CN1071318C - 邻取代的苯甲酰胍、其制备方法、其用作药物或诊断剂及含其药物 - Google Patents
邻取代的苯甲酰胍、其制备方法、其用作药物或诊断剂及含其药物 Download PDFInfo
- Publication number
- CN1071318C CN1071318C CN97102833A CN97102833A CN1071318C CN 1071318 C CN1071318 C CN 1071318C CN 97102833 A CN97102833 A CN 97102833A CN 97102833 A CN97102833 A CN 97102833A CN 1071318 C CN1071318 C CN 1071318C
- Authority
- CN
- China
- Prior art keywords
- medicine
- prepare
- treatment
- hydroxyl
- chemical compounds
- 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 - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 26
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 title abstract description 30
- 238000000034 method Methods 0.000 title description 21
- 239000003153 chemical reaction reagent Substances 0.000 title description 3
- 230000008569 process Effects 0.000 title description 3
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 44
- -1 benzene formyl guanidine Chemical class 0.000 claims description 38
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 210000000056 organ Anatomy 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 8
- 206010003497 Asphyxia Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 206010020718 hyperplasia Diseases 0.000 claims description 3
- UNFXZTUFUAETRQ-UHFFFAOYSA-N n-(diaminomethylidene)-4-hydroxy-2-methyl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC1=CC(O)=C(C(F)(F)F)C=C1C(=O)NC(N)=N UNFXZTUFUAETRQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000035939 shock Effects 0.000 claims description 3
- AJVDLNUUCMVGCJ-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-hydroxy-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.NC(=N)NC(=O)C1=CC(C(F)(F)F)=C(O)C=C1Cl AJVDLNUUCMVGCJ-UHFFFAOYSA-N 0.000 claims description 2
- YHVCIAJRNJWSEY-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-hydroxy-5-iodobenzamide;hydrochloride Chemical compound Cl.NC(=N)NC(=O)C1=CC(I)=C(O)C=C1Cl YHVCIAJRNJWSEY-UHFFFAOYSA-N 0.000 claims description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 230000003178 anti-diabetic effect Effects 0.000 claims description 2
- 230000002300 anti-fibrosis Effects 0.000 claims description 2
- 239000003472 antidiabetic agent Substances 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- FGKLRYHLWMYTHD-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-hydroxybenzamide;hydrochloride Chemical compound Cl.NC(=N)NC(=O)C1=CC=C(O)C=C1Cl FGKLRYHLWMYTHD-UHFFFAOYSA-N 0.000 claims 1
- 230000003176 fibrotic effect Effects 0.000 claims 1
- 208000031225 myocardial ischemia Diseases 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 230000003288 anthiarrhythmic effect Effects 0.000 abstract description 3
- 230000006378 damage Effects 0.000 abstract description 3
- 238000011321 prophylaxis Methods 0.000 abstract description 3
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 2
- 230000003293 cardioprotective effect Effects 0.000 abstract description 2
- 230000035778 pathophysiological process Effects 0.000 abstract description 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract 1
- 206010061216 Infarction Diseases 0.000 abstract 1
- 206010003119 arrhythmia Diseases 0.000 abstract 1
- 230000007574 infarction Effects 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 12
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 8
- 229960004198 guanidine Drugs 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000001624 naphthyl group Chemical group 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229940095102 methyl benzoate Drugs 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000001631 hypertensive effect Effects 0.000 description 3
- 230000004941 influx Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 125000005493 quinolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- WIPYZRZPNMUSER-UHFFFAOYSA-N 2-chloro-4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1Cl WIPYZRZPNMUSER-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 244000166550 Strophanthus gratus Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
- 229960002576 amiloride Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000012447 hatching Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- KCQMUFYIGUHOMQ-UHFFFAOYSA-N iodomethyl benzoate Chemical compound ICOC(=O)C1=CC=CC=C1 KCQMUFYIGUHOMQ-UHFFFAOYSA-N 0.000 description 2
- XSYRXMCVUVABLL-UHFFFAOYSA-N methyl 2-chloro-4-phenylmethoxy-5-(trifluoromethyl)benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(C(F)(F)F)=C1OCC1=CC=CC=C1 XSYRXMCVUVABLL-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 2
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 2
- 229960003343 ouabain Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- GNLJBJNONOOOQC-UHFFFAOYSA-N $l^{3}-carbane;magnesium Chemical compound [Mg]C GNLJBJNONOOOQC-UHFFFAOYSA-N 0.000 description 1
- GMMBCZOQHIBHME-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-phenylmethoxy-5-(trifluoromethyl)benzamide Chemical compound C1=C(Cl)C(C(=O)NC(=N)N)=CC(C(F)(F)F)=C1OCC1=CC=CC=C1 GMMBCZOQHIBHME-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- FRZSZEGXVDROGK-UHFFFAOYSA-N 3-chloro-n-(diaminomethylidene)-2,6-dimethoxybenzamide;hydrochloride Chemical compound Cl.COC1=CC=C(Cl)C(OC)=C1C(=O)NC(N)=N FRZSZEGXVDROGK-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000692822 Bacteroidales Species 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PGZPUCWKLXOYIF-UHFFFAOYSA-N Cl.IN(C(=N)N)C(C1=CC=CC=C1)=O Chemical compound Cl.IN(C(=N)N)C(C1=CC=CC=C1)=O PGZPUCWKLXOYIF-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010021137 Hypovolaemia Diseases 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
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical class ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical compound C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BJZFMXJQJZUATE-UHFFFAOYSA-N methyl 2-chloro-4-hydroxybenzoate Chemical class COC(=O)C1=CC=C(O)C=C1Cl BJZFMXJQJZUATE-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- JKAVIAZKNQOPQU-UHFFFAOYSA-N n-(diaminomethylidene)-2,3,5,6-tetrafluoro-4-hydroxybenzamide;hydrochloride Chemical compound Cl.NC(=N)NC(=O)C1=C(F)C(F)=C(O)C(F)=C1F JKAVIAZKNQOPQU-UHFFFAOYSA-N 0.000 description 1
- JQNAATUEAWWCFM-UHFFFAOYSA-N n-(diaminomethylidene)-2-methyl-4-phenylmethoxy-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.C1=C(C(=O)NC(N)=N)C(C)=CC(OCC=2C=CC=CC=2)=C1C(F)(F)F JQNAATUEAWWCFM-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical class [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- SIMZKPFFQPBRPY-UHFFFAOYSA-N potassium;2,2,2-trifluoroacetic acid Chemical compound [K].OC(=O)C(F)(F)F SIMZKPFFQPBRPY-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000010850 salt effect Methods 0.000 description 1
- 208000037921 secondary disease Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AYRVGWHSXIMRAB-UHFFFAOYSA-M sodium acetate trihydrate Chemical compound O.O.O.[Na+].CC([O-])=O AYRVGWHSXIMRAB-UHFFFAOYSA-M 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000006478 transmetalation reaction Methods 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Neurology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Surgery (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及式Ⅰ邻取代的苯甲酰胍
其中R(1)至R(4)如权利要求所定义，尤其适于作为有效的带有心脏保护成分的抗心律失常药物用于心肌梗塞的预防和治疗以及心绞痛的治疗，它也预防性地抑制由局部缺血诱发的损伤的形成中的，特别是由局部缺血引起的心律失常的诱发中的病理生理过程。
Description
本发明涉及式Ⅰ的苯甲酰胍其中：R(1)代表H、F、Cl、Br、I、CN、NO2、具有1、2、3、4、5、6、7或8个C原子的烷基、具有1、2、3、4、5、6、7或8个C原子的烷氧基、具有3、4、5、6、7或8个C原子的环烷基、具有3、4、5、6、6、7或8个C原子的环烷氧基或Xa-(CH2)b-(CF2)c-CF3；X代表氧、S、NR(5),a为零或1；b为零、1或2；c为零、1、2或3；R(5)为H、具有1、2、3或4个C原子的烷基或-CdH2dR(6)；d为零、1、2、3或4；R(6)为具有3、4、5、6、7或8个C原子的环烷基，苯基、联苯基或萘基，其中苯基、联苯基或萘基为未取代的或由选自F、Cl、CF3、甲基、甲氧基和NR(7)R(8)的1-3个取代基取代，R(7)和R(8)相互独立地为H或具有1、2、3或4个C原子的烷基；或R(1)为-SR(10)、-OR(10)或-CR(10)R(11)R(12)；R(10)为在环烷基环上有3、4、5、6、7或8个C原子的-CfH2f-环烷基，或苯基，其中苯基为未取代的或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代，f为零、1或2；R(11)和R(12)相互独立地如R(10)所定义，或为氢或具有1、2、3或4个C原子的烷基；或R(1)为苯基、萘基、联苯基或具有1、2、3、4、5、6、7、8或9个C原子的杂芳基，该杂芳基经一个环C-或N-原子连接，这些基团各是未取代的或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代，或R(1)是-SR(13),-OR(13),-NHR(13),-NR(13)R(14),-CHR(13)R(15),-C〔R(15)R(16)OH〕,-C≡CR(18),-C〔R(19)〕=CHR(18),-C〔R(20)R(21)〕k-(CO)-〔CR(22)R(23)〕1-R(24),k是零，1,2,3或4；l是零，1,2,3或4；R(13)和R(14)是相同的或不相同的并且是-(CH2)g-(CHOH)h-(CH2)i-(CHOH)j-R(17)或-(CH2)g-O-(CH2-CH2O)h-R(24)；R(17)是氢或甲基；g,h和i是相同的或不相同的是零，1、2、3或4；j是1、2、3或4；R(15)和R(16)是相同的或不相同的是氢，具有1、2、3、4、5或6个C-原子的烷基，或者共同与带有它们的碳原子一起形成具有3、4、5、6、7或8个C-原子的环烷基；R(18)是苯基，它为未取代的或由选自F、Cl、CF3、甲基、甲氧基和NR(25)R(26)的1-3个取代基所取代；R(25)和R(26)是H或具有1、2、3或4个C原子的烷基；或R(18)是具有1、2、3、4、5、6、7、8或9个碳原子的杂芳基、它为未取代或如苯基一样被取代的；或R(18)是具有1、2、3、4、5或6个C原子的烷基、它为未取代的或被1-3个OH所取代；或R(18)是具有3、4、5、6、7或8个C原子的环烷基；R(19)、R(20)、R(21)、R(22)和R(23)是相同的或不相同的且是氢或甲基；R(24)是H、具有1、2、3、4、5或6个C原子的烷基、具有3、4、5、6、7或8个C原子的环烷基或-CmH2m-R(18)；m是1、2、3或4；取代基R(2)和R(3)两者之一为羟基；以及取代基R(2)和R(3)的另一个如R(1)所定义；R(4)为具有1、2、3或4个C原子的烷基；具有1、2、3或4个C原子的烷氧基、F、Cl、Br、I或-(CH2)n-(CF2)o-CF3；n为零或1；o为零或1；以及其药学上耐受的盐。优选这样的式Ⅰ化合物，其中R(1)代表H、F、Cl、Br、I、CN、NO2、具有1、2、3、4、5、6、7或8个C原子的烷基、具有1、2、3、4、5、6、7或8个C原子的烷氧基、具有3、4、5、6、7或8个C原子的环烷基、具有3、4、5、6、7或8个C原子的环烷氧基或Xa-(CF2)c-CF3；X代表氧；a为零或1；c为零、1、2或3；或R(1)为-SR(10)或-OR(10)；R(10)为在环烷基环上有3、4、5、6、7或8个C原子的-CfH2f-环烷基，或苯基，其中苯基为未取代的或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代，f为零或1；或R(1)为苯基、萘基、联苯基或具有1、2、3、4、5、6、7、8或9个C原子的杂芳基，该杂芳基经一个环C-或N-原子连接，这些基团各是未取代的或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代，或R(1)是-SR(13),-OR(13),-NHR(13),-NR(13)R(14),-C≡CR(18)或-C〔R(19)〕=CHR(18)；R(13)和R(14)是相同的或不相同的并且是-(CH2)g-(CHOH)h-(CH2)i-(CHOH)j-R(17)或-(CH2)g-O-(CH2-CH2O)h-R(24)；R(17)是氢或甲基；g,h和i是相同的或不相同的是零，1或2；j是1或2；R(18)是苯基，它为未取代的或由选自F、Cl、CF3、甲基、甲氧基和NR(25)R(26)的1-3个取代基所取代；R(25)和R(26)是H或具有1、2、3或4个C原子的烷基；或R(18)是具有1、2、3、4、5、6、7、8或9个碳原子的杂芳基、它为未取代或如苯基一样被取代的；或R(18)是具有1、2、3、4、5或6个C原子的烷基、它为未取代的或被1-3个OH所取代；或R(18)是具有3、4、5、6、7或8个C原子的环烷基；R(19)为氢或甲基；取代基R(2)和R(3)之一为羟基；以及取代基R(2)和R(3)的另一个如R(1)所定义；R(4)为具有1或2个C原子的烷基、甲氧基、F、Cl、Br、CN或-(CH2)n-(CF2)o-CF3；n为零或1；o为零或1；以及其药学上耐受的盐。更优选这样的式Ⅰ化合物，其中：R(1)为H、F、Cl、具有1、2、3或4个C原子的烷基、具有1、2、3或4个C原子的烷氧基、具有5或6个C原子的环烷基、具有5或6个C原子的环烷氧基或Xa-(CF2)c-CF3；X代表氧；a为零或1；c为零或1；或R(1)为-SR(10)或-OR(10)；R(10)为具有4、5或6个C原子的环烷基，或苯基，其中苯基是未取代的或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代；或R(1)为喹啉基、异喹啉基，吡啶基，它们是经一个环C-或N-原子连接的；并且它们是未取代或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代，或R(1)为苯基，它是未取代的或由选自F、Cl、CF3、CH3、甲氧基、羟基、氨基、甲基氨基和二甲基氨基的1-3个取代基取代，或R(1)为-C≡CR(18)；R(18)为苯基或具有5或6个C原子的环烷基；取代基R(2)和R(3)两者之一为羟基；以及取代基R(2)和R(3)的另一个如R(1)定义；R(4)为甲基、甲氧基、F、Cl或CF3；以及其药学上耐受的盐。特别尤其优选这样的式Ⅰ化合物，其中R(1)代表H、F、Cl、具有1、2、3或4个C原子的烷基，具有1、2、3或4个C原子的烷氧基、具有5或6个C原子的环烷基、具有5或6个C原子的环烷氧基或CF3取代基R(2)和R(3)之一为羟基，以及取代基R(2)和R(3)的另一个如R(1)所定义；R(4)为甲基、甲氧基、F、Cl或CF3；以及其药学上耐受的盐。特别优选以下的式Ⅰ化合物，2,6-二氯-苯甲酰胍盐酸盐，3-氯-2,6-二甲氧基-苯甲酰胍盐酸盐，4-羟基-2,3,5,6-四氟-苯甲酰胍盐酸盐，4-羟基-2,5-三氟甲基-苯甲酰胍盐酸盐，4-羟基-2-甲基-5-三氟甲基-苯甲酰胍盐酸盐，
具有1、2、3、4、5、6、7、8或9个C原子的杂芳基理解为这样的基团，它们衍生自苯基或萘基，其中一或多个CH-基团被N替代和/或其中至少两个相邻的CH-基团(在形成五元芳环的情况下)被S、NH或O替代。此外双环基(如中氮茚基)的缩合位的一个或二个原子可以是N-原子。具有1、2、3、4、5、6、7、8或9个C原子的杂芳基尤其是：呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、吲唑基、喹啉基、异喹啉基、2,3-二氮杂萘基、喹喔啉基、喹唑啉基、肉啉基；尤其是呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、噻唑基、吡啶基、吲哚基、喹啉基和异喹啉基。
如果取代基R(1)-R(4)之一含有一个或多个非对称中心，则其可为S或R构型。该化合物可以以光学异构体、非对映体、外消旋物或它们的混合物的形式存在。
所述的烷基可以是直链或支化的。
此外，本发明还涉及式Ⅰ化合物的制备方法，其特征是，将式Ⅱ化合物
与胍反应，其中R(1)-R(4)具有已给定的含义并且L代表易于被亲核取代的离去基团．
式Ⅱ的活化了的酸衍生物，其中L是一个烷氧基，尤其是一个甲氧基、苯氧基，苯硫基-，甲硫基-，2-吡啶硫基，或一个氮杂环，优选1-咪唑基，是适合用已知的方法由基础的羧酰氯(式Ⅱ,L=Cl)制备的，而这个化合物又可以用已知的方法由基础的羧酸(式Ⅱ,L=OH)譬如与亚硫酰(二)氯制备。
除了化学式Ⅱ(L=Cl)的羧酰氯外，化学式Ⅱ的其它活化的酸衍生物也可以用已知的方法直接由基础的苯甲酸衍生物(化学式Ⅱ,L=OH)制得，例如L=OCH3的化学式Ⅱ的甲酯是通过用气态的HCl在甲醇中处理获得，化学式Ⅱ的咪唑化物是通过用羰基二咪唑处理[L=1-咪唑基，Staab，应用化学，英文第1版，351-367页(Angew,Chem.Int.Ed.Engl.1,351-367)(1962)]，混合的酐Ⅱ是用Cl-COOC2H5或者是甲苯磺酰氯在三乙胺存在下在一种惰性溶剂中处理，也可以用二环已基碳化二亚胺(DCC)或者用O-[(氰基(乙氧羰基)亚甲基)氨基]-1,1,3,3,-四甲基
-四氟硼酸盐(“TOTU”)活化苯甲酸[Weiss和Krommer，化学工作者周报(Chemiker Zeitung)98,817(1974)]。一系列制备化学式Ⅱ的活化羧酸衍生物的适合方法在J.March，高等有机化学，第三版(Advanced Organic Chemistry,Third Edition)(John Wiley&Sons,1985),350页中给出引用文献。
化学式Ⅱ的活化了的羧酸衍生物与胍的反应是用已知的方法在一种质子传递或质子惰性的、极性的但是惰性的有机溶剂中进行，对于苯甲酸甲酯(Ⅱ,L=OMe)与胍反应，甲醇、异丙醇或者THF(四氢呋喃)从20℃至这些溶剂的沸点的温度证明是适用的。化合物Ⅱ与无盐的胍的大多数反应适合在质子惰性的惰性溶剂如THF，二甲氧基乙烷，二噁烷中进行。但在式Ⅱ化合物与胍的反应中使用碱如NaOH时，水也可以用作溶剂。
当L=Cl时，适合加入一种酸捕捉剂例如以过量的胍的形式来结合除去氢卤酸。
一部分式Ⅱ的基础苯甲酸衍生物是已知的并描述于文献中。未知的式Ⅱ化合物可通过文献已知的方法制取。将得到的苯甲酸按所述方法的方案中的一种转化成本发明的化合物Ⅰ。
在2-、3-、4-和5-位引入一些取代基可通过文献已知的方法进行，即通过芳基卤化物或三氟甲磺酸芳基酯与例如有机锡烷、有机硼酸或有机硼烷或有机铜和有机锌化合物的钯-媒介交叉偶合(cross-coupling)方法。
苯甲酰胍Ⅰ一般为弱碱，可以结合酸形成盐。作为酸加成盐，所有药理学上适合的酸的盐均在考虑之列，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，乙酸盐，磷酸盐，甲磺酸盐，对甲苯磺酸盐。
式Ⅰ化合物为取代的酰基胍
欧洲公开说明书612723 A1(HOE93/F054)公开了类似于式Ⅰ化合物的化合物。该化合物在苯基核上含有羟基作为取代基，但在邻位没有取代基。
与已知的化合物相比，本发明的化合物具有特别高的Na+/H+交换的抑制活性以及改善的水溶性。
与已知的化合物一样，它没有所不希望的和不利的利尿盐作用，但具有很好的抗心律失常特性，它例如对于治疗缺氧引起的疾病是非常重要的。这种化合物由于它们的药理学特性特别适合作为带有心脏保护成分的抗心律失常药用于梗塞预防和梗塞治疗以及心绞痛的治疗，并且它可以预防性地抑制和明显减轻由局部缺血诱发的损伤的形成中的，特别是由局部缺血引起的心律失常的诱发中的病理生理过程。由于它们对于病理性缺氧和局部缺血状态的防护作用，按本发明的化学式Ⅰ化合物由于对细胞的Na+/H+交换机制的抑制可以作为药物用于所有通过局部缺血引起的急性或者慢性损伤或者是由此引起的原发或继发疾病。这涉及到它们作为外科手术药物的应用，例如在器官移植时，这种化合物可用于在供体内摘取器官前和摘取器官过程中对器官的保护，用于已摘取下的器官的保护，例如用于器官在生理溶液中的处理与贮藏，并且也应用在将器官向受体移植的过程。这种化合物在进行血管成形术手术时例如对心脏和在周围血管手术时同样是很有价值的具有保护作用的药物。根据它们对于局部缺血引起的损伤的防护作用，这些化合物也适合用作治疗神经系统，特别是中枢神经系统的局部缺血的药物，例如它们对于中风或者脑水肿的治疗是适合的。此外按本发明的式Ⅰ的化合物同样也适合用于休克状态的治疗，例如变应的、心原性的、(循环)血容量减少的和细菌性的休克。
此外按照本发明化学式Ⅰ的化合物对于细胞增殖，例如对于成纤维细胞细胞增殖和对于血管平滑肌细胞的增殖，具有的强大抑制作用。因此化学式Ⅰ化合物适合作为一些疾病的有价值的治疗剂，这类疾病中细胞增生构成原发或继发原因，所以可以将其用作抗动脉粥样硬化剂，抗糖尿病晚期并发症，抗癌症，抗纤维化疾病如肺纤维化，肝纤维化或肾纤维化，器官肥大和器官增生，特别是前列腺增生以及前列腺肥大的药物。
按照本发明的化合物是细胞的钠-质子-反向转移体(Na+/H+交换器)的有效抑制剂，对于许多疾病(自发性高血压，动脉粥样硬化，糖尿病等)，这种Na+/H+交换器在那些很容易进行测定的细胞中也是升高的，例如在红细胞，血小板或白细胞中。因此按照本发明的化合物适合作为卓越的和简单的科学工具，例如它作为诊断剂用于确定和区分高血压，动脉粥样硬化症，糖尿病，增生疾病等的特定形式，此外化学式Ⅰ的化合物适合用于预防性治疗以阻止高血压的发生，例如自发性高血压的预防性治疗。
含有化合物Ⅰ的药物可以经口、非肠道、静脉内、直肠或者通过吸入法来给药，优选的方法取决于各疾病的症状。在此化合物Ⅰ可以单独地或者是与盖伦氏制药的辅助材料一起使用，既可用作兽医药也可用作人用药。
至于哪些辅助材料对于所需要的药物制剂是适合的，则对于本领域技术人员来说根据他们的专业知识是很熟悉的。除了溶剂，凝胶形成剂，栓剂基质，片剂辅助材料，和其它的活性物质载体外，还例如可使用抗氧化剂，分散剂，乳化剂，除泡沫剂，矫味剂，保藏剂，增溶剂或者染色剂。
对于一种经口使用形式，则可将活性化合物与对此适合的添加物，如载体物质、稳定剂或惰性稀释剂混合并且通过常用的方法制成合适的给药形式，如片剂，糖衣丸，胶囊，水质的、醇的或油质的溶液。作为惰性载体可以应用例如阿拉伯胶，氧化镁，碳酸镁，磷酸钾，乳糖，葡萄糖，淀粉，特别是玉米淀粉。在此药物配制可以做成干燥的或者是潮湿的粒剂。作为油质的载体物质或者作为溶剂可以考虑例如植物油或动物油，如葵花油或鱼肝油。
为了皮下或静脉内给药，则将活性化合物任选地与为此常用的物质如增溶剂、乳化剂或其它辅助物质制成溶液、悬浮液或者乳剂，作为溶剂可以考虑：水，生理盐水或者醇类，例如乙醇、丙醇，丙三醇，此外还有糖溶液如葡萄糖或者甘露醇溶液，或者是由不同的已提到过的溶剂组成的一种混合物。
对于以气溶胶或喷雾的形式给药的药物制剂，适合使用化学式Ⅰ的活性物质在一种制药上适宜的溶剂如特别是乙醇或水或者这些溶剂的混合物中的溶液、悬浮液或者乳剂。制剂根据需要还可以含有其它的制药的辅助材料如表面活性剂、乳化剂和稳定剂以及一种推进气体。这种制剂一般含有活性物质的浓度约为0.1至10，特别是约0.3至3重量％。
化学式Ⅰ的有效物质的给药剂量和给药频率是与所应用的化合物的作用强度和作用持续时间长短有关，此外与所治疗疾病的种类和严重程度，以及所治疗哺乳动物的性别、年龄、体重、个体敏感性有关。
对于约75公斤重的病人，式Ⅰ化合物的平均日剂量为至少0.001mg/kg(体重)，优选至少0.01mg/kg(体重)，至多10mg/kg(体重)，优选至多1mg/kg(体重)。在疾病急性发作期，如心肌梗塞刚发作之后，则需要较高剂量和尤其是较高给药频率，如每天直到4次给药。对于在监护期的心肌梗塞病人，有可能需要每天直至200mg的剂量，尤其通过静脉给药。缩写表
MeOH 甲醇
DMF N,N-二甲基甲酰胺
RT 室温
EE 乙酸乙酯(EtOAc)
Smp 熔点
THF 四氢呋喃
eq. 当量
实验部分制备苯甲酰胍(Ⅰ)的共同准则方法A：由苯甲酸(Ⅱ,L=OH)开始
将1.0eq.的式Ⅱ苯甲酸衍生物溶于或悬浮于无水THF(5毫升/毫摩尔)中，接着与1.1eq.的羰基二咪唑混合。于RT下搅拌2小时后向反应溶液加入5.0eq.胍。搅拌过夜后于减压下馏去THF(于旋转蒸发器中)，与水混合，用2NHCl调PH至6-7并过滤出相应的苯甲酰胍(式Ⅰ)。如此得到的苯甲酰胍可通过用含水的、含甲醇的或含醚的盐酸或其它药理上适合的酸进行处理转化成相应的盐。制备苯甲酰胍(1)的共同准则方法B：从苯甲酸烷基酯(Ⅱ,L=O-烷基)开始
将1.0eq.式Ⅱ的苯甲酸烷基酯以及5.0eq.胍(游离碱)溶于异丙醇中或悬浮于THF中并且加热至沸腾直至完全反应(一般2-5小时)(薄层色谱监控)。于减压下(旋转蒸发器)蒸去溶剂，残余物吸收于EE中并用NaHCO3溶液洗涤三次。经Nat2SO4干燥，于真空下蒸去溶剂，在硅胶上用合适的展开剂如EE/MeOH5∶1色谱纯化。(成盐参照方法A)。实施例1：2-氯-4-羟基-苯甲酰胍-盐酸盐无色晶体，Smp.247℃由2-氯-4-羟基-苯甲酸按方法A制得。实施例2：2-氯-4-羟基-5-碘-苯甲酰胍-盐酸盐无色晶体 Smp.246-47℃合成途径a)2-氯-4-羟基-苯甲酸甲酯，由2-氯-4-羟基-苯甲酸通过在10当量乙酰氯存在下于RT在24小时内用甲醇(过量)酯化制得。水处理后由乙醚/环己烷中结晶，无色晶体，Smp.128-30℃b)2-氯-4-羟基-5-碘-苯甲酸甲酯，由a)通过在10当量乙酸钠存在下在半浓冰醋酸中于RT在1.5小时内与1.1当量N-氯琥珀酰亚胺和2.1当量碘化钾组成的混合物反应制得。水处理并用环己烷/乙酸乙酯9∶1柱色谱纯化得到所需的无色固体产物，Smp.191-92℃，还得到2-氯-4-羟基-3,5-二碘-苯甲酸甲酯，无色固体，Smp.131-32℃。c)2-氯-4-羟基-5-碘-苯甲酰胍-盐酸盐，由2-氯-4-羟基-5-碘-苯甲酸甲酯(参见2b)按方法B制得。实施例3：2-氯-4-羟基-3,5-二碘-苯甲酰胍-盐酸盐无色固体，Smp.205-10℃(分解)由2-氯-4-羟基-3,5-二碘-苯甲酸甲酯(参见2b)按方法B制得。实施例4：2-氯-4-羟基-5-三氟甲基-苯甲酰胍-盐酸盐无色固体，无定形，(M+H)+:282合成途径：a)2-氯-4-苄氧基-5-碘-苯甲酸甲酯，由2-氯-4-羟基-5-碘-苯甲酸甲酯通过在碳酸钾存在下在DMF中于80℃3小时内与1.1当量苄基溴反应制得。水处理之后从异丙醇中重结晶，无色晶体，Smp.102-08℃。b)2-氯-4-苄氧基-5-三氟甲基-苯甲酸甲酯，由4a)通过与2当量三氟乙酸钾于N-甲基吡咯烷-2-酮中在碘化铜(Ⅰ)存在下加热至160℃于5小时内制得。水处理并用环己烷/乙酸乙酯9∶1柱色谱纯化得到无色晶体，Smp.126-27℃。c)2-氯-4-苄氧基-5-三氟甲基-苯甲酰胍，由4b)按方法B(不成盐)制得，无色晶体，Smp.180℃d)2-氯-4-羟基-5-三氟甲基-苯甲酰胍-盐酸盐，由4c)通过借助于钯/炭的氢化并接着成盐酸盐制得，无色固体，无定形，(M+H)+:282。实施例5：4-羟基-2,5-三氟甲基-苯甲酰胍-盐酸盐：无色晶体，Smp.211℃。合成途径：a)4-苄氧基-2,5-三氟甲基-苯甲酸甲酯由4b)通过类似的三氟甲基化，但在提高的温度(180℃)和5小时的反应时间制得，无色晶体，Smp.116℃。b)4-苄氧基-2,5-三氟甲基-苯甲酰胍-盐酸盐由5a)按共同准则制得，无色晶体，Smp.221℃c)4-羟基-2,5-三氟甲基-苯甲酰胍-盐酸盐由5b)通过在10％钯/炭上于甲醇中室温下氢化制得。实施例6：4-羟基-2-甲基-5-三氟甲基-苯甲酰胍-盐酸盐：无定形固体。合成途径：a)2-甲基-4-苄氧基-5-三氟甲基-苯甲酸甲酯由2-氯-4-苄氧基-5-三氟甲基苯甲酸甲酯(4b)与1.2当量甲基锌氯化物(由甲基镁氯化物通过与氯化锌(Ⅱ)-THF配合物的金属转移作用制得)于80℃在DMF中、在催化量乙酸钯(Ⅱ)和碘化铜(Ⅰ)的存在下、在搅拌条件下交叉偶合制得，无色晶体，Smp.105℃。b)4-苄氧基-2-甲基-5-三氟甲基-苯甲酰胍-盐酸盐由6a)按共同准则制得，无色晶体，Smp.255℃。c)4-羟基-2-甲基-5-三氟甲基-苯甲酰胍-盐酸盐由6b)类似于5c)制得。
药理学数据：
家兔红细胞的Na+/H+交换器的抑制：
白色新西兰家兔(Ivanovas)配给一种含有2％胆固醇的标准饮食六周时间，以激活Na+/H+交换并且这样可以用火焰光谱分析法来测定通过Na+/H+交换Na+进入红细胞的流入量。血液由耳动脉采取并且通过25IE钾-肝素来抗凝。每一个样品的一部分用来通过离心进行血细胞比容的双重测定。各为100μl的等份试样用于测量红细胞的Na+的起始含量。
为了测定氨氯吡脒-敏感的钠流入量，将100μl各血样在各5ml的高渗透压的盐-蔗糖介质中(mmol/升：140NaCl,3KCl,150蔗糖，0.1哇巴因，20三羟甲基氨基甲烷)在pH为7.4和37℃下孵育。然后将红细胞用冰冷的MgCl2-哇巴因-溶液(mmol/升：112MgCl2,0.1哇巴因)洗涤三次并在2.0ml的蒸馏水中使之溶血。细胞内的钠含量用火焰光谱分析来测定。
Na+净流入量是由红细胞的钠起始含量和孵育后的红细胞的钠含量之差来计算，氨氯吡脒可以抑制的钠流入量是由红细胞在加入和不加入氨氯吡脒3×10-4mol/升孵育后的红细胞钠含量之差得出。将同样方法用于本发明的化合物。结果对Na+/H+-交换器的抑制：实施例 IC50(mol/1)1： 4.0×10-62： 0.24×10-63： 0.10×10-64： 0.14×10-6
Claims (14)
1．式Ⅰ邻取代苯甲酰胍
其中：R(1)代表H、F、Cl、具有1、2、3或4个C原子的烷基，具有1、2、3或4个C原子的烷氧基、具有5或6个C原子的环烷基、具有5或6个C原子的环烷氧基或CF3取代基R(2)和R(3)之一为羟基，以及取代基R(2)和R(3)的另一个如R(1)所定义；R(4)为甲基、甲氧基、F、Cl或CF3；以及其药学上耐受的盐。
2．根据权利要求1的式Ⅰ化合物，选自：
2-氯-4-羟基-苯甲酰胍盐酸盐，
2-氯-4-羟基-5-碘-苯甲酰胍盐酸盐，
2-氯-4-羟基-3,5-二碘-苯甲酰胍盐酸盐，
2-氯-4-羟基-5-三氟甲基-苯甲酰胍盐酸盐，
4-羟基-2,5-三氟甲基-苯甲酰胍盐酸盐，
4-羟基-2-甲基-5-三氟甲基-苯甲酰胍盐酸盐。
3．按权利要求1的式Ⅰ化合物用于制备一种治疗或预防由局部缺血状态引起的疾病的药物。
4．按权利要求1的化合物Ⅰ用于制备一种治疗或预防心肌梗塞的药物。
5．按权利要求1的化合物Ⅰ用于制备一种治疗或预防心绞痛的药物。
6．按权利要求1的化合物Ⅰ用于制备一种治疗或预防心脏局部缺血状态的药物。
7．按权利要求1的化合物Ⅰ用于制备一种治疗或预防周围和中枢神经系统局部缺血状态和中风的药物。
8．按权利要求1的化合物Ⅰ用于制备一种治疗或预防周围器官和四肢局部缺血状态的药物。
9．按权利要求1的化合物Ⅰ用于制备一种治疗休克状态的药物。
10．按权利要求1的化合物Ⅰ用于制备一种应用于外科手术和器官移植的药物。
11．按权利要求1的化合物Ⅰ用于制备一种为外科手段保存和贮藏移植物的药物。
12．按权利要求1的化合物Ⅰ用于制备一种治疗一些疾病的药物，在这些疾病中细胞增生为原发或继发原因，以及因此它们用于制备抗动脉粥样硬化药，抗糖尿病晚期并发症、抗癌症、抗纤维化疾病、前列腺增生的药物。
13．按权利要求12的应用，其中所述纤维化疾病为肺纤维化、肝纤维化或肾纤维化。
14．一种具有权利要求3-13之任一项所述用途的药物，其特征在于，它含有有效量的按权利要求1或2的一种式Ⅰ化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19608161A DE19608161A1 (de) | 1996-03-04 | 1996-03-04 | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19608161.0 | 1996-03-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1160042A CN1160042A (zh) | 1997-09-24 |
| CN1071318C true CN1071318C (zh) | 2001-09-19 |
Family
ID=7787087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97102833A Expired - Fee Related CN1071318C (zh) | 1996-03-04 | 1997-02-28 | 邻取代的苯甲酰胍、其制备方法、其用作药物或诊断剂及含其药物 |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US6262123B1 (zh) |
| EP (1) | EP0794172B1 (zh) |
| JP (1) | JP4039586B2 (zh) |
| KR (1) | KR970065511A (zh) |
| CN (1) | CN1071318C (zh) |
| AR (1) | AR006051A1 (zh) |
| AT (1) | ATE207462T1 (zh) |
| AU (1) | AU707619B2 (zh) |
| BR (1) | BR9701159A (zh) |
| CA (1) | CA2198980A1 (zh) |
| CZ (1) | CZ293144B6 (zh) |
| DE (2) | DE19608161A1 (zh) |
| DK (1) | DK0794172T3 (zh) |
| ES (1) | ES2166481T3 (zh) |
| HR (1) | HRP970125B1 (zh) |
| HU (1) | HUP9700542A3 (zh) |
| ID (1) | ID16106A (zh) |
| IL (1) | IL120358A (zh) |
| MX (1) | MX9701619A (zh) |
| MY (1) | MY116861A (zh) |
| NO (1) | NO308793B1 (zh) |
| NZ (1) | NZ314325A (zh) |
| PL (1) | PL185751B1 (zh) |
| PT (1) | PT794172E (zh) |
| RU (1) | RU2212400C2 (zh) |
| SI (1) | SI0794172T1 (zh) |
| SK (1) | SK283934B6 (zh) |
| TR (1) | TR199700131A2 (zh) |
| TW (1) | TW440558B (zh) |
| ZA (1) | ZA971815B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10001879A1 (de) * | 2000-01-19 | 2001-07-19 | Aventis Pharma Gmbh | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| CN100371328C (zh) * | 2006-01-19 | 2008-02-27 | 中国药科大学 | 取代苯甲酰基胍衍生物、其制备方法及其医药用途 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0612723A1 (de) * | 1993-02-20 | 1994-08-31 | Hoechst Aktiengesellschaft | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, als Inhibitioren des zellulären Na+/H+-Austauschs oder als Diagnostikum sowie sie enthaltendes Medikament |
| CN1106381A (zh) * | 1993-08-27 | 1995-08-09 | 赫彻斯特股份公司 | 邻位取代的苯甲酰胍、制法、含有它们的药品及用途 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ284456B6 (cs) * | 1992-02-15 | 1998-12-16 | Hoechst Aktiengesellschaft | Aminosubstituované benzoylguanidiny, způsob jejich přípravy, jejich použití jako léčiv a léčivo, které je obsahuje |
| TW250477B (zh) | 1992-12-15 | 1995-07-01 | Hoechst Ag | |
| DE4318756A1 (de) | 1993-06-05 | 1994-12-08 | Hoechst Ag | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4404183A1 (de) * | 1994-02-10 | 1995-08-17 | Merck Patent Gmbh | 4-Amino-1-piperidylbenzoylguanidine |
| DE4417004A1 (de) | 1994-05-13 | 1995-11-16 | Hoechst Ag | Perfluoralkyl-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4421495A1 (de) * | 1994-06-20 | 1995-12-21 | Merck Patent Gmbh | Heterocyclyloxy-benzoylguanidine |
| DE4422685A1 (de) * | 1994-06-29 | 1996-01-04 | Hoechst Ag | Ortho-amino-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4430213A1 (de) * | 1994-08-28 | 1996-02-29 | Merck Patent Gmbh | Arylbenzoylguanidine |
| DE4430861A1 (de) * | 1994-08-31 | 1996-03-07 | Merck Patent Gmbh | Heterocyclyl-benzoylguanidine |
| DE19517848A1 (de) * | 1995-05-16 | 1996-11-21 | Merck Patent Gmbh | Fluorhaltige Benzoylguanidine |
| DE19531138A1 (de) * | 1995-08-24 | 1997-02-27 | Merck Patent Gmbh | Alkenyl-benzoylguanidin-Derivate |
| DE19624178A1 (de) * | 1996-06-18 | 1998-01-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
-
1996
- 1996-03-04 DE DE19608161A patent/DE19608161A1/de not_active Withdrawn
-
1997
- 1997-02-11 PL PL97318415A patent/PL185751B1/pl not_active IP Right Cessation
- 1997-02-19 DK DK97102607T patent/DK0794172T3/da active
- 1997-02-19 PT PT97102607T patent/PT794172E/pt unknown
- 1997-02-19 DE DE59705019T patent/DE59705019D1/de not_active Expired - Lifetime
- 1997-02-19 ES ES97102607T patent/ES2166481T3/es not_active Expired - Lifetime
- 1997-02-19 AT AT97102607T patent/ATE207462T1/de not_active IP Right Cessation
- 1997-02-19 SI SI9730252T patent/SI0794172T1/xx unknown
- 1997-02-19 EP EP97102607A patent/EP0794172B1/de not_active Expired - Lifetime
- 1997-02-27 TW TW086102369A patent/TW440558B/zh not_active IP Right Cessation
- 1997-02-28 SK SK276-97A patent/SK283934B6/sk unknown
- 1997-02-28 AU AU14997/97A patent/AU707619B2/en not_active Ceased
- 1997-02-28 CN CN97102833A patent/CN1071318C/zh not_active Expired - Fee Related
- 1997-02-28 NZ NZ314325A patent/NZ314325A/en unknown
- 1997-02-28 AR ARP970100820A patent/AR006051A1/es unknown
- 1997-03-03 NO NO970963A patent/NO308793B1/no unknown
- 1997-03-03 ID IDP970641A patent/ID16106A/id unknown
- 1997-03-03 KR KR1019970006865A patent/KR970065511A/ko not_active Ceased
- 1997-03-03 IL IL12035897A patent/IL120358A/en not_active IP Right Cessation
- 1997-03-03 ZA ZA9701815A patent/ZA971815B/xx unknown
- 1997-03-03 TR TR97/00131A patent/TR199700131A2/xx unknown
- 1997-03-03 RU RU97103361/04A patent/RU2212400C2/ru not_active IP Right Cessation
- 1997-03-03 JP JP04747997A patent/JP4039586B2/ja not_active Expired - Fee Related
- 1997-03-03 CZ CZ1997654A patent/CZ293144B6/cs not_active IP Right Cessation
- 1997-03-03 BR BR9701159A patent/BR9701159A/pt not_active Application Discontinuation
- 1997-03-03 MX MX9701619A patent/MX9701619A/es not_active IP Right Cessation
- 1997-03-03 MY MYPI97000835A patent/MY116861A/en unknown
- 1997-03-03 CA CA002198980A patent/CA2198980A1/en not_active Abandoned
- 1997-03-03 HR HR970125A patent/HRP970125B1/xx not_active IP Right Cessation
- 1997-03-04 HU HU9700542A patent/HUP9700542A3/hu unknown
-
1999
- 1999-09-17 US US09/398,196 patent/US6262123B1/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0612723A1 (de) * | 1993-02-20 | 1994-08-31 | Hoechst Aktiengesellschaft | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, als Inhibitioren des zellulären Na+/H+-Austauschs oder als Diagnostikum sowie sie enthaltendes Medikament |
| CN1106381A (zh) * | 1993-08-27 | 1995-08-09 | 赫彻斯特股份公司 | 邻位取代的苯甲酰胍、制法、含有它们的药品及用途 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5965744A (en) | Ortho-substituted benzoylguanidines, including composition and methods of using them | |
| IL109887A (en) | Substituted benzoylguanidines, process for their preparation and pharmaceutical compositions containing them | |
| CZ280896A3 (en) | Substituted benzoylguanidines, process of their preparation, their use as a medicament or a diagnostic agent as well as medicaments containing such benzoylguanidines | |
| JP4101904B2 (ja) | オルト−置換されたベンゾイルグアニジン、その製法、医薬または診断剤としてのその使用およびそれを含有する医薬 | |
| CN1071318C (zh) | 邻取代的苯甲酰胍、其制备方法、其用作药物或诊断剂及含其药物 | |
| CN1060764C (zh) | 邻取代的苯甲酰胍、其制备方法、其用作药物或诊断剂及含其药物 | |
| US6617344B2 (en) | Heterocyclically substituted benzoylguanidines, process for their preparation, their use as medicaments or diagnostics, and medicaments comprising them | |
| CN1159444A (zh) | 磺酰基氨基取代的苯甲酰胍，其制备方法及其作为药物或诊断剂的应用及含其的药物 | |
| SK282351B6 (sk) | Orto-substituované benzoylguanidíny, spôsob ich výroby, ich použitie ako liečiva alebo diagnostického prostriedku a liečivo, ktoré ich obsahuje | |
| US6153651A (en) | Ortho-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament comprising them | |
| MXPA97001619A (es) | Benzoilguanidinas sustituidas en posicion orto, procedimiento para su preparacion, su utilizacion como medicamento o agente de diagnostico, asi como medicamento que las contiene | |
| CA2206198A1 (en) | Bis-ortho-substituted benzoylguanidines, processes for their preparation, their use as a medicament or diagnostic, and medicament comprising them | |
| US5731350A (en) | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them | |
| MXPA97001323A (en) | Benzoilguanidinas replaced in orthodous position, a procedure for its preparation, its use as a diagnostic medicine or agent, so i composed that conti |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1030539 Country of ref document: HK |
|
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |