HRP970101A2 - Ortho-substituted benzoylguanidines, process for their preparation and their use as medicament or diagnostic agent as well as medicaments containing them - Google Patents
Ortho-substituted benzoylguanidines, process for their preparation and their use as medicament or diagnostic agent as well as medicaments containing themInfo
- Publication number
- HRP970101A2 HRP970101A2 HR19606509.7A HRP970101A HRP970101A2 HR P970101 A2 HRP970101 A2 HR P970101A2 HR P970101 A HRP970101 A HR P970101A HR P970101 A2 HRP970101 A2 HR P970101A2
- Authority
- HR
- Croatia
- Prior art keywords
- chloro
- trifluoromethyl
- compound
- production
- benzoylguanidine
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 21
- 238000000034 method Methods 0.000 title claims description 13
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 3
- 239000000032 diagnostic agent Substances 0.000 title 1
- 229940039227 diagnostic agent Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 44
- -1 2-chloro-4-methoxy-5-trifluoromethyl-benzoylguanidine hydrochloride 2-chloro-3-methoxy-5-trifluoromethyl-benzoylguanidine hydrochloride 2-chloro-3-iodo-5-trifluoromethyl-benzoylguanidine hydrochloride Chemical compound 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 13
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000011321 prophylaxis Methods 0.000 claims description 7
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- WYZGKIHRMZVZJJ-UHFFFAOYSA-N 2-chloro-4-cyclopentyl-n-(diaminomethylidene)-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.C1=C(Cl)C(C(=O)NC(=N)N)=CC(C(F)(F)F)=C1C1CCCC1 WYZGKIHRMZVZJJ-UHFFFAOYSA-N 0.000 claims description 4
- HHPXGJUQKXDCKU-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-propyl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CCCC1=CC(Cl)=C(C(=O)NC(N)=N)C=C1C(F)(F)F HHPXGJUQKXDCKU-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 230000004663 cell proliferation Effects 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 206010020718 hyperplasia Diseases 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- 230000035939 shock Effects 0.000 claims description 3
- USOWZWSPFODKJZ-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-propan-2-yl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC(C)C1=CC(Cl)=C(C(=O)NC(N)=N)C=C1C(F)(F)F USOWZWSPFODKJZ-UHFFFAOYSA-N 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 230000003176 fibrotic effect Effects 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 230000002093 peripheral effect Effects 0.000 claims 2
- 210000001428 peripheral nervous system Anatomy 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- 208000005069 pulmonary fibrosis Diseases 0.000 claims 1
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 150000004702 methyl esters Chemical class 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000004132 cross linking Methods 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OCZOVSRYKHMNIN-UHFFFAOYSA-N 2-chloro-3-cyclopentyl-n-(diaminomethylidene)-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.NC(=N)NC(=O)C1=CC(C(F)(F)F)=CC(C2CCCC2)=C1Cl OCZOVSRYKHMNIN-UHFFFAOYSA-N 0.000 description 3
- JECCCYHYVJVZDD-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-3-methyl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC1=CC(C(F)(F)F)=CC(C(=O)NC(N)=N)=C1Cl JECCCYHYVJVZDD-UHFFFAOYSA-N 0.000 description 3
- DBCDTXZZJHUJID-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-3-propyl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CCCC1=CC(C(F)(F)F)=CC(C(=O)NC(N)=N)=C1Cl DBCDTXZZJHUJID-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-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
- 150000007513 acids Chemical class 0.000 description 3
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 3
- 229960002576 amiloride Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229960003343 ouabain Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- CUNPJFGIODEJLQ-UHFFFAOYSA-M potassium;2,2,2-trifluoroacetate Chemical compound [K+].[O-]C(=O)C(F)(F)F CUNPJFGIODEJLQ-UHFFFAOYSA-M 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- DJKOXFCVKCOEMT-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-3-iodo-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.NC(=N)NC(=O)C1=CC(C(F)(F)F)=CC(I)=C1Cl DJKOXFCVKCOEMT-UHFFFAOYSA-N 0.000 description 2
- QTOQFQHPMHYIAC-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-3-propan-2-yl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC(C)C1=CC(C(F)(F)F)=CC(C(=O)NC(N)=N)=C1Cl QTOQFQHPMHYIAC-UHFFFAOYSA-N 0.000 description 2
- NVMFQTOHSCBYEH-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-methoxy-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.COC1=CC(Cl)=C(C(=O)NC(N)=N)C=C1C(F)(F)F NVMFQTOHSCBYEH-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 208000007530 Essential hypertension 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108091006672 Sodium–hydrogen antiporter Proteins 0.000 description 2
- 244000166550 Strophanthus gratus Species 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- QZDLPGZQNPSDFE-UHFFFAOYSA-M [Cl-].CCC[Zn+] Chemical compound [Cl-].CCC[Zn+] QZDLPGZQNPSDFE-UHFFFAOYSA-M 0.000 description 2
- YPIAGTACDKOXKS-UHFFFAOYSA-M [Cl-].[Zn+]C1CCCC1 Chemical compound [Cl-].[Zn+]C1CCCC1 YPIAGTACDKOXKS-UHFFFAOYSA-M 0.000 description 2
- 125000005907 alkyl ester group Chemical group 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
- 230000033228 biological regulation Effects 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
- 125000001309 chloro group Chemical group Cl* 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
- 230000006378 damage Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005048 flame photometry Methods 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- JSNXIWYWUKTWAX-UHFFFAOYSA-N methyl 4-bromo-2-chlorobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1Cl JSNXIWYWUKTWAX-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
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 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
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IBANGHTVBPZCHF-UHFFFAOYSA-N 2-chloro-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(Cl)=C1 IBANGHTVBPZCHF-UHFFFAOYSA-N 0.000 description 1
- WLXRKCGYQAKHSJ-UHFFFAOYSA-N 2-chloro-5-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC=C1Cl WLXRKCGYQAKHSJ-UHFFFAOYSA-N 0.000 description 1
- BYQFOHVCSZIKEW-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-3-methoxy-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.COC1=CC(C(F)(F)F)=CC(C(=O)NC(N)=N)=C1Cl BYQFOHVCSZIKEW-UHFFFAOYSA-N 0.000 description 1
- CFYXNFBLQFBEPR-UHFFFAOYSA-N 2-chloro-n-(diaminomethylidene)-4-methyl-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC1=CC(Cl)=C(C(=O)NC(N)=N)C=C1C(F)(F)F CFYXNFBLQFBEPR-UHFFFAOYSA-N 0.000 description 1
- RBVZTMRLMZCQMG-UHFFFAOYSA-N 3-tert-butyl-2-chloro-n-(diaminomethylidene)-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC(C)(C)C1=CC(C(F)(F)F)=CC(C(=O)NC(N)=N)=C1Cl RBVZTMRLMZCQMG-UHFFFAOYSA-N 0.000 description 1
- UUHDOKOJHXNAOM-UHFFFAOYSA-N 4-tert-butyl-2-chloro-n-(diaminomethylidene)-5-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CC(C)(C)C1=CC(Cl)=C(C(=O)NC(N)=N)C=C1C(F)(F)F UUHDOKOJHXNAOM-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 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
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010021137 Hypovolaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000050381 Na+/H+ exchanger Human genes 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000052126 Sodium-Hydrogen Exchangers Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 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
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- QWQOLXDTTZSJBQ-UHFFFAOYSA-M [Cl-].CC(C)[Zn+] Chemical compound [Cl-].CC(C)[Zn+] QWQOLXDTTZSJBQ-UHFFFAOYSA-M 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
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001629 magnesium chloride 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
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- CYEMHQMJKBKSCI-UHFFFAOYSA-N methyl 2-chloro-3-cyclopentyl-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=CC(C2CCCC2)=C1Cl CYEMHQMJKBKSCI-UHFFFAOYSA-N 0.000 description 1
- QUIKJCFZTYHUQH-UHFFFAOYSA-N methyl 2-chloro-3-propan-2-yl-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=CC(C(C)C)=C1Cl QUIKJCFZTYHUQH-UHFFFAOYSA-N 0.000 description 1
- IJSQOCZEMXADSC-UHFFFAOYSA-N methyl 2-chloro-3-propyl-5-(trifluoromethyl)benzoate Chemical compound CCCC1=CC(C(F)(F)F)=CC(C(=O)OC)=C1Cl IJSQOCZEMXADSC-UHFFFAOYSA-N 0.000 description 1
- BKHNRGZKPJTWDP-UHFFFAOYSA-N methyl 2-chloro-4-cyclopentyl-5-(trifluoromethyl)benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(C(F)(F)F)=C1C1CCCC1 BKHNRGZKPJTWDP-UHFFFAOYSA-N 0.000 description 1
- POPURTFPXSYMDV-UHFFFAOYSA-N methyl 2-chloro-4-methoxy-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=C(OC)C=C1Cl POPURTFPXSYMDV-UHFFFAOYSA-N 0.000 description 1
- JYWCIJMCOHVZLE-UHFFFAOYSA-N methyl 2-chloro-4-propylbenzoate Chemical compound CCCC1=CC=C(C(=O)OC)C(Cl)=C1 JYWCIJMCOHVZLE-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052757 nitrogen 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
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 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
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect 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
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000054 salidiuretic effect Effects 0.000 description 1
- 208000037921 secondary disease Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- NMLXKNNXODLJIN-UHFFFAOYSA-M zinc;carbanide;chloride Chemical compound [CH3-].[Zn+]Cl NMLXKNNXODLJIN-UHFFFAOYSA-M 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Reproductive Health (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)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
Izum se odnosni na orto-supstituirane benzoilgvanidine formule 1
[image]
u kojoj
R(2) i R(3) medusobno neovisno predstavljaju vodik, Cl, Br, J, (C1-C8)-alkil, (C3-C8) -cikloalkil ili -OR(5);
R(5) je (C1-C8)-alkil ili –CdC2d-(C3-C8)-clkloalkil; d je nula, 1 ili 2;
pri čemu je uvijek jedan od dvaju supstituenta R(2) i R(3) vodik, dok obadva supstituenta, R(2) i R(3), ne mogu istovremeno biti vodik, te njihove farniaceutski prihvatljive soli.
Prednost imaju spojevi formule I, u kojoj
R(2) i R(3) medusobno neovisno predstavljaju vodik, Cl, Br, J, (C1-C8)-alkil, (C3-C8)-cikloalkil ili -OR(5);
R(5) je (C1-C8)-alkil; te njihove farmaceutski prihvatljive soli.
Posve osobitu prednost imaiu spojevi:
2-klor-4-metoksi-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-metoksi-5-trirluormetil-benzoilgvanidin-hidroklorid
2-klor-3-jod-5-trirluormetil-benzoilgvanidin-hidroklorid
2-klor-3-metil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-n-propil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-izopropil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-terc butil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-ciklopentil-5-trlfluormetil-benzoilgvanidin-hidroklorid
2-klor-4-metil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-4-n-propil-5-trifluormetil-benzoilgvanidin-hidroklorid,
2-klor-4-izopropil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-4-terc butil-5-trifluormetil-benzoilgvanidin-hidroklorid i
2-klor-4-ciklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid.
Ako jedan od supstituenata R(2) ili R(3) ima jedno ili više središta asimetrije, oni mogu biti u S kao također i u R konfiguraciji. Spojevi mogu postojati kao optički izomeri, kao diastereomeri, kao racemati ili kao njihova smjesa.
Označeni alkilni ostaci mogu biti ravnog ili razgranatog lanca.
Izum se također odnosi nadalje na postupak za proizvodnju spoja I, koji je naznačen time, da se spoj formule II
[image]
kemijski pretvori s gvanidinom, pri čemu R(2) i R(3) imaju navedena značenja, a L predstavlja laku nukleofilnu otpusnu skupinu, koja se može supstituirati.
Aktivirani kiselinski derivati formule II, u kojoj L predstavlja alkoksi-, ponajprije metoksi skupinu, fenoksi skupinu, feniltio, metiltio, 2-piridiltio skupinu, heterocikl s dušikom, ponajprije 1-imidazolil, dobiju se prikladno na sam po sebi poznat način iz klorida osnovnih karbonskih kiselina (formula II, L = Cl) , koji se opet sa svoje strane na sam po sebi poznat način pripreme od osnovnih karbonskih kiselina (formula II, L = OH) , primjerice s tionilkloridom.
Pored klorida karbonskih kiselina formule II (L = Cl) aktivirani kiselinski derivati tormule II mogu se proizvesti na sam po sebi poznat način izravno iz osnovnih derivata benzojeve kiseline (formula II, L = OH) , kao primjerice metilester formule II sa L = OCH3 obradom s plinovitom HCl u metanolu, imidazolid formule II obradom s karbonildilmidazolom [L = 1-imldazolil, Staab, Angew. Chem. InL. Ed. Engl. 1, 351-367 (1962)], miješani anhidridi II sa Cl-COOC2H5 ili tosilkloridom u prisutnosti trietilamina u inertnoni otapalu, kao također aktiviranjem benzojeve kiseline može s dicikloheksilkarbodiimidom (DCC) ili s 0-[(cijano (etoksikarbonil)metilen) amino]-1,1,3,3-tetrametil-uronijevi tetrafluorboratoni (“TOTU”) [Weiss 1 Krommer, Chemiker Zeitung 98, 817 (1974)]. Niz prikladnih metoda za proizvodnju aktiviranih derivata karbonskih kiselina formule II naveden je zajedno s izvornom literaturom u J. March, Advanced Organic Chemistry, treće izdanje (John Wiley & Sons, (1985), str. 350.
Kemijska pretvorba aktiviranog derivata karbonske kisellne formule II s gvanidinom odvija se na sam po sebi poznat način u protičkom ili aprotičkom polarnom, ali inertnom organskom otapalu. Pri tome, kod kemijske pretvorbe metilestera benzojeve kiseline (II, L = OMe) s gvanidlnoni kao otapala dobrim su se pokazali metanol, izopropanol ili THF pri 20°C do vrelišta tog otapala. Kod većine pretvorbi spojeva II s gvanidlnom, koji nije u obliku soli, korisno je raditi u aprotičnim inertnim otapalima kao što su THF, dimetoksietan, dioksan. Kod pretvorbe II s gvanidinom, uz upotrebu baze kao primjerice NaOH, kao otapalo se također može upotrijebiti voda.
Ako L predstavlja Cl, korisno je raditi uz dodatak kiselinskog akceptora, npr. u obliku suviška gvanidina, zbog vezanja halogenovodične kiseline.
Jedan dio osnovnih derivata benzojeve kiseline formule II je poznat i opisan je u literaturi. Nepoznati spojevi formule II mogu se proizvesti po metodama poznatim iz literature. Dobiveni derivati benzojeve kiseline pretvaraju se u spojeve I prema izumu po jednoj od gore opisanih inačica postupka. Uvoderne nekolicine supstituenata u položaje 3 i 4 uspjeva po metodama poznatim iz literature poprečnim povezivanjem aril-halogenida, odnosno ariltriftalata s primjerice organostananima, organobornim kiselinama ili organoboranima ili organskim spojevima bakra ili cinka, posredatvom paladija.
Benzoilgvanidini I sa općenito slabe baze i mogu vezati kiseline uz tvorbu soli. Kao kiselinske adicijske soli u obzir dolaze sve soli farmakološki podnošljivih kiselina, primjerice halogenidi, naročito hidrokloridi, laktati, sulfati, citrati, tartarati, acetati, fosfati, metilsulfonati, p-toluolsulfonati. Spojevi I su supstituirani acilgvanidini.
Iz europskog patentnog splsa 640 588 A 1 poznati su spojevi slične grade, koji u položaju 5 pored mnoštva drugih supstituenata R(1) također niogu nositi CF3 skupinu, a u položaju 2 mogu pored mnoštva supstituenata nositi također i atom klora. Međutim nije se moglo predvidjeti da će baš ti spojevi s jednom trifluormetilnom skupinom i s jednim klorovim atomom ostvariti istaknuto djelovanje.
Iznenađuje da spojevi prema izumu ne samo da ne pokazuju neželjena i štetna salidiuretička svojstva, već oni istovremeno imaju posebno povoljno niže vrijeme poluraspada, koje je kod poznatih spojeva često neželjeno dugo. Spojevi prema izumu odlikuju se nadalje dobrom biološkom raspoloživošću što proizlazi iz vrijednostl dobivenih in vivo.
Slično poznatim spojevima, oni su zbog svojih farmakoloških svojstava izrazito prikladni kao antiaritmici s kardioprotektivnom komponentom za profilaksu infarkta i liječenje infarkta, te za liječenje angine pectoris, pri čemu oni također preventivno inhibiraju ili jako smanjuju patotiziološke procese kod nastanka ozljeda induciranih ishemijom, naročito kod pojave srćanih aritmija induciranih ishemijom.
Zbog svog zaštitnog djelovanja protiv patoloških hipoksičkih i ishemijskih stanja, spojevi prema izumu formule I, zbog inhibicije staničnog mehanizma izmjene Na+/H+ mogu se upotrijebiti kao lijekovi za liječenje svih akutnih ili kroničnih ozljeda izazvanih ishemijom ili time induciranih primarnih ili sekundarnih oboljenja.
To se odnosi na njihovu upotrebu kao lijekova kod operativnih zahvata, npr. kod transplantacija organa, pri čemu se spojevi mogu upotrijebiti za zaštitu organa u darovatelju prije i tljekom uzimanja, za zaštitu izvađenih organa, primjerice za obradu ili njihovo odlaganje u fiziloškim tekućim kupeljima, kao također i kod prenošenja u organizam primatelja. Spojevi su također dragocjeni protektlvno učinkoviti lijekovi kod provedbe angioplastičnih operativnih zahvata, primjerice na srcu, kao također i na perifernim krvnim žilama.
U skladu s njihovim protektivnim djelovanjem protiv ishemijski induciranih ozljeda, spojevi su također prikladni kao lijekovi za liječenje ishemije nervnog sistema, naročito središnjeg nervnog sistema, pri čemu su oni prikladni npr. za liječenje udara kapi ili moždanog edema. Spojevi prema izumu formule 1 prikladni su nadalje također za liječenje oblika šoka, kao primjerice alergijskog, kardiogenog, hipovolemičkog i bakterijskog šoka.
Nadalje, spojevi prema izumu formule 1 odlikuju se jakim inhibicijskim djelovanjem na proliferaciju stanica, primjerice staničnu proliferaclju fibroplasta i proliferaciju glatkih mišićnih stanica žila. Zbog toga spojevi formule 1 dolaze u obzir kao dragocjeni terapeutici za bolestl kod kojih stanična proliferacija predstavlja primarni ili sekundarni uzrok, i zbog toga se mogu upotrijebiti kao antiaterosklerotici, sredstva protiv dijabetičkih kasnih komplikacija, raka, fibrotičkih bolesti kao plućne ribroze, jetrene fibroze ili fibroze bubrega, hipertrofije ili hiperplazije organa, naročito kod hiperplazije prostate, odnosno hipertrofije prostate.
Spojevi prema izumu su učinkoviti inhibitori staničnih antiportera natrij-protona (izmjenjivača Na+/H+) koji su također u takovim stanicama povišeni kod brojnih bolestl (esencijalna hipertonija, ateroskleroza, dijabetes, itd.), mjerenja su lako dostupna, kao primjerice u eritocitima, trombocitima ili leukocitima. Spojevi prema izumu prikladni su stoga kao istaknuto i jednostavno znanstveno sredstvo, pa se primjerice mogu upotrijebiti kao dijagnostici za određivanje i razlikovanje određenih oblika hipertonije, ali također i za aterosklerozu, dijabetes, proliferativne bolesti itd. Nadalje, spojevi formule 1 prikladni su za preventivnu terapiju za sprečavanje geneze visokog krvnog tlaka, primjerice esencijalne hipertonije.
Pri tome lijekovi koji sadrže spoj 1 mogu se aplicirati oralnoj parenteralno, intravenski, rektalno ili inhalacijom, pri čemu aplikacija kojoj se daje prednost ovisi o dotičnoj pojavnoj slici bolesti. Pri tome spojevi 1 mogu doći u primjenu sami ili zajedno s galenskim pomoćnim tvarima, i to kako u veterini, tako također i u humanoj medicini. Pomoćne tvari prikladne za željenu formulaciju lijeka poznate su stručnjaku na osnovu njegovog stručnog znanja. Pored otapala, sredstava za tvorbu gela, podloga za čepiće, pomoćnih tvari za tablete i drugih nosača aktivne tvari, mogu se upotrijebiti, primjerice, i antioksidanti, sredstva za dispergiranje, emulgatori, sredstva protiv pjenjenja, sredstva za korekciju ukusa, konzervansi, sredstva za pospješivanje otapanja ili bojila.
Za oralnu aplikaciju aktivni spojevi pomiješaju se s prikladnim dodatnim tvarima, kao nosećim tvarima, stabilizatorima ili inertnim sredstvima za razređenje i uobičajenim metodama prevode se u prikladne oblike za davanje, kao tablete, dražeje, kapsule, vodene alkoholne ili uljne otopine. Kao inertni nosači mogu se uporijebiti npr. guma arabika, magnezijev oksid, magnezijev karbonat, kalijev fosfat, mliječni šećer, glukoza ili škrob, naročito kukcuruzni škrob. Pri tome pripravak može biti suhi ili također i vlažan granulat. Kao uljni nosači ili kao otapala dolaze u obzir primjerice biljna ili životinjska ulja, kao suncokretovo ulje ili riblje jetreno ulje.
Za subkutanu ili intravensku aplikaciju aktivni spojevi, zajedno s uobičajenim tvarima kao sredstvima za pospješivanje otapanja emulgatorima ili drugini pomoćnim tvarima,. po želji, prevedu se u otopine, suspenzije ili emulzije. Kao otapala dolaze u obzir npr. voda, fiziološka otopina kuhinjske soli ili alkoholi, npr. etanol, propanol, gllcerin, a također i otopine šećera, kao otopine glukoze ili manlta, ili također mješavina različitih navedenih otapala.
Kao farmaceutske formulacije za davanje u obliku aerosola ili spreja prikladne su npr. otopine suspenzije ili emulzije aktivne tvari formule 1 u farmaceutski nedvojbenom otapalu, naročito etanolu ili vodi, ili u mješavini takovih otapala po potrebi formulacija može sadržavati još i druge farmaceutske pomoćne tvari kao tenzide, emulgatore i stabilizatore, te potisni plin. Takav pripravak sadrži aktivnu tvar obično koncentracijom od otprilike 0,1 do 10, naročito od otprilike 0,3 do 3 mas. %.
Doziranja aktivne tvari formule 1 koju se daje i učestalost davanja ovise o jačini djelovanja i trajanju djelovanja upotrijebljenog spoja, a osim toga također i o vrsti i jačini liječene bolesti, te o vrsti, starosti, težini i individualnoj podražljivosti liječenog sisavca u prosjeka dnevna doza spoje formule 1 kod pacijenta teškog otprilike 75 kg iznosi najmanje 0,001 mg/kg, ponajprije 0,01 mg/kg, do najviše 10 mg/kg, ponajprije 1 mg/kg tjelesne težine. Kod akutnih izbijanja bolesti, otprilike neposredno nakon pretprjelog srčanog infarkta, mogu biti potrebna također I viša, a prije svega češća doziranja, npr. Do 4 pojedinačne doze dnevno. Naročito kod i.v. primjene, eventualno kod pacijenta s infarktom na stanici za intenzivnu njegu, može biti potrebno i do 200 mg po danu.
Popis kratica:
MeOH metanol
NMP N-metll-2-pirolidinon
RT sobna temperatura
EE etilacetat (EtOAc)
Smp talište
THF tetrahidrofuran
Eksperimentalni dio
Opći propis za proizvodnju benzoil-gvanidina (I)
iz alkil estera benzojeve kiseline (II/ L = O-alkil) 1,0 ekv. alkil estera benzojeve kiseline formule II te 5,0 ekv. gvanidina (slobodne baze) otopi se u izopropanolu, ili se suspenđira THF-u, i grije se do ključanja do potpune kemijske pretvorbe (tankoslojna kontrola) (tipično vrijeme reakcije je 2 do 5 sati). Otapalo se odstrani destilacijom pod smanjenim tlakom (rotacijski uređaj za isparavanje), ostatak se preuzme u EE i tri puta se ispere s otopinom NaHCO3. Osuši se preko Na2SO4, otapalo se odstrani destilacijom u vakuumu i kromatografija se na silika gelu s prikladnim protočnim sredstvom, npr. EE/MeOH 5:1.
Primjer 1
2-klor-4-metoksi-5-trifluormetil-benzoilgvandin-hidroklorid
[image]
Bezbojni kristali, talište 232°C.
Put sinteze:
a) Metil ester 2-klor-5-jod-4-metoksi-benzojeve kiseline dobije se iz metil estera 2-klor-4-metoksi-benzojeve kiseline reakcijom s 1,1 ekvivalenta N-klor-sukcinimida u prisutnosti 2 ekvivalenta kalijevog jodida u octenoj kiselini pri sobnoj temperaturi tijekom 1 sata. Žučkasti kristali, talište 120°C.
b) Metil ester 2-klor-4-metoksi-5-trifluormetil-benzojeve kiseline dobije se iz a) grijanjem pri 90°C s kalijevim trifluoracetatom u NMP-u u prisutnosti bakar(I) jodida. Bezbojni kristali, tailište 112°C.
c) 2-klor-4-metoksi-5-trifluormetil-benzoilgvanidin-hidroklorid dobije se iz b) po općem propisu.
Primjer 2
2-klor-3-jod-5-trifluorinetil-benzoilgvanidin-hidroklorid:
bezbojni kristali, talište 268°C.
Put sinteze
a) Metil ester 2-klor-3-jod-5-trlfluornietil-benzojeve klseline dobije se iz metil estera 2-klor-5-trifluormetil-benzojeve kiseline reakcijom s 1 ekvivalentom N-jod-sukcinimida u 5 ekvivalenata trifluormetansulfonske kiseline pri sobnoj temperaturi tijekom 24 sata. Bezbojno ulje, (M+H)+ = 365.
b) 2-klor-3-jod-5-trifluormetil-benzoilgvanidin-hidroklorid dobije se iz a) po općem propisu.
Primjer 3
2-klor-3-metil-5-trifluormetil-benzoilgvanidin-hidroklorid:
bezbojni kristali, talište 236°C.
Put sinteze
a) Metil ester 2-klor-3-metil-5-trifluormetil-benzojeve kiseline dobije se iz 2a) poprečnim povezivanjem s 1,5 ekvivalenta metil cinkovog klorida (koji se dobije iz metil magnezijevog klorida transmetiliranjem sa cink(II) klorid-eteratom u THF-u) miješanjem pri sobnoj temperaturi u prisutnosti katalizatora paladij(II)[1,1 -bis-(difenil-fostino)terocen]klorida i bakar(I) jodida, vodenom obradom, ekstrakcijom s octenim esterom i na kraju kromatografijom u koloni na silika gelu s octeni ester/n-heptanom (3:7), bezbojno ulie, (M+H)+ = 253
b) 2-klor-3-metil-5-trifluormetil-benzoilgvanidin-hidroklorid dobije se iz b) po općem propisu.
Primjer 4
2-klor-3-n-propil-5-trifluormetil-benzoilgvanidin-hidroklorid
Bezbojni kristali, tallšte 208°C.
Put sinteze
a) Metil ester 2-klor-3-n-propil-5-trifluormetil-benzojeve kiseline dobije se iz 2a) poprečnim povezivanjem s 1,5 ekvivalenta n-propil-cinkovog klorida kako je oplsano u 3a), bezbojno ulje, (M+H)+ = 281.
b) 2-klor-3-n-propil-5-trifluormetil-benzoilgvanidin-hidro-klorid dobije se iz a) po općem propisu.
Primjer 5
2-klor-3-izopropil-5-trifluormetil-benzoilgvanidin-hidroklorid:
bezbojni kristali, talište 208°C.
Put sinteze
a) Metil ester 2-klor-3-izopropil-5-trifluormetil-benzojeve kiseline dobije se iz 2a) poprečnim povezivanjem s 1,5 ekvivalentom izopropil-cinkovog klorida kako je opisano u 3a) bezbojno ulje, (M+H)+ = 281
b) 2-klor-3-izopropil-5-trifluormetil-benzogvanidin-hidroklorid dobije se iz a) po općem propisu
Primjer 6
2-klor-3-ciklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid
Bezbojni kristali, talište 160°C,
Put sinteze
a) Metil ester 2-klor-3-ciklopentil-5-trifluormetil-benzojeve kiseline dobije se iz 2a) poprečnim povezivanjem s 1,5 ekvivalenta ciklopentil-cinkovog klorida kako je opisano u 3a), bezbojno ulje, (M+H)+ = 307.
b) 2-klor-3-ciklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid dobije se iz a) po općem propisu.
Primjer 7
2-klor-4-clklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid
Bezbojni kristali, talište 245°C.
Put sinteze
a) Metil ester 2-klor-4-ciklopentil-5-trifluormetil-benzojeve kiseline dobije se iz metil estera 2-klor-4-brom-benzojeve kiseline poprečnim povezivanjem s 1,5 ekvivalenta ciklopentil-cinkovog klorida kako 10 opisano u 3a),
bezbojno ulje, (M+H)+ = 238.
b) Metil ester 2-klor-4-cikiopentll-5-jod-benzojeve kiseline dobije se iz 7a) reakcijom s 1 ekvivalentoin N-jod-sukcinimida u 5 ekvivalenata trifluormetansulfonske kiseline pri sobnoj temperaturi tijekom 24 sata,
bezbojno ulje, (M+H)+ = 364.
c) Metil ester 2-klor-4-ciklopentil-5-trifluormetil-benzojeve kiseline dobije se iz 7b) grijanjem na 90°C s kalijevim trifluoracetatom u NPM-u u prisutnosti bakar(I) jodida analogno 1b),
bezbojno ulje, (M+H)+ = 306.
d) 2-klor-4-ciklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid dobije se iz 7c) analogno općem propisu.
Primjer 8
2-klor-4-n-propil-5-trifluormetil-benzoilgvanidin-hidroklorid
Bezbojni kristali, talište 213°C.
Put sinteze
a) Metil ester 2-klor-4-n-propil-benzojeve kiseline dobije se iz metil estera 2-klor-4-brom-benzojeve kiseline poprečnim povezivanjem s 1,5 ekvivalenta n-propil-cinkovog klorida kako je opisano u 3a),
bezbojno ulje, (M+H)+ = 212.
b) Metil-ester 2-klor-4-n-propil-5-jod-benzojeve kiseline dobije se iz 8a) reakcijom s 1 ekvivalentom N-jod-sukcinimida u 5 ekvivalenata trifluormetansulfonske kiseline pri sobnoj temperaturi tijekom 24 sata,
bezbojno ulje, (M+H)+ = 338
c) Metil ester 2-klor-4-n-propil-5-trifluormetil-benzojeve kiseline dobije se iz 8b) grljanjem pri 90°C s kalijevim trifluoracetatom u NPM-u u prisutnosti- bakar(I) jodida analogno Ib),
bezbojno ulje, (M+H)+ -= 280.
d.) 2-klor-4-n-propil-5-trifluormetil-benzoilgvanidin-hidroklorid dobije se iz 8c) po općem propisu.
Farmakološki podaci
Inhibicija Na+/H+-izmjenjivača u eritrocitima kunića
Bijeli novozelandski kunići (Ivanovas) dobivali su standardnu dijetu s 2% kolesterina tijekom šest tjedana da bi se aktiviralo Na+/H+-izmjenu i tako plamenom fotometrijom moglo odrediti ulaz Na+ u eritrocite Na+/'H+-izmjenom. Krv je uzeta iz arterija uha i zgrušavanje je spriječeno s 25 IE kalij-heparinom. Jedan dio svakog uzorka korišten je za dvostruko određivanje hematokrita centrifugiranjem.
Alikvoti od po 100 μl služlli su za mjerenje polaznog sadrzaja Na+ u eritrocitima.
Da bi se odredio ulaz natrija osjetljiv prema amiloridu, inkubirano je 100 μl svakog uzorka krvi u 5 ml hiperosmotske otopine sol-saharoza (mmol/1: 140 NaCl, 3 KCl, 150 saharose, 0,1 ouabain, 20 tris-hidroksimetil-aminometan) pri pH 7,4 i 37°C. Nakon toga eritrociti su tri puta isprani s ledeno hladnom otopinom MgCl2-ouabaina (mmol/1: 112 MgCl2, 0,1 ouabain) i hemolizirani u 2,0 ml destilirane vode. Intracelularni sadržaj natrija određen je plamenom fotometrijom.
Ulaz Na+ izračunat je iz razlike između polazne vrijednosti sadržaja natrija i sadržaja natrija u eritrocitima nakon inkubacije. Ulaz natrija suzbijen amiloridom dobiven je iz razlike sadržaja natrija u eritrocitima nakon inkubacije sa i bez 3 x 10-4 mol/1 amilorida. Na taj način postupilo se je i kod spojeva prema izumu.
Rezultati
[image]
[image]
Claims (15)
1. Orto-supstituirani benzoilgvanidini formule I
[image]
naznačeni time, da
R(2) i R(3) međusobno neovisno predstavljaju vodik, Cl, Br, J, (C1-C8)-alkil, {C3-C8) -cikloalkil ili -OR(5);
R(5) je (C1-C8)-alkil ili -CdC2d-(C3-C8) -cikloalkil;
d je nula 1 ili 2;
pri čemu je uvijek jedan od dvaju supstituenta R(2) i R(3) vodik, dok obadva supstituenta R(2) i R(3), ne mogu istovremeno biti vodik, te njihove farmaceutski prihvatljive soli.
2. Spojevi formule I prema zahtjevu 1, naznačeni time, da
R(2) i R(3) međusobno neovisno predstavljaju vodik, Cl, Br, J, (C1-C8)-alkil, (C3-C8) -cikloalkil ili -OR(5) ;
R(5) je (C1-C8)-alkil;
te njihove farmaceutski prihvatljive soli.
3. Spoj formule I prema zahtjevu 1, naznačen time, da je odabran iz skupine koju čine:
2-klor-4-metoksi-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-metoksi-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-jod-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-metil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-n-propil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-izopropil-5-trifluormetil-benzoilgvanidin-hidroklorid,
2-klor-3-terc.butil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-3-ciklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-4-metil-5-trifluormetil-benzoilgvanidin-hidroklond
2-klor-4-n-propil-5trifluormetil-benzoilgvanidin-hidrokloirid,
2-klor-4-izopropil-5-trifluormetil-benzoilgvanidin-hidroklorid
2-klor-4-terc.butil-5-trifluormetil-benzoilgvanidin-hidroklorid i
2-klor-4-ciklopentil-5-trifluormetil-benzoilgvanidin-hidroklorid.
4. Postupak za proizvodnju spoja I, naznačen time, da se spoj formule II
[image]
kemijski pretvori s gvanidinom, pri čemu R(2) i R(3) imaju navedena značenja, a L predstavlja laku nukleofilnu otpusnu skupinu, koja se može supstituirati.
5. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu bolesti izazvanih ishemijskim stanjima.
6. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu srčanog infarkta.
7. Upotreba spoja I prema zahtjevu 1, naznačena. time, da se on koristi za proizvodnnu lijeka za liječenje ili profilaksu angine pectoris.
8. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja srca.
9. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja perifernog i središnjeg živčanog sustava i udara kapi.
10. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja perifernih organa i udova.
11. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje stanja šoka.
12. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka koji se upotrebljava kod kirurških operacija i transplantacija organa.
13. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka koji se upotrebljava za konzerviranje i odlaganje transplantata za kirurške zahvate.
14. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje bolesti kod kojih primarni ili sekundarni uzrok predstavlja stanična proliferacija, i zbog toga se on upotrebljava za proizvodnju antiaterosklerotika, sredstvo protiv kasnih komplikacija dijabetesa, raka, fibrotičnih oboljenja kao plućne fibroze, fibroze jetre ili fibroze bubrega, hiperplazije prostate.
15. Lijek, naznačen time, da sadrži učinkovitu količinu spoja formule I prema jednom ili više zahtjeva 1 do 3.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19606509A DE19606509A1 (de) | 1996-02-22 | 1996-02-22 | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HRP970101A2 true HRP970101A2 (en) | 1998-04-30 |
| HRP970101B1 HRP970101B1 (en) | 2001-02-28 |
Family
ID=7786043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR19606509.7 HRP970101B1 (en) | 1996-02-22 | 1997-02-21 | Ortho-substituted benzoylguanidines, process for their preparation and their use as medicament or diagnostic agent as well as medicaments containing them |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US5856574A (hr) |
| EP (1) | EP0791577B1 (hr) |
| JP (1) | JP3974677B2 (hr) |
| KR (1) | KR100476796B1 (hr) |
| CN (1) | CN1060764C (hr) |
| AR (1) | AR005933A1 (hr) |
| AT (1) | ATE186296T1 (hr) |
| AU (1) | AU723096B2 (hr) |
| BR (1) | BR9701046A (hr) |
| CA (1) | CA2198176A1 (hr) |
| CZ (1) | CZ287843B6 (hr) |
| DE (2) | DE19606509A1 (hr) |
| DK (1) | DK0791577T3 (hr) |
| ES (1) | ES2140922T3 (hr) |
| GR (1) | GR3032293T3 (hr) |
| HR (1) | HRP970101B1 (hr) |
| HU (1) | HUP9700502A3 (hr) |
| ID (1) | ID16042A (hr) |
| IL (1) | IL120259A (hr) |
| MX (1) | MX9701323A (hr) |
| MY (1) | MY117642A (hr) |
| NO (1) | NO307046B1 (hr) |
| NZ (1) | NZ314268A (hr) |
| PL (1) | PL185752B1 (hr) |
| RU (1) | RU2218329C2 (hr) |
| SI (1) | SI0791577T1 (hr) |
| SK (1) | SK281753B6 (hr) |
| TR (1) | TR199700144A2 (hr) |
| TW (1) | TW404937B (hr) |
| ZA (1) | ZA971514B (hr) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19713427A1 (de) * | 1997-04-01 | 1998-10-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| CN111099959B (zh) * | 2019-12-30 | 2022-09-02 | 西安瑞联新材料股份有限公司 | 一种1,4-二溴-2,5-二碘苯的工业化生产方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0612723B1 (de) * | 1993-02-20 | 1997-08-27 | Hoechst Aktiengesellschaft | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, als Inhibitoren des zellulären Na+/H+-Austauschs oder als Diagnostikum sowie sie enthaltendes Medikament |
| DE4328869A1 (de) * | 1993-08-27 | 1995-03-02 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19517848A1 (de) * | 1995-05-16 | 1996-11-21 | Merck Patent Gmbh | Fluorhaltige Benzoylguanidine |
| US5596407A (en) * | 1995-06-07 | 1997-01-21 | Varian Associates, Inc | Optical detector for echelle spectrometer |
-
1996
- 1996-02-22 DE DE19606509A patent/DE19606509A1/de not_active Withdrawn
-
1997
- 1997-01-20 DK DK97100777T patent/DK0791577T3/da active
- 1997-01-20 SI SI9730024T patent/SI0791577T1/xx not_active IP Right Cessation
- 1997-01-20 ES ES97100777T patent/ES2140922T3/es not_active Expired - Lifetime
- 1997-01-20 AT AT97100777T patent/ATE186296T1/de not_active IP Right Cessation
- 1997-01-20 EP EP97100777A patent/EP0791577B1/de not_active Expired - Lifetime
- 1997-01-20 DE DE59700640T patent/DE59700640D1/de not_active Expired - Lifetime
- 1997-02-11 PL PL97318417A patent/PL185752B1/pl not_active IP Right Cessation
- 1997-02-19 NZ NZ314268A patent/NZ314268A/en unknown
- 1997-02-19 AU AU14773/97A patent/AU723096B2/en not_active Ceased
- 1997-02-20 MY MYPI97000647A patent/MY117642A/en unknown
- 1997-02-20 SK SK237-97A patent/SK281753B6/sk unknown
- 1997-02-20 CN CN97102493A patent/CN1060764C/zh not_active Expired - Fee Related
- 1997-02-20 IL IL12025997A patent/IL120259A/en not_active IP Right Cessation
- 1997-02-20 CZ CZ1997528A patent/CZ287843B6/cs not_active IP Right Cessation
- 1997-02-20 AR ARP970100687A patent/AR005933A1/es active IP Right Grant
- 1997-02-20 TW TW086101993A patent/TW404937B/zh not_active IP Right Cessation
- 1997-02-20 TR TR97/00144A patent/TR199700144A2/xx unknown
- 1997-02-21 US US08/804,023 patent/US5856574A/en not_active Expired - Lifetime
- 1997-02-21 JP JP03724197A patent/JP3974677B2/ja not_active Expired - Fee Related
- 1997-02-21 CA CA002198176A patent/CA2198176A1/en not_active Abandoned
- 1997-02-21 KR KR1019970005214A patent/KR100476796B1/ko not_active IP Right Cessation
- 1997-02-21 HU HU9700502A patent/HUP9700502A3/hu unknown
- 1997-02-21 RU RU97102581/04A patent/RU2218329C2/ru not_active IP Right Cessation
- 1997-02-21 ZA ZA9701514A patent/ZA971514B/xx unknown
- 1997-02-21 HR HR19606509.7 patent/HRP970101B1/xx not_active IP Right Cessation
- 1997-02-21 MX MX9701323A patent/MX9701323A/es unknown
- 1997-02-21 NO NO970798A patent/NO307046B1/no unknown
- 1997-02-21 BR BR9701046A patent/BR9701046A/pt not_active Application Discontinuation
- 1997-02-24 ID IDP970554A patent/ID16042A/id unknown
-
1999
- 1999-12-30 GR GR990403381T patent/GR3032293T3/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HRP960230A2 (en) | Fluorophenyl substituted alkenyl carboxylic acid guanidines, processes for their preparation, their use as medicinal or diagnostic agent as well as medicaments containing them | |
| NO300416B1 (no) | 3,5-substituerte aminobenzoylguanidiner, deres anvendelse til fremstilling av medikament eller diagnostikum | |
| HRP960356A2 (en) | Substituted cinnamic acid guanidides, process for their preparation, their use as medicaments or diagnostic agents, as well as medicaments containing them | |
| HRP960430A2 (en) | Substituted benzoyl guanidines, process for their preparation, their use as antiarrhythmics or diagnostic agent as well as pharmaceuticals containing them | |
| EP0811610B1 (de) | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament | |
| HRP970101A2 (en) | Ortho-substituted benzoylguanidines, process for their preparation and their use as medicament or diagnostic agent as well as medicaments containing them | |
| HRP960343A2 (en) | 4-fluoroalkyl-substituted benzoylguanidines, processes for their preparation, their use as medicaments or diagnostics as well as medicaments containing them | |
| EP0814077B1 (de) | Benzoylguanidine, Verfahren zu ihrer Herstellung sowie sie enthaltendes Medikament | |
| RU2193033C2 (ru) | Замещенные гуанидиды тиофенилалкенилкарбоновой кислоты и лекарственное средство | |
| HRP950570A2 (en) | Substituted benzoylguanidine, process for its preparation, its use as medicament or diagnostic agent as well as medicaments containing it | |
| RU2212400C2 (ru) | Орто-замещенные бензоилгуанидины и содержащие их лекарственные средства | |
| HRP960534A2 (en) | Sulfonylamino-substituted benzoylguanidines, process for their preparation, their use as medicaments or diagnostics, as well as medicaments containing them | |
| CZ290027B6 (cs) | Benzoylguanidin, jeho použití jako léčivo a léčivo tento benzoylguanidin obsahující | |
| US6153651A (en) | Ortho-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament comprising 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 | |
| HRP980169A2 (en) | Ortho-substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent as well as medicaments containing 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 | |
| HRP960548A2 (en) | Substituted benzodicarboxylic acid diguanidines, process for their preparation, and their use as medicament or diagnostic agent | |
| MXPA97001618A (en) | Benzoilguanidinas replaced in orthodous position, procedure for its preparation, its use as a diagnostic medicine or agent, as well as a medication that conti |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| AIPI | Request for the grant of a patent on the basis of a substantive examination of a patent application | ||
| B1PR | Patent granted | ||
| ODRP | Renewal fee for the maintenance of a patent |
Payment date: 20051221 Year of fee payment: 10 |
|
| PBON | Lapse due to non-payment of renewal fee |
Effective date: 20070222 |