中加入17.2g(0.08mol)羧基-2-氟苯亚磺酸,过滤除去悬浮物后,蒸去溶剂,用丙酮结晶残余物,得到14b)。无色结晶性物质,mp:>320℃14c)4-氟-3-甲基磺酰基苯甲酸甲酯
将30g(0.21mol)甲基碘加入15g(0.06mol)5-羧基-2-氟苯亚磺酸二钠盐于80ml干燥DMF的悬浮液中,将混合物于60℃搅拌6小时;蒸去溶剂并将水加入残余物。搅拌该混合物30分钟,同时用冰冷却并滤出沉淀。无色结晶性物质,mp:102-105℃14d)3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕-苯甲酸甲酯
在含有60ml二甲基乙酰胺、3.6g(0.022mol)N,N-二甲基-2-(4-羟苯基)乙基胺和9.08g(0.066mol)粉末状无水K2CO3的混合物中加入4.64g(0.02mol)4-氟-3-甲基磺酰基苯甲酸甲酯,将该悬浮液于90℃搅拌4小时。蒸去溶剂后向残余物中加入水,将随后的混合物用乙酸乙酯萃取数次;合并有机相并减压浓缩,得到黄色物质,为油状液体。14e)3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕-苯甲酸盐酸化物的制备
将1.88g(0.005mol)3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)-苯氧基〕苯甲酸甲酯于40ml半浓缩盐酸中回流煮沸5小时,然后蒸出盐酸溶液并用丙酮结晶残余物。无色结晶性物质,mp:246-248℃14f)3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕苯甲酰胍
按照与方案A类似的步骤,从3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕苯甲酸在PH为7与8之间获得14f)。无色结晶,mp:214-218℃3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕-苯甲酰胍二甲磺酸酯
按照与方案A类似的步骤,从3-甲基磺酰基-4-〔4-(2-二甲基氨基乙基)苯氧基〕苯甲酰胍在乙醇中用2.5当量甲烷磺酸进行处理,得到上式化合物。无色固体mp:102℃
实施例15:4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-甲基磺酰基-苯甲酰胍二盐酸化物
15a)4-(2-二甲基氨基乙基)硫代甲基-苯酚的制备
将含有200mg对甲苯磺酸、14.1g(0.1mol)2-二甲基氨基乙基硫醇盐酸化物和12.4g(0.1mol)4-羟基苄醇于250ml甲苯中的混合物煮沸,回流约5小时,在Kutscher和Steudel水分离器上赶出溶剂,将残余物溶于甲醇中,然后过滤该溶液。再次浓缩之后,从丙酮中结晶残余物,滤出结晶性产物,将略微潮解的团块在隔绝空气的条件下经NaOH干燥。mp:134-140℃15b)4-〔4-(2-二甲基氨基甲基)硫代甲基-苯氧基〕-3-甲基磺酰基苯甲酸甲酯
将含有3.48g(0.015mol)4-(2-二甲基氨基乙基)硫代甲基苯酚、40ml无水四甲基脲、6.8g(0.049mol)无水粉末状K2CO3和3.48g(0.015mol)4-氟-3-甲基磺酰基苯甲酸甲酯的混合物于90-100℃搅拌6小时,蒸去溶剂将残余物溶于水中。用乙酸乙酯萃取后,干燥并浓缩所合并的有机相,得到油状的所需产物。15c)4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-甲基磺酰基苯甲酸盐酸化物
用与实施例14d)所述步骤相似的方法,在20%HCl中水解4-氟-3-甲基磺酰基苯甲酸甲酯,得到上述化合物。无色至淡黄色结晶性物质,mp:179-185℃15d)4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
用与实施例14e)所述步骤相似的方法,从4-〔4-(2-二甲基氨基乙基)-硫代甲基-苯氧基〕-3-甲基磺酰基苯甲酸盐酸化物获得上述化合物。吸湿性物质,mp:230℃。
实施例16:4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
在保护性气体(氩)气氛中,向12.6g(0.1mol)4-巯基苯酚于100ml无水DMF的溶液中加入17.28g(0.11mol)2-二乙基氨基乙基氯化物盐酸化物,再加入19.38g(0.15mol)乙基二异丙基胺,将反应混合物于110℃加热12小时,同时用电磁搅拌。蒸去溶剂后,向残余中加入水,用2N NaOH调节混合物至PH8-9;将无定形沉淀用乙酸乙酯萃取数次,将合并的有机相经硫酸钠干燥。蒸去溶剂,将残余物在硅胶上进行柱层析,用含有8份乙酸乙酯和1份甲醇的混合物洗脱。无色结晶mp108-110℃16b)4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-甲基磺酰基苯甲酸甲酯
按照与14d)所述步骤类似的方法,将N,N-二甲基-2-(4-羟基苯基硫代)乙基胺与4-氟-3-甲基磺酰基苯甲酸甲酯反应,用DMF代替二甲基乙酰胺作为反应介质,得到黄色油状上述化合物。黄色油状液体。16c)4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-甲基磺酰基苯甲酸
在10ml冰醋酸和70ml半浓缩HCl中将6.8g 4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-甲基磺酰基苯甲酸甲酯煮沸,回流条件下保持5小时。蒸去溶剂后得到无定形的固态所需产物,其不具有特定熔点。16d)4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
按照与方案A中的步骤类似的方法获得上述物质。无色固体,分解温度:160℃并起泡沫
实施例17:4-〔4-(2-二甲基氨基乙基磺酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
在5-10℃向3.8g(0.008mol)4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-甲基磺酰基苯甲酸于50ml冰乙酸的溶液中分次加入6.9g(0.028mol)3-氯过苯甲酸,将混合物于RT搅拌12小时。加水后滤出3-氯苯甲酸沉淀,并用乙酸乙酯从滤液中萃取其它杂质。浓缩水相,用乙酸乙酯结晶无定形残余物。无色晶体,mp:167-171℃17b)4-〔4-(2-二甲基氨基乙基磺酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
按照与方案A中的步骤类似的方法,用TMU作为反应介质从4-〔4-(2-二甲基氨基乙基磺酰基)-苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。用甲醇结晶二盐酸化物无色晶体,mp:233-240℃(分解)
实施例18:4-〔(4-胍基羰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
按照与14d)中的步骤类似的方法将4-羟基苯甲酸乙酯与4-氟-3-甲基磺酰基苯甲酸甲酯反应,得到无色至淡黄色油状的4-(4-乙氧基羰基苯氧基)-苯甲酸甲酯,不需要进一步纯化步骤,用与步骤16c)类似的方法将其水解,得到4-(4-羧基苯氧基)-3-甲基磺酰基苯甲酸。无色结晶mp:272-275℃18b)4-〔(4-胍基羰基)苯氧基〕-3-甲基磺酰基-苯甲酰胍二盐酸化物
按照与方案A所述的步骤类似的方法,将0.74g(0.0022mol)(4-羧基苯氧基)-3-甲基磺酰基苯甲酸与0.78g(0.0048mol)羰基二咪唑及1.55g(0.026mol)胍于DMA中进行反应,得到上述化合物。无色结晶mp:252℃(分解)
实施例19:4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物
19a)4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-三氟甲基苯甲酸甲酯
与实施例15b)中所述步骤类似,从4-(2-二甲基氨基乙基)其中用硫代甲基-苯酚和4-氟-3-三氟甲基苯甲酸甲酯获得上述化合物,其中用DMU作为反应介质,为无定形油状产物。19b)4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-三氟甲基苯甲酸
与实施例14d)中所述步骤类似,用酸水解4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-三氟甲基甲酸甲酯,得到上述化合物。无色吸湿性晶体mp158-168℃(分解)19c)4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,在反应介质TMU中从4-〔4-(2-二甲基氨基乙基)硫代甲基-苯氧基〕-3-三氟甲基苯甲酸获得上述化合物。为无定形的强吸湿性固体,于80-85℃分解。
实施例20:4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物
与实施例15b)中所述步骤类似,在反应介质DMU中从4-(2-二甲基氨基乙基硫代)苯酚和4-氟-3-三氟甲基苯甲酸甲酯获得上述化合物。为无定形油状产物。20b)4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-三氟甲基苯甲酸
与实施例14d)中所述步骤类似,用酸水解4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-三氟甲基苯甲酸甲酯,获得上述化合物。用丙酮结晶所需的4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-三氟甲基苯甲酸。无色晶体,mp174-182℃(分解)20c)4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,在反应介质THF中从4-〔4-(2-二甲基氨基乙基硫代)苯氧基〕-3-三氟甲基苯甲酸获得上述化合物。无定形、吸湿性结晶性固休。mp:240
实施例21:3-三氟甲基-4-〔4-(2-二甲基氨基乙基)苯氧基〕苯甲酰胍二盐酸盐
21a)4-氯-3-三氟甲基-苯甲酸
先从100mg5-溴-2-氯苯并三氟化物和10.2g镁于600ml乙醚中制备格利雅(Grignarcl)化合物。在RT下向该溶液中通入60g无水CO2。逐滴加入NaHSO4饱和水溶液500ml并进行相分离;用2×100ml乙醚进一步萃取。再将有机相萃取3次,每次用1N NaOH300ml,然后将水相洗涤3次,每次用100ml乙醚。用HCl调节水相至PH=2,加水稀释至4升。抽滤出产物并真空干燥。75g白色粉末Rf(MTB2%HOAc)=0.6821b)4-氯-3-三氟甲基苯甲酸甲酯
将75g4-氯-3-三氟甲基苯甲酸溶于500ml MeOH,逐滴加入75ml SOCl2。将混合物回流煮沸5小时,再真空除去挥发性成分。将残余物加入1升EE中,用500ml Na2CO3饱和水溶液洗涤该溶液。在NaSO4上干燥有机相,真空除去溶剂并真空蒸馏该产物。b.p.94℃(2托)Rf(DIP)=0.49 MS(DCI):239(M+H)+21c)4-〔4-(2-(二甲基氨基)乙基)苯氧基〕-3-三氟甲基苯甲酸甲酯
将1.9g4-氯-3-三氟甲基苯甲酸甲酯、1.3g4-(2-二甲基氨基)乙基-苯酚和7.8g(CS2CO3于50ml四甲基脲中于140℃搅拌5小时。冷却混合物,然后加入300ml NaHCO3饱和水溶液和150ml水,将所有混合物萃取3次,每次用100ml EE。经Na2SO4干燥有机相并真空除去溶剂。用丙酮/水10∶1层析,得到2.0g无色油状物。Rf(丙酮/水10∶1)=0.15MS(DCI):368(M+H)+21d)4-〔4-(2-(二甲基氨基)乙基)苯氧基〕-3-三氟甲基苯甲酰胍
按照方案B的方法,在60ml异丙醇中用1.6g胍使2.0g4-〔4-(2-(二甲基氨基)乙基〕苯氧基-3-三氟甲基苯甲酸甲酯脒基化。将粗产品转化成二盐酸化物并从1,2-二甲氧基乙烷/水9∶1中重结晶mp(游离碱):164℃mp(二盐酸化物):236℃ MS(DCI):395(M+H)+其二盐酸化物于水中的溶解度,49mg/ml(PH=5.3)
实施例22:4-〔4-N,N-二甲基氨基乙基苯氧基〕-3-氨磺酰苯甲酰胍二甲磺酸盐
与方案A中所述步骤类似,以二甲基乙酰胺或N-甲基吡咯烷酮为反应介质,从4-〔4-(2-二甲基氨基乙基)苯氧基〕-3-氨磺酰苯甲酸获得上式化合物。无定形、吸湿性、结晶性固体。mp:183℃a)4-〔4-(2-二甲基氨基乙基)苯氧基〕-3-氨磺酰苯甲酸甲酯
将0.011mol N,N-二甲基-2-(4-羟苯基)-乙基胺、0.033mol碳酸钾(研磨后)和0.01mol4-氟-3-氨磺酰苯甲酸甲酯于40ml二甲基乙酰胺中在90-100℃加热5小时。蒸出溶剂后,用水搅拌残余物,用乙酸乙酯处理棕色无定形产物;滤出结晶性沉淀,并从滤液中蒸去溶剂。得到无定形油状产物b)4-〔4-(2-二甲基氨基乙基)苯氧基〕-3-氨磺酰苯甲酸
在60ml沸腾的中等浓度盐酸中水解0.0066mol相应的甲酯(a)5小时,获得上述化合物。真空蒸出盐酸后。用丙酮处理残余物并滤出沉淀。蒸出溶剂,获得所需的苯甲酸。从60℃开始软化。
实施例23:3-氯-4-〔4-(2-二甲基氨基乙基)苯氧基〕-5-甲基磺酰基苯甲酰胍二甲磺酸盐
与方案A中所述步骤类似,以二甲基乙酰胺或N-甲基吡咯烷酮为反应介质,从3-氯-4-〔4-(2-二甲基氨基乙基)-苯氧基〕-5-甲基磺酰基苯甲酸获得上述化合物。吸湿性、结晶性固体,mp:200a)3-氯-4-〔4-(2-二甲基氨基乙基)苯氧基〕-5-甲基磺酰基苯甲酸甲酯
与实施例22a)类似,将3,4-二氯-5-甲基磺酰基苯甲酸甲酯与N,N-二甲基-2-(4-羟苯基)乙基胺反应,获得上述化合物。无定形油状物质。b)3-氯-4-〔4-(2-二甲基氨基乙基)苯氧基〕-5-甲基磺酰基苯甲酸
与实施例22a)类似,获得上述化合物,结晶性固体,分解:238-244℃
实施例24:4-〔(4-胍基羰基)苯氧基〕-3-甲基磺酰基苯甲酰胍
与实施例18的无盐碱类似,在DMF中用三乙胺处理4-〔(4-胍基羰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物,获得上述化合物无色结晶性固体,mp:237℃
实施例25:4-〔4-(2-N-咪唑基-1-氧-乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以干二乙基乙酰胺或N-甲基吡咯烷酮为反应介质,从4-〔4-(2-N-咪唑基-1-氧-乙基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,分解:255℃a)4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸
于0-5℃向含有0.08mol氯代乙酰基氯、16g无水氯化铝和150ml 1,2-二氯乙烷的混合物中分次加入0.02mol 3-甲基磺酰基-4-苯氧基苯甲酸,将该混合物于室温搅拌2小时,然后于40-45℃搅拌2小时。放置过夜后,边搅拌边将反应混合物倾入冰水中,滤出结晶性沉淀,用水洗涤并干燥。黄色结晶,mp:184-187℃b)4-〔4-(2-N-咪唑基-1-氧-乙基)苯氧基〕-3-甲基-磺酰基苯甲酸
将0.005mol 4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(25a)于25ml无水DMF中的溶液于60℃与0.0225mol咪唑一起搅拌4小时,然后蒸出溶剂。用水处理无定形残余物之后,用2N盐酸调节PH至2-3,搅拌混合物1小时,滤出结晶性沉淀。晶体,分解:235-241℃
实施例26:4-〔4-(2-咪唑基硫代乙酰基)苯氧基〕-3-甲基
磺酰基苯甲酰胍二盐酸化物
与方案A中所述类似,以含有50mlTHF和10ml二甲基乙酰胺的混合物作为反应介质,从4-〔4-(2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:220℃a)4-〔4-(2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸
将4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(实施例25a)与1mol2-巯基咪唑于20ml丙酮中反应,短时间内加热至沸点。将混合物于室温搅拌约5天,滤出结晶性沉淀。分解:202-205℃
实施例27:4-〔4-(4,5-二氢-2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以含有50mlTHF和10ml二甲基乙酰胺的混合物为反应介质,从4-〔4-(4,5-二氢-2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:210℃a)4-〔4-(4,5-二氢-2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸,
与26a)的步骤类似,将4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(实施例25a)与2-巯基-4,5-二氢咪唑反应,获得上述化合物。分解:305-310℃
实施例28:4-〔4-(N,N’-二甲基-S-异硫脲基乙酰基)-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A所述步骤类似,以含有50ml THF和10ml二甲基乙酰胺的混合物为反应介质,从4-〔4-(N,N’-二甲基-S-异硫脲基乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体。mp:150℃a)4-〔4-(N,N’-二甲基-S-异硫脲基-乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸
从26a)的步骤类似,在室温下将4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(实施例25a)与N,N’-二甲基硫脲反应,获得上述化合物。无色晶体。分解:185-190℃
实施例29:4-〔4-(2-苯并咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以THF为反应介质从4-〔4-(2-苯并咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体。mp:228℃a)4-〔4-(2-苯并咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸
按照步骤26a),将4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(实施例25a)与2-巯基苯并咪唑在DMF中反应,生成上述化合物。mp:182℃
实施例30:4-〔4-(2-吡啶基硫代乙酰基)苯氧基〕-3-甲基
与方案A中所述步骤类似,以THF作为反应介质,从4-〔4-(2-吡啶基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp203℃a)4-〔4-(2-吡啶基硫代乙酰基)苯氧基〕-3-甲基磺酰基-苯甲酸
与步骤26a)类似,将4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(实施例25a)与2-巯基吡啶反应,获得上述化合物。mp:194-196℃
实施例31;4-〔4-(2-喹啉基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以THF为反应介质,从4-〔4-(2-喹啉基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:192℃a)4-〔4-(2-喹啉基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸
与步骤26a)类似,在DMF中,将4-(4-氯乙酰基苯氧基)-3-甲基磺酰基苯甲酸(实施例25a)与2-巯基喹啉反应。mp210-214℃。
实施例32:4-〔4-(2-N-咪唑基-1-羟乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以二甲基乙酰胺或N-甲基吡咯烷为反应介质,从4-〔4-(2-N-咪唑基-1-羟乙基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物,无色结晶物质,分解温度:260℃a)4-〔4-(2-N-咪唑基-1-羟乙基)苯氧基〕-3-甲基磺酰基苯甲酸
在40ml乙醇中,用0.0068mol氢硼化钠还原0.0034mol4-〔4-(2-N-咪唑基-1-氧-乙基)苯氧基〕-3-甲基磺酰基苯甲酸,获得上述化合物。蒸去溶剂,用水处理残渣,用2N HCl调节至PH=4,将混合物于室温下搅拌数小时,滤出结晶。mp240-248℃
实施例33:3-甲基磺酰基-4-(4-氨磺酰苯氧基)苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以二甲基乙酰胺为反应介质,从3-甲基磺酰基-4-(4-氨磺酰苯氧基)苯甲酸获得上述化合物。无色结晶性固体,分解温度:267℃a)3-甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸
在0-5℃于60ml二氯甲烷中将0.03mol4-苯氧基-3-甲基磺酰基苯甲酸与0.15mol氯磺酸反应,然后将混合物于室温搅拌4小时,用冰水处理混合物后,分离二氯甲烷相,用水洗涤并于硫酸镁上干燥,然后馏掉溶剂,获得上述化合物。晶体,mp:167-170℃b)3-甲基磺酰基-4-(4-氨磺酰苯氧基)苯甲酸
将3-甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸与浓氨水于室温下反应24小时,蒸出氨并用2N HCl酸化水溶液至PH1-2,获得上述化合物。滤出结晶,用水洗涤并干燥。无色结晶性物质,mp240-245℃
实施例34:4-〔4-(1-羟基-2-(2-吡啶基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以THF为反应介质从4-〔4-(1-羟基-2-(2-吡啶基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:116℃
a)4-〔4-(1-羟基-2-(2-吡啶基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酸,
用与实施例32a)类似的方法获得。无色结晶性物质,mp:169-174℃。
实施例35:4-〔4-(1-羟基-2-(2-苯并咪唑基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以二甲基乙酰胺作为反应介质,从4-〔4-(1-羟基-2-(2-苯并咪唑基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:213℃。a)4-〔4-(1-羟基-2-(2-苯并咪唑基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酸
用与实施例32a)类似的方法获得。无色结晶性物质,mp:186-188℃。
实施例36:4-〔4-(1-羟基-2-(2-喹啉基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以THF为反应介质,从4-〔4-(1-羟基-2-(2-喹啉基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:180℃a)4-〔4-(1-羟基-2-(2-喹啉基硫代)乙基)苯氧基〕-3-甲基磺酰基苯甲酸
用与实施例32a)类似的方法,从4-〔4-(2-喹啉基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酸(实施例31a)获得。无色结晶性物质。
实施例37:4-〔4-(N,N-二甲基甘氨酰氨基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以THF为反应介质,从4-〔4-(N,N-二甲基甘氨酰氨基)苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:233℃a)3-甲基磺酰基-4-(4-硝基苯氧基)苯甲酸
在-10℃,于含有8ml乙酸酐和4ml冰乙酸的混合物中将0.02mol3-甲基磺酰基-4-苯氧基苯甲酸与0.96ml 100%硝酸反应,制成上述化合物。将混合物于该温度搅拌1.5小时后,将其在室温搅拌24小时,再于40℃搅拌6小时,然后倾入冰水中,搅拌下用水结晶无定形油状产物。黄色结晶性物质,mp:140-150℃b)4-(4-氨基苯氧基)-3-甲基磺酸基苯甲酸
在标准压力下于甲醇中用阮内镍催化氢化3-甲基磺酰基-4-(4-硝基苯氧基)苯甲酸(实施例37a)直至氢吸收完全,生成上述化合物。蒸去溶剂后获得均一的无定形油状物质。c)N,N-二甲基甘氨酸咪唑烷盐酸化物
将N,N’-二甲基甘氨酸咪唑烷盐酸化物与羰基二咪唑于无水二甲基乙酰胺中反应,从中分离出产物,获得上述化合物。混合物不需经过其它处理步骤便可用于下一步反应。d)4-〔4-(N,N-二甲基甘氨酰氨基)苯氧基〕-3-甲基磺酰基苯甲酸,
在二甲基乙酰胺中将N,N-二甲基甘氨酸咪唑烷盐酸化物(实施例37c)与4-(4-氨基苯氧基)-3-甲基磺酰基苯甲酸(实施例37b)于室温下搅拌反应5小时,获得上述化合物。蒸出溶剂,用HCl调节PH至1-2,用乙酸乙酯萃取混合物。蒸出水相,用甲醇处理残余物。滤出不溶性物质后,获得无色油状的所需产物。
实施例38:4-〔4-N,N-二乙基氨基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以无水二甲基乙酰胺为反应介质,从4-〔4-(N,N-二乙基氨基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:206℃a)4-〔4-(N,N-二乙基氨基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
在过量三乙胺(约0.015mol)存在下以甲醇为反应介质,将0.05mol3-甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与0.06mol N,N-二乙基氨基乙基胺反应,获得上述化合物。蒸去溶剂混合物,用少量水混合残余物,将混合物调到PH4-5。滤出结晶性沉淀。mp:263-268℃
实施例39:4-〔4-(1-甲基-4-哌嗪)磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤相似,用THF为反应介质,从4-〔4-(1-甲基-4-哌嗪磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,分解:234-244℃a)4-〔4-(1-甲基-4-哌嗪)磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实施例38a)类似,将甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与N-甲基哌嗪反应,获得上述化合物。无色晶体,分解:287-292℃
实施例40:4-〔4-(4-咪唑基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以二甲基乙酰胺为反应介质,从4-〔4-(4-咪唑基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:264℃a)4-〔4-(4-咪唑基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实施例38a)类似,将甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与组胺反应得到。无色无定形固体,分解:265℃。
实施例41:4-〔4-(3-N-咪唑基-1-丙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以THF为反应介质,从4-〔4-(3-N-咪唑基-1-丙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,分解:257℃a)4-〔4-(3-N-咪唑基-1-丙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实施例38a)类似,将甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与1-(3-氨基丙基)咪唑反应,获得上述化合物。无色不定形固体,mp:250℃。
实施例42:4-〔4-(1-甲基-2-吡咯烷基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以二甲基乙酰胺为反应介质,从4-〔4-(1-甲基-2-吡咯烷基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:254℃a)4-〔4-(1-甲基-2-吡咯烷基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实施例38a)类似,将甲基磺酰-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与2-(2-氨基乙基)-1-甲基吡咯烷反应,生成上述化合物。mp242-247℃
实施例43:4-〔4-(N-吗啉代乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以二甲基乙酰胺为反应介质,从4-〔4-(N-吗啉代乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp272℃。a)4-〔4-(N-吗啉代乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实例38a)类似,将甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与N-(2-氨基乙基)吗啉反应,生成上述化合物。无色结晶性化合物,mp220-224℃。
实施例44:4-〔4-(N-哌啶子基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A中所述步骤类似,以无水二甲基乙酰胺为反应介质,从4-〔4-(N-哌啶子基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:266℃a)4-〔4-(N-哌啶子基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实施例38a)类似,将甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与N-(2-氨基乙基)哌啶反应,获得上述化合物。无色结晶性物质,mp:271-273℃。
实施例45:4-〔4-(2-吡啶基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
与方案A所述步骤类似,以无水二甲基乙酰胺为反应介质,从4-〔4-(2-吡啶基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸获得上述化合物。无色结晶性固体,mp:257℃。a)4-〔4-(2-吡啶基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酸
与实施例38a)类似,将甲基磺酰基-4-(4-氯磺酰基苯氧基)苯甲酸(实施例33a)与2-(氨基乙基)吡啶反应,生成上述化合物。无色晶体,mp268-270℃。
实施例46:4-〔4-(2-二甲基氨基乙基)磺酰基甲基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物
用过酸氧化法,与实施例“4”中所述步骤类似,从4-〔4-(2-二甲基氨基乙基)硫代甲基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物(实施例15)获得上述化合物。无色晶体,mp:245℃。
实施例47:4-〔4-(2-二甲基氨基乙基)磺酰基甲基-苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物
用过酸氧化法,与实施例1 7中所述步骤类似,从4-〔4-(2-甲基氨基乙基)硫代甲基-苯氧基)-3-三氟甲基苯甲酰胍二盐酸化物(实施例19)获得上述化合物。无色晶体,mp140℃。药理数据对兔的红细胞Na+/H+交换器的抑制作用
给予新西兰大白兔(Ivanovas)以含有2%胆固醇的标准饮食6周,用以激活Na+/H+交换,从而可用火焰分光光度计测定Na+通过Na+/H+交换进入红细胞的量。从耳动脉取血,并加入25IE杆素钾抗凝。用每份样品中的一部分测定血球比率,一式二份,用离心法测定。用每份样品中的100μl试样测定红细胞中Na+的初始含量。
为了测定对氨氯吡脒敏感的钠摄入量,取每份血样100μl分别于PH7.4及37℃下温育于5ml高渗盐/蔗糖介质中(毫摩尔/升:140NaCl,3KCl,150蔗糖,0.1乌本苷,20三-羟甲基氨基甲烷)。然后将红细胞用冰冷的MgCl2/乌本苷溶液(毫摩尔/升:112MgCl2,0.1乌本苷)洗涤3次,并于2ml蒸馏水中溶血。用火焰分光光度计测定细胞内的钠含量。
从初始的钠值与温育后细胞中的钠含量的差计算单纯的Na+摄入量。通过用或不用3×10-4mol/升氨氯吡脒温育的红细胞中钠含量的差得出氨氯吡脒抑制性钠摄入量。用本发明的化合物进行同样的步骤。结果对Na+/H+交换器的抑制作用
实施例 | IC50(微摩尔/升) |
1 | 0.8 |
2 | 0.32 |
3 | 0.05 |
4 | 0.082 |
5 | 0.3 |
6 | 0.1 |
7 | 0.06 |
8 | 0.005 |
9 | 0.1 |
14 | 0.05 |
15 | 0.01 |
16 | 0.16 |
17 | 1 |
18 | 0.2 |
19 | 0.008 |
20 | 0.04 |
21 | 0.014 |
28 | 0.12 |
32 | 0.44 |
33 | 0.20 |
46 | 0.09 |
47 | 0.07 |
Claims (19)
1.具有式I的化合物其中:三个取代基R(1)、R(2)和R(3)之一为
R(6)-A-B-D-;
R(6)为可质子化的碱性基团,即氨基基团-NR(7)R
R(7)、R(8)、R(9)和R(10)彼此独立地为氢或具有1、2、
3或4个碳原子的烷基;
或者
R(7)和R(8)一起为CaH2a;
a为4,5,6或7;
其中,当a=5,6或7时基团CaH2a的一个亚甲基基团可被杂原子基团O、SOm或NR(11)代替,或者
R(8)和R(9)或R(9)和R(10)或R(7)和R(10)为基团CaH2a;
a为2、3、4或5;
其中,当a=3、4或5时,基团CaH2a的一个亚甲
基基团可被杂原子基团O、SOm或NR(11)代替;
m为零、1或2;
R(11)为氢或甲基;或者
R(6)为具有1-9个碳原子的碱性芳香杂环体系;
A为CbH2b;
b为1、2、3、4、5、6、7、8、9或10;
其中,在基团CbH2b中,一个或两个亚甲
基基团可被选自下列一组基团中的一个
所取代,包括-O-、-CO-、-CH〔OR(20〕-、
-SOm-、-NR(20)-、
-NR(20)-CO-、-NR(20)-CO-NH-、
和-SOOaa〔NR(19)〕bb-;
并且其中在基团CbH2b中的一个亚甲基
基团可被-CH-R(99)替代,其中R(99)
与R(7)一起形成一个吡咯烷或哌啶环;
aa为1或2;
bb为0或1;
aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的
烷基,
R(12)和R(13)彼此独立地为氢、甲基、F、Cl、
Br、I、CF3或-SOW-R(14);
R(14)为甲基或NR(15)R(16);
R(15)和R(16)彼此独立地为氢或具有1、2、3
或4个碳原子的烷基;
W为零、1或2;
D为-CdH2d-Xf-;
d为零、1、2、3或4;
X为-O-、-CO-、-CH〔OR(21)〕-、
-SOm-或-NR(21)-;
f为零或1;
R(21)为氢或甲基;
m为零、1或2;并且在每种情况下,取代基R(1)和R(2)和R(3)中的另外两个彼此独立地为氢、F、Cl、Br、I、-CN-、-(C1-C8)-烷基、-(C2-C8)-链烯基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
g为零、1、2、3或4;
h为零或1;
R(35)和R(36)彼此独立地为氢或具有1、2、3、4、5或6个碳原子的烷基;
或者
R(35)和R(36)一起为4-7个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-、-NCH3或-N-苄基所替代;
Z为-O-、-CO-、-SOV-、-NR(18)-、-NR(18)-CO-、-NR(18)-CO-NH-或-NR(18)-SO2-;
R(18)为氢或甲基;
V为零、1或2;
R(17)为氢、具有3、5或6个碳原子的环烷基、或CkF2k+1-;
k为1、2或3,
或者
R(17)为吡咯-1-基、吡咯-2-基或吡咯-3-基,其不被取代或被选自下列基团的1-4个取代基取代,包括F、Cl、Br、I、-CN、(C2-C8)-链烷酰基、(C2-C8)-烷氧羰基、甲酰基、羧基、-CF3、甲基和甲氧基;
或者
R(17)为-(C3-C8)-环烷基或苯基,其不被取代或被选自下列基团的1-3个取代基取代,包括F和Cl、-CF3、甲基、羟基、甲氧基、-NR(37)R(38)、CH3SO2-和H2NO2S-;
R(37)和R(38)为氢或-CH3;R(4)和R(5)彼引独立地为氢、具有1、2、3或4个碳原子的烷基、F、Cl、-OR(32)、-NR(33)R(34)或-CrF2r+1;
R(32)、R(33)和R(34)彼此独立地为氢或具有1、2
或3个碳原子的烷基;
r为1、2、3或4。
及其药理上可接受的盐。
2.根据要求1的具有式I的化合物,其中:
R(1)为氢、F、Cl、-(C1-C4)-烷基、-(C2-C4)-链烯基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
R(35)和R(36)彼此独立地为氢、甲基或乙基;
或者
R(35)和R(36)一起为4-5个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-或-NCH3替代;
R(17)为氢、具有5或6个碳原子的环烷基、或CkF2k+1-;
k为1、2或3,
g为零、1、2、3或4;
h为零或1;
Z为-O-,-CO-,-SOV-、-NR(18)-、-NR(18)-CO-、-NR(18)-CO-NH-或-NR(18)-SO2-;
R(18)为氢或甲基;
V为零、1或2;
或者,如果g和h为零,
R(17)为吡咯-1-基、吡咯-2-基或吡咯-3-基,其不被取代或被选自下列基团的1-2个取代基取代,包括F、Cl、(C2-C5)-链烷酰基、(C2-C5)-烷氧羰基、甲酰基、羧基、-CF3、甲基和甲氧基;
或者
R(17)为-(C3-C8)-环烷基或苯基,其不被取代或被选自下列基团的1-2个取代基取代,包括F和Cl、-CF3、甲基、甲氧基、-NR(37)R(38)、CH3SO2-和H2NO2S-;
R(37)和R(38)彼此独立地为氢或-CH3;
取代基R(2)和R(3)之一为R(6)-A-B-D;
R(6)为-NR(7)R(8)、脒基基团R(7)R(8)N-C〔=N-R(9)〕-或胍基基团
R(7)、R(8)、R(9)和R(10)彼此独立地为氢或具有1、2、3或4个碳原子的烷基;或者
R(7)和R(8)一起为CaH2a;
a为4、5、6或7;
其中,当a=5、6或7时,基团CaH2a中的一个
亚甲基基团可被杂原子基团O、SOm或
NR(11)代替
R(11)为氢或甲基;或者
R(8)和R(9)一起为CaH2a;
a为2、3、4或5;
其中,当a=3、4或5时,基团CaH2a中的一个
亚甲基基团可被杂原子基团O、SOm或
NR(11)代替;
m为零、1或2;或者R(6)为咪唑基、吡啶基、喹啉基或异喹啉基;A为CbH2b
b为1、2、3、4或5,
其中,基团CbH2b中的一个或两个亚甲基基团
可被选自下列一组基团中的一个所替代,包括
-O-、-CO-、-CH〔OR(20)〔-、-SOm-、
NR(20)、-NR(20)-CO-、-NR(20)-CO-NH-
和-SOaa〔NR(19)〕bb-;
并且其中基团CbH2b中的一个亚甲基基团可被
-CH-R(99)替代,其中R(99)与R(7)一起形
成一个吡咯烷或哌啶环;
aa为1或2;
bb为0或1;
aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的烷
基,
R(14)为甲基或NR(15)R(16);
R(15)和R(16)彼此独立地为氢或具
有1、2、3或4个碳原子的烷基;D为-CdH2d-Xf-;
d为零、1、2、3或4;
X为-O-、-CO-、-CH〔OR(21)〕-
、-SOm-或-NR(21)-;
f为零或1;
R(21)为氢或甲基;
m为零、1或2;并且在每种情况下,取代基R(2)和R(3)的另一个为氢、具有1、2、3或4个碳原子的烷基、F、Cl或CF3;R(4)和R(5)彼此独立地为氢、具有1、2或3个碳原子的烷基、F、Cl或-CF3;
3.根据权利要求1或2的具有式I的化合物,其中:R(1)为氢、F、Cl、具有1、2、3、或4个碳原子的烷基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
g为零、1、2、3或4;
h为零或1;
Z为-O-、-CO-、-SOV-、-NR(18)-
、-NR(18)-CO-、-NR(18)-CO-NH
或-NR(18)-SO2-;
R(18)为氢或甲基;
V为零、1或2;
R(17)为氢、含有5或6个碳原子的环烷基、或CF3-
或者,如果g和h为零,
R(17)为吡咯-1-基,其不被取代或被选
自下列基团的1-2个取代基取代,包括F、Cl、
(C2-C5)-链烷酰基、(C2-C5)-烷氧羰基、
-CF3和甲基;
或者
R(17)为-(C5-C6)-环烷基或苯基,其不被取代或被选自下列基团的一个取代基取代,包括F和Cl、-CF3、甲基、CH3SO2-和H2NO2S-;
R(35)和R(36)彼此独立地为氢、甲基或乙基;
或者
R(35)和R(36)一起为4-5个亚甲基基团,其中的一个CH2基团可被氧、-S-、-NH-或-NCH3替代;取代基R(2)和R(3)之一为R(6)-A-B-D-;
R(7)为氢或具有1、2、3或4个碳原子的烷基;
R(8)、R(9)和R(10)彼此独立地为氢、甲基或
乙基;
或者
R(7)和R(8)一起为CaH2a;a为4或5;其中当
a=5时,基团CaH2a中的一个亚甲基基团可被
NR(11)替代,R(11)为氢或甲基;或者R(6)为咪唑基或吡啶基;A为CbH2b;b为1、2、3、4或5,其中,在基团CbH2b中,一个或两个亚甲基基团可被选自下列一组基团中的一个所替代,包括-CO-、-CH〔OR(20)〕-、-NR(20)-CO-、-SOaa〔NR(19)〕bb和-SO2-;并且其中,基团C2bH2b中的一个亚甲基基团可被-CH-R(99)替代,其中R(99)与R(7)一起形成一个吡咯烷或哌啶环;aa为1或2,bb为0或1;aa+bb=2;R(19)为氢或具有1、2、3或4个碳原子的烷基,
R(20)为氢或甲基;
或者,如果b为2、3、4或5,CbH2b中的一个碳原子
可被-O-、-S-、-NR(20)-、-NR(20)-CO-
或-NR(20)-CO-NH-替代;B为亚苯基残基,
R(12)和R(13)彼此独立地为氢、甲基、F、Cl、CF3
或-SO2R(14);
R(14)为甲基或NH2;D为-CH2-、-O-、-CO-、-SOm-或-NR(21);
m为零或2
R(21)为氢或甲基;并且在每种情况下残基R(2)和R(3)的另一个为氢;R(4)和R(5)彼此独立地为氢、具有1、2或3个碳原子的烷基、F、Cl或-CF3;
4.根据权利要求1-3中至少一项的具有式I的化合物,其中:R(1)为氢、F、Cl具有1、2、3或4个碳原子的烷基、-NR(35)R(36)或R(17)-CgH2g-Zh-;
g为零或1;
h为零或1;
Z为-O-、-CO-、-NR(18)-CO-、-NR(18)-CO-NH-
或-NR(18)-SO2-;
R(18)为氢或甲基;
或者,如果g为1;
Z为-SO2-;
R(17)为氢或CF3-;
R(35)为R(36)彼此独立地为氢、甲基或乙基;
或者
R(35)和R(36)一起为4-5个亚甲基基团,其中一个CH2基团可被氧、-S-、-NH-或-NCH3替代;取代基R(2)和R(3)之一为R(6)-A-B-D-;
R(6)为-NR(7)R(8)或胍基基团R(7)为氢或具有1、2、3或4个碳原子的烷基;R(8)、R(9)和R(10)彼此独立地为氢、甲基或乙基;或者
R(7)和R(8)一起为CaH2a;a为4或5;其中,
当a=5时,基团CaH2a中的一个亚甲基基团可
被-NH-或-NCH3-替代,或者R(6)为咪唑基;A为CbH2b
b为1、2、3或4;其中,基团CbH2b中的一个或
两个亚甲基基团可被选自下列基团中的一个
所替代,包括-CO,-SOaa〔NR(19)〕bb和-SO2-,并且其中,基团CbH2b中的一个亚甲基基团可被-CH-R(99)替代,其中R(99)与R(7)一起可形成吡咯烷或哌啶环;或者,如果b为2、3或4,基团CbH2b中的一个亚甲基基可被原子团-O-或-S-替代;aa为1或2;bb为0至1;aa+bb=2;
R(19)为氢或具有1、2、3或4个碳原子的烷
基;
R(20)为氢或甲基;B为亚苯基残基,
R(12)和R(13)为氢;并且在每种情况下残基R(2)和R(3)中的另一个为氢;R(4)和R(5)为氢;
5.根据权利要求1的具有式I的化合物,其特征是它是选自下列一组化合物,4-〔4-N-(二甲基氨基乙基)甲基氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍二盐酸化物;4-〔4-(4-甲基哌嗪磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物;4-〔4-(2-吡咯烷乙基氨基磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍马来酸氢酯;4-〔4-(2-哌啶乙基氨基磺酰基)苯氧基〕-3-三氟甲基苯甲酰胍马来酸氢酯;4-〔4-(N-二甲基氨基-正丙基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍;4-〔4-(N-二甲基氨基乙基)氨磺酰〕苯氧基-3-三氟甲基苯甲酰胍;4-(4-亚氨基氨磺酰)苯氧基-3-三氟甲基苯甲酰胍;3-三氟甲基-4-(4-N-甲基亚氨基氨磺酰)苯氧基-苯甲酰胍;3-甲基-4-(4-(1-甲基哌嗪-4-基磺酰基)苯氧基)-苯甲酰胍;4-(4-胍基磺酰基)苯氧基-3-三氟甲基苯甲酰胍;4-〔4-(2-咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(N,N’-二甲基-S-异硫脲基乙酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸;4-〔4-(2-苯并咪唑基硫代乙酰基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(2-N-咪唑基-1-羟基乙基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(N,N-二甲基甘氨酰氨基)苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(N,N-二乙基氨基乙基)氨基磺酰基苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(4-咪唑基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(3-N-咪唑基-1-丙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(1-甲基-2-吡咯烷基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物4-〔4-(N-哌啶子基乙基)氨基磺酰基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(2-二甲基氨基乙基)磺酰基甲基-苯氧基〕-3-甲基磺酰基苯甲酰胍二盐酸化物;4-〔4-(2-二甲基氨基乙基)磺酰基甲基-苯氧基〕-3-三氟甲基苯甲酰胍二盐酸化物。
7.权利要求1所要求的化合物I用于制备治疗心律失常药物的用途。
8.治疗心律失常的方法,其中用常用的添加剂与有效量的权利要求1所要求的化合物I混合并且以适当的给药形式给药。
9.权利要求1所要求的化合物I用于制备治疗或预防心肌梗塞的药物的用途。
10.权利要求1所要求的化合物I用于制备治疗或预防心绞痛的药物的用途。
11.权利要求1所要求的化合物I用于制备治疗或预防心脏局部缺血状态的药物的用途。
12.权利要求1所要求的化合物I用于制备治疗或预防外周及中枢神经系统局部缺血状态和中风的药物的用途。
13.权利要求1所要求的化合物I用于制备治疗或预防周围器官和四肢局部缺血状态的药物的用途。
14.权利要求1所要求的化合物I用于制备治疗休克状态的药物的用途。
15.权利要求1所要求的化合物I用于制备外科手术和器官移植所用药的用途。
16.权利要求1所要求的化合物I用于制备保藏或贮存外科操作用移植物的药物的用途。
17.权利要求1所要求的化合物I用于制备治疗下列疾病的药物的用途,在这些疾病中细胞增生为原发性和继发性原因,因此化合物I用作抗动脉粥样硬化剂、抗糖尿病晚期并发症、癌症、纤维变性疾症例如肺纤维化、肝纤维化或肾纤维化、以及前列腺增生的药剂。
18.权利要求1所要求的化合物I用于制备抑制Na+/H+交换器,用于诊断高血压和增生性疾病的科学工具。
19.含有有效量的根据权利要求1-4中一项或几项所要求的化合物I的药物。
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DE1995104805 DE19504805A1 (de) | 1995-02-14 | 1995-02-14 | Basisch-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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EP0765867A1 (de) * | 1995-09-27 | 1997-04-02 | Hoechst Aktiengesellschaft | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Antiarrhytmika oder Diagnostikum sowie sie enthaltendes Medikament |
DE19540995A1 (de) * | 1995-11-03 | 1997-05-07 | Hoechst Ag | Substituierte Sulfonimidamide, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE19542306A1 (de) * | 1995-11-14 | 1997-05-15 | Hoechst Ag | Sulfonylamino-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
PL316439A1 (en) * | 1995-11-20 | 1997-05-26 | Hoechst Ag | Novel substituted derivatives of benzoyloguanidine, method of obtaining them, their application in production of pharmaceutic and diagnostic agents and pharmaceutic agent as such |
DE19546736A1 (de) * | 1995-12-14 | 1997-06-19 | Hoechst Ag | Substituierte Chromanylsulfonyl(thio)harnstoffe, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung pharmazeutischer Präparate |
PA8444901A1 (es) * | 1997-01-28 | 2000-05-24 | Hoffmann La Roche | Derivados de 5-aroilnaftaleno como agentes anti-inflamatorios |
US6291425B1 (en) * | 1999-09-01 | 2001-09-18 | Guilford Pharmaceuticals Inc. | Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage |
DE19951418A1 (de) * | 1999-10-26 | 2001-05-03 | Merck Patent Gmbh | Verfahren zur Herstellung von N-(4,5-Bismethansulfonyl-2-methyl-benzoyl) -guanidin, Hydrochlorid |
DE10024319A1 (de) * | 2000-05-17 | 2001-11-22 | Merck Patent Gmbh | Bisacylguanidine |
DE10046993A1 (de) | 2000-09-22 | 2002-04-11 | Aventis Pharma Gmbh | Substituierte Zimtsäureguanidide, Verfahren zur ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltendes Medikament |
DE10338554A1 (de) * | 2003-08-22 | 2005-03-31 | Aventis Pharma Deutschland Gmbh | Pentafluorosulfanylphenyl-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US7297817B2 (en) * | 2004-04-13 | 2007-11-20 | Cephalon France | Thio-substituted arylmethanesulfinyl derivatives |
DE102004043938A1 (de) * | 2004-09-11 | 2006-03-30 | Sanofi-Aventis Deutschland Gmbh | Pentafluorosulfanylphenyl-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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ES2097409T3 (es) * | 1992-09-22 | 1997-04-01 | Hoechst Ag | Benzoilguanidinas, procedimiento para su preparacion, asi como su empleo como antiarritmicos. |
TW250479B (zh) * | 1992-12-15 | 1995-07-01 | Hoechst Ag | |
EP0604852A1 (de) * | 1992-12-28 | 1994-07-06 | Hoechst Aktiengesellschaft | 2,4-Substituierte 5-(N-substituierte-Sulfamoyl)-Benzoylguanidine, als Antiarrythmika, Inhibitoren der Proliferationen von Zellen, und Inhibitoren des Natrium-Protonen-Antiporters |
IL109570A0 (en) * | 1993-05-17 | 1994-08-26 | Fujisawa Pharmaceutical Co | Guanidine derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof |
DE4325822A1 (de) * | 1993-07-31 | 1995-02-02 | Hoechst Ag | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105008332A (zh) * | 2013-01-08 | 2015-10-28 | 巴斯夫欧洲公司 | 作为杀真菌剂的取代的咪唑和(1,2,4)三唑类化合物 |
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