KR20010093631A - 항고혈압제의 질산염 - Google Patents
항고혈압제의 질산염 Download PDFInfo
- Publication number
- KR20010093631A KR20010093631A KR1020007014179A KR20007014179A KR20010093631A KR 20010093631 A KR20010093631 A KR 20010093631A KR 1020007014179 A KR1020007014179 A KR 1020007014179A KR 20007014179 A KR20007014179 A KR 20007014179A KR 20010093631 A KR20010093631 A KR 20010093631A
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- dihydro
- dimethyl
- residues
- chloro
- Prior art date
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- 150000002823 nitrates Chemical class 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 229940079593 drug Drugs 0.000 title claims abstract description 6
- 230000003276 anti-hypertensive effect Effects 0.000 title abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 125000004429 atom Chemical group 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 35
- -1 IXc Chemical class 0.000 claims description 33
- 150000001721 carbon Chemical group 0.000 claims description 32
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 30
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 229910002651 NO3 Inorganic materials 0.000 claims description 27
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical group CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims description 26
- 229960002274 atenolol Drugs 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 150000003254 radicals Chemical class 0.000 claims description 16
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical group C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 15
- 229960003310 sildenafil Drugs 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 14
- 229910017604 nitric acid Inorganic materials 0.000 claims description 14
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 13
- 206010020772 Hypertension Diseases 0.000 claims description 13
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical group O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 11
- 239000002243 precursor Substances 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 10
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 10
- 229960004605 timolol Drugs 0.000 claims description 10
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 claims description 9
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims description 8
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229940124530 sulfonamide Drugs 0.000 claims description 7
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 claims description 6
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 claims description 6
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 claims description 6
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical group CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- AKLNLVOZXMQGSI-UHFFFAOYSA-N bufetolol Chemical group CC(C)(C)NCC(O)COC1=CC=CC=C1OCC1OCCC1 AKLNLVOZXMQGSI-UHFFFAOYSA-N 0.000 claims description 6
- 229960002155 chlorothiazide Drugs 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 229960003883 furosemide Drugs 0.000 claims description 6
- 125000000468 ketone group Chemical group 0.000 claims description 6
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims description 6
- 229960001597 nifedipine Drugs 0.000 claims description 6
- 229960000715 nimodipine Drugs 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229960001289 prazosin Drugs 0.000 claims description 6
- 229960003712 propranolol Drugs 0.000 claims description 6
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 6
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 229960004773 losartan Drugs 0.000 claims description 5
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 5
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 claims description 5
- 229960001722 verapamil Drugs 0.000 claims description 5
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 claims description 4
- NXQMNKUGGYNLBY-GFCCVEGCSA-N (2r)-1-(3-methylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical group CC(C)NC[C@@H](O)COC1=CC=CC(C)=C1 NXQMNKUGGYNLBY-GFCCVEGCSA-N 0.000 claims description 4
- SGUAFYQXFOLMHL-ACJLOTCBSA-N (R,R)-labetalol Chemical group C([C@@H](C)NC[C@H](O)C=1C=C(C(O)=CC=1)C(N)=O)CC1=CC=CC=C1 SGUAFYQXFOLMHL-ACJLOTCBSA-N 0.000 claims description 4
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims description 4
- HGLLQAPXHCAZBP-UHFFFAOYSA-N 1,3-dimethyl-7-(morpholin-4-ylmethyl)purine-2,6-dione Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CN1CCOCC1 HGLLQAPXHCAZBP-UHFFFAOYSA-N 0.000 claims description 4
- VGLGVJVUHYTIIU-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3-[(prop-2-enylthio)methyl]-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC=C)NS2(=O)=O VGLGVJVUHYTIIU-UHFFFAOYSA-N 0.000 claims description 4
- NCUCGYYHUFIYNU-UHFFFAOYSA-N Aranidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)=O)C1C1=CC=CC=C1[N+]([O-])=O NCUCGYYHUFIYNU-UHFFFAOYSA-N 0.000 claims description 4
- BWSSMIJUDVUASQ-UHFFFAOYSA-N Benzylhydrochlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 BWSSMIJUDVUASQ-UHFFFAOYSA-N 0.000 claims description 4
- VXLCNTLWWUDBSO-UHFFFAOYSA-N Ethiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC)NC2=C1 VXLCNTLWWUDBSO-UHFFFAOYSA-N 0.000 claims description 4
- SMANXXCATUTDDT-UHFFFAOYSA-N Flunarizinum Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(CC=CC=2C=CC=CC=2)CC1 SMANXXCATUTDDT-UHFFFAOYSA-N 0.000 claims description 4
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 claims description 4
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002213 alprenolol Drugs 0.000 claims description 4
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 claims description 4
- 229960000528 amlodipine Drugs 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- FYJJXENSONZJRG-UHFFFAOYSA-N bencyclane Chemical compound C=1C=CC=CC=1CC1(OCCCN(C)C)CCCCCC1 FYJJXENSONZJRG-UHFFFAOYSA-N 0.000 claims description 4
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 claims description 4
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 claims description 4
- UIEATEWHFDRYRU-UHFFFAOYSA-N bepridil Chemical compound C1CCCN1C(COCC(C)C)CN(C=1C=CC=CC=1)CC1=CC=CC=C1 UIEATEWHFDRYRU-UHFFFAOYSA-N 0.000 claims description 4
- HXLAFSUPPDYFEO-UHFFFAOYSA-N bevantolol Chemical group C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC(C)=C1 HXLAFSUPPDYFEO-UHFFFAOYSA-N 0.000 claims description 4
- 229950009385 bufetolol Drugs 0.000 claims description 4
- 229960004064 bumetanide Drugs 0.000 claims description 4
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 claims description 4
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229960004166 diltiazem Drugs 0.000 claims description 4
- ZCKKHYXUQFTBIK-KTKRTIGZSA-N etozoline Chemical compound O=C1N(C)C(=C/C(=O)OCC)/SC1N1CCCCC1 ZCKKHYXUQFTBIK-KTKRTIGZSA-N 0.000 claims description 4
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 claims description 4
- WRYZEGZNBYOMLE-UHFFFAOYSA-N hydracarbazine Chemical compound NNC1=CC=C(C(N)=O)N=N1 WRYZEGZNBYOMLE-UHFFFAOYSA-N 0.000 claims description 4
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 4
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 claims description 4
- 229960004427 isradipine Drugs 0.000 claims description 4
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229960000227 nisoldipine Drugs 0.000 claims description 4
- 229960005425 nitrendipine Drugs 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052760 oxygen Chemical group 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- AGMMTXLNIQSRCG-UHFFFAOYSA-N quinethazone Chemical compound NS(=O)(=O)C1=C(Cl)C=C2NC(CC)NC(=O)C2=C1 AGMMTXLNIQSRCG-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 229960001693 terazosin Drugs 0.000 claims description 4
- 229960001288 triamterene Drugs 0.000 claims description 4
- REZGGXNDEMKIQB-UHFFFAOYSA-N zaprinast Chemical compound CCCOC1=CC=CC=C1C1=NC(=O)C2=NNNC2=N1 REZGGXNDEMKIQB-UHFFFAOYSA-N 0.000 claims description 4
- KMBQOSGPHMRPBA-UHFFFAOYSA-N 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC2=NON=C12 KMBQOSGPHMRPBA-UHFFFAOYSA-N 0.000 claims description 3
- 229910021607 Silver chloride Inorganic materials 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 claims description 3
- 229960004046 apomorphine Drugs 0.000 claims description 3
- 235000021170 buffet Nutrition 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- RINBGYCKMGDWPY-UHFFFAOYSA-N epitizide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC(F)(F)F)NS2(=O)=O RINBGYCKMGDWPY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229960002474 hydralazine Drugs 0.000 claims description 3
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- UIAGMCDKSXEBJQ-UHFFFAOYSA-N nimodipine Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical group CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 claims description 2
- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical group CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 claims description 2
- JCVAWLVWQDNEGS-UHFFFAOYSA-N 1-(2-hydroxypropylamino)propan-2-ol;thiolane 1,1-dioxide;hydrate Chemical group O.O=S1(=O)CCCC1.CC(O)CNCC(C)O JCVAWLVWQDNEGS-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
항고혈압활성을 가지는 약제들과 질산염들
Description
본 발명은 고혈압의 치료 및 예방에 사용되는 화합물 및 그들의 조성물에 관한 것이다. 더욱 상세하게는, 본 발명은 전신 또는 국소적 이용, 특히 심장혈관영역을 위한 상기 고혈압증에 대한 용도에 관한 것이다. 더욱 더 상세하게는, 본 발명은 향상된 효능을 갖는 새로운 항고혈압화합물에 관한 것이다.
고혈압치료에서 사용되는 종래기술로서 알려진 화합물들은 일반적으로 제한된 효능을 가진다. 고혈압치료는 통상, 칼슘-길항약제들, 이뇨제들, 베타차단제들, ACE저해제들과 같은 혈관계에 작용하는 다른 약제들과 결합하여 항혈압제를 환자에게 투여하여 실행된다. 안지오테신(예, 로사탄), 칼슘길항제들(예, 디히드로피리딘), 이뇨제들(예를 들어, 티아자이드유도체), 직접 및 간접 혈관확장약물(예, 미녹시딜, 자프리나스트)의 항고혈성길항제의 예는, 단독으로 사용될 때는 치료성과를 확신할 수 없다.
더욱이, 몇몇 항고혈압제는 기관지수축, 호흡곤란과 같은 호흡기관에 대한 부작용들을 일으킨다는 것을 지적할 필요가 있다. 예를 들어 티모롤 및 프로파노롤과 같은, 협심증 및 심장 부정맥 치료에 사용되는 항고혈압제의 경우, 상기 부작용들을 나타낸다.
다른 항고혈압제는 포스포디에스테라제 저해를 통해 혈관확장을 유도하고, 다양한 기관(위장, 심장혈관, 안구 등)에 대한 부작용들을 나타낸다. 예를 들어실데나필(Sildenafil) 및 자프리나스트(Zaprinast)를 보면 알 수 있다.
향상된 치료효능을 가지며, 전신용 및 국소용 특히 심장혈관영역의 고혈압병치료에 효과적으로 이용할 수 있는 조성물을 필요로 했다. 더욱이, 부작용이 작으며 베타차단 또는 항포스포디에스테라제작용을 가지는 이용가능한 항고혈압제들을 특히 필요로 했다.
출원인은, 향상된 치료효능을 가지며 알려진 고혈압제들의 부작용이 없는 전신용 및 국소용 특히 심장혈관영역의 고혈압병의 치료에 이용할 수 있는 화합물들 및 약제조성물들을 발명하였다.
본 발명의 목적은 전신용 및 국소용 특히 심장혈관영역에 이용될 수 있는 항고혈압활성을 가지는 화합물들의 질산염들 또는 그들의 약제조성물들을 제공하는 것이고, 상기 화합물들은 적어도 하나의 염화될 수 있는 반응기를 함유하는 것을 특징으로 하고, 다음 클래스들에서 선택된다.
클래스(Alb):
RⅢ Al자유원자가이면서 RAl= -O이어서, 5위치 탄소원자와 결합하여 케톤기를 형성하고,
RⅣ Al및 RⅢ Al자유원자가들이면서, RI Al및 식(Alb)의 화합물에서 이종고리의 4 및 5위치의 탄소원자들과 RAl은, -COOH기를 함유하는 6탄소원자들을 가지는 방향족고리를 형성한다:
RⅠ Al= H, Cl;
RAl, RⅣ Al, RⅢ Al및 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들과 RⅠ Al은, COOH기를 함유하는 방향족고리 (IXc)를 형성하고,
RⅣ Al및 식(Alb)의 이종고리의 4위치의 탄소원자와 RⅠ Al는, 5 탄소원자들을 가지는 다음의 포화고리를 형성한다:
RⅡ Al= -(CH2)3-CH3, -O-CH2-CH3;
RⅢ Al= H, 자유원자가,
RⅣ Al자유원자가와 RⅢ Al자유원자가는, 식(Alb)의 이종고리의 4 및 5 위치의탄소원자들 사이에서 이중결합을 형성하고,
RⅣ Al, RⅠ Al및 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들과 RⅢ Al은 -COOH기를 함유하는 방향족고리 (IXc)를 형성한다;
RⅣ Al= 자유원자가, 식(Alb)의 이종고리의 4위치의 탄소원자와 RⅠ Al와 함께 RⅣ Al은, 5탄소원자들을 가지는 포화고리 (IXd)를 형성하고,
RⅢ Al, RⅠ Al및 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들과 RⅣ Al은 -COOH기를 함유하는 방향족고리 (IXc)를 형성하고,
RⅢ Al와 RⅣ Al양 자유원자가들은, 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들 사이에서 이중결합을 형성하고;
클래스 (Alc):
발사탄(Valsartan)으로 알려진;
클래스 (A2):
이 클래스의 전구체들은 다음과 같다:
1(2H)-프탈라지논 히드라존(히드랄라진); 6-(1-피페리디닐-1)-2,4-피리미딘디아민3-옥사이드(미녹시딜); 1-[[3-(4,7-디히드로-1-메틸-7-옥소-3-프로필-1H-피라졸[4,3-d]피리미딘-5-일)-4-에톡시페닐]설포닐1-4-메틸-피페라진(실데나필), 2-(2-프로필옥시페닐)-8-아자푸린-6-원(one)(자프리나스트);
클래스 (A3):
서로 같거나 다른 RⅠ B1및 RⅡ B1은 H, CH3이고,
식 (XId)에서 t = 0, 1.
식 (XIe)에서 YB1은 다음 의미들을 가질 수 있다:
식 (XIf)에서 Z = H, -OCH3;
식 (A3)에서:
XBI= -O-, -S-;
서로 같거나 다른 n 및 m은 0, 1이고;
식 (XIp)에서:
S1= H, CN, OCH3, CH3, -CH2-CH3, -O-CH2-CONH-CH3, -COCH3, -CO-(CH2)2-CH3, -O-CH2-CH=CH2, -CH2-CH=CH2, 시클로펜틸 또는
S2= H, CH3, Cl, -SOCH3, -CONH2;
S2및 동일한 라디칼 (XIp)의 C6방향족고리의 2 및 3 위치의 탄소원자들과S1은, 다음의 고리를 형성한다:
여기서:
[식 XIpⅦ의 방향족고리에 인접한(*)원자]
B = -CH2-, -NH-, -CH=CH-,(*)-CO-CH2-;
A = -O-,(*)-CH2-CH(OH)-,(*)-O-CH2-,(*)-S-CH2, -CH2-CH2, -CH2-,
A는 3차탄소원자이고, 동시에 W1은, A와 1' 위치의 탄소원자 사이에 이중결합 -CH=CH-을 형성하기 위해서 자유원자가이고,
5 원자들을 가지는 고리 (XIpⅦ)에서 A는, 치환기를 함유하는 3차탄소이기 때문에, 1'위치의 탄소원자 및 2개의 W1 또는 W2 라디칼들중 하나와, 자유원자가인다른 라디칼은, 다음 식에 따른 6탄소원자들을 가지는 방향족고리를 형성한다:
W1 = H, 자유원자가, W1은 자유원자가이고 A는 상기에 규정된 대로 3차탄소원자일 때, A와 1'위치의 탄소원자 사이의 이중결합이 형성되고,
W2, 1'위치의 탄소원자 및 치환기 A와 W1은, 6 탄소원자들을 가지는 방향족고리를 형성하고;
W2 = 자유원자가, H, OH, -CH3, -ONO2, W1 = 자유원자가 및 1'위치의 탄소원자와는 케톤기를 형성하는 -O이고,
W1, 1'위치의 탄소원자 및 치환기 A와 W2는, 6 탄소원자들을 가지는 방향족고리를 형성하고;
S3= H, F, Cl, OH, NO2, -CH2-CO-NH2, -(CH2)2-OCH3, -NH-COCH3, -CH2-O-CH2-CH2-O-CH(CH3)2, -CH2-CH2-COOCH3, -NH-CO-N(C2H5)2, -NH-CO-(CH2)2-CH3, -NH-SO2-CH3, -NH-CO-NH-[시클로헥실], -CH2-CH2-O-CH2-[시클로프로필];
S4= H, Cl, -CH2-CH2-이고, m = n = 1 및 RⅦ B1자유원자가이며, 동일한 라디칼(XIp)의 방향족고리의 1 및 6 위치의 탄소원자 및 산소인 식(A3)의 XB1와는, 다음의 고리를 형성한다:
S4은 3차탄소원자이고, 라디칼 (XIp)의 방향족고리의 1 및 6 위치의 탄소원자들 및 식 (A3)의 다음 구성요소(탄소원자 -|C|n- (n=1), 산소와 같은(m=1) 라디칼 XB1및 RⅥ B1자유원자가들와 함께 RⅦ B1)와는 다음 고리를 형성한다:
RⅥ B1= H, 자유원자가;
RⅦ B1= H, 자유원자가;
이 클래스에 속하는 다른 화합물들은 다음과 같다:
2-히드록시-5-[1-히드록시-2-[(1-메틸-3-페닐프로필)아미노]에틸]벤즈아미드(라베타롤), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-[(테트라히드로-2-푸라닐)카르보닐]피페라진(테라조신), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-(2-푸라닐카르보닐)피페라진(프라조신);
클래스 (A4):
화합물의 다음 기들은 이 클래스에 속한다:
(A4a):
β-[(2-메틸프로폭시)메틸]-N-페닐-N-(페닐메틸)-1-피롤리딘에탄아민(베프리딜), (2S-시스)-3-(아세틸옥시)-8-클로로-5-[2-(디메틸아미노)에틸]-2,3-디히드로-2-(4-메톡시페닐)-1,5-벤조티아제핀-4(5H)-원(클렌티아젬), (2S-시스)-3-(아세틸옥시)-5-[2-(디메틸아미노)에틸]-2,3-디히드로-2-(4-메톡시페닐)-1,5-벤조티아제핀-4(5H)-원(딜티아젬), γ-페닐-N-(1-페닐에틸)벤젠-프로판아민(펜딜린), α-[3-[[2-(3,4-디메톡시페닐)에틸]메틸아미노]프로필]-3,4,5-트리메톡시-α-(1-메틸에틸)-벤젠아세토니트릴(갈로파밀), (1S-시스)메톡시아세트산 2-[2[[3-(1H-벤즈이미다졸-2-일)프로필]메틸아미노]에틸]-6-플루오로-1,2,3,4-테트라히드로-1-(1-메틸에틸)-2-나프탈에닐 에스테르(미베프라딜), N-(1-메틸-2-페닐에틸)-γ-페닐벤젠프로판아민(프레닐아민), (R)-2-[2-[3-[[2-(1,3-베조디옥솔-5-일옥시)에틸]메틸아미노]프로폭시]-5-메톡시페닐]-4-메틸-2H-1,4-벤조티아진-3(4H)-원(세모티아딜), N-(1,1,-디메틸에틸)- α-메틸-γ-페닐벤젠프로판아민(테로딜린), α-[3-[[2-(3,4-디메톡시페닐)에틸]메틸아미노]프로필]-3,4-디메톡시-α-(1-메틸에틸)-벤젠아세토니트릴(베라파밀);
(A4b):
2-[(2-아미노에톡시)메틸]-4-(2-클로로페닐)-1,4-디히드로-6-메틸-3,5-피리딘디카르복실산 3-에틸 5-메틸에스테르(암로디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 메틸 2-옥소프로필 에스테르(아라니디핀), [S-(R*, R*)]-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 1-(페닐메틸)-3-피롤리디닐 에스테르(바니디핀), (R*,R*)-±-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 1-(페닐메틸)-3-피페리디닐 에스테르(베니디핀), (E)-±-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-메톡시에틸 3-페닐-2-프로페닐 에스테르(실니디핀), 5-(5,5-디메틸-1,3,2-디옥사포스포리난-2-일)-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3-피리딘-카르복실산 2-[페닐(페닐메틸)아미노]에틸 에스테르 P-옥사이드(에포니디핀), ±-4-(1,3-벤조디옥솔-4-일)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 2-[[(4-플루오로페닐)메틸]메틸아미노]에틸 1-메틸에틸 에스테르(엘고디핀), 4-(2,3-디클로로페닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 에틸 메틸 에스테르(펠로디핀), 4-(4-벤조푸라자닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 5-메틸 3-(1-메틸)에틸 에스테르(이스라디핀), (E)-4-[2-[3-(1,1-디메틸에톡시)-3-옥소-1-프로페닐]페닐]-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 디에틸 에스테르(라시디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-[(3,3-디페닐-프로필)메틸아미노]-1,1-디메틸에틸 메틸 에스테르(레카니디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-[4-(디페닐메틸)-1-피페라지닐]에틸 메틸 에스테르(마니디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 2[메틸-(페닐메틸)아미노]에틸 에스테르(니카디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 디메틸 에스테르(니페디핀), 2-시아노-1,4-디히드로-6-메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 3-메틸 5-(1-메틸에틸)에스테르(닐바디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-메톡시에틸 1-메틸에틸 에스테르(니모디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 메틸 2-메틸프로필 에스테르(니솔디핀), 1,4-디히로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 에틸 메틸 에스테르(니트렌디핀);
(A4c) :
1-(디페닐메틸)-4-(3-페닐-2-프로페닐)피페라진(신나리진), (E)-1-[비스(4-플루오르페닐)메틸]4-(3-페닐-2-프로페닐) 피페라진(프루나리진), 4-[4,4-비스(4-플루오로페닐)부틸]-N-(2,6-디메틸페닐)-1-피페라진아세트아미드(리도프라진), 1-[비스(4-플루오로페닐)메틸]-4-[(2,3,4-트리메톡시페닐)메틸]피페라진(로메리진);
(A4d):
N,N-디메틸-3-[[1-(페닐메틸)-시클로헵틸]옥시]-1-프로판아민(벤시클란), 1-[2-[2-(디에틸아미노)에톡시]페닐]-3-페닐-1-프로파논(에타페논), 3,4-디메톡시-N-메틸-N-[3-[4-[[2-(1-메틸에틸)-1-인돌리지닐]설포닐]페녹시]-프로필]벤젠에탄아민(판토파론);
클래스(A7):
화합물들의 다음 기들이 이 클래스에 속한다:
(A7a):
6-클로로-3,4-디히드로-3-[(2-프로페닐티오)메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(알티아지드), 3,4-디히드로-3-(페닐메틸)-6-(트리플루오로메틸)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(벤드로플루메티아지드), (6-클로로-3-[[(페닐메틸)티오]메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(벤즈티아지드), (6-클로로-3,4-디히드로-3-(페닐메틸)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(벤질히드로클로로티아지드), 6-클로로-3,4-디히드로-3-(2-메틸프로필)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(부티아지드), 6-클로로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(클로로티아지드), 2-클로로-5-(2,3-디히드로-1-히드록시-3-옥소-1H-이소인돌-1-일)벤즈베설폰아미드(클로탈리돈), 6-클로로-3-(시클로펜틸메틸)-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(시클로펜티아지드), 3-바이시클로[2.2.1]-헵트-5-엔-2-일-6-클로로-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(시클로티아지드), 6-클로로-3,4-디히드로-3-[[(2,2,2-트리플루오로에틸)티오]메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(에피티아지드), 6-클로로-3-에틸-3,4-디-히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(에티아지드), 7-클로로-1,2,3,4-테트라히드로-4-옥소-2-페닐-6-퀴나졸린설폰아미드(펜퀴존), 3-(아미노설포닐)-4-클로로-N-(2,3-디히드로-2-메틸-1H-인돌-1-일)벤즈아미드(인다프아미드), 6-클로로-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(히드로클로로티아지드), 3,4-디히드로-6-(트리플루오로메틸)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(히드로플루메티아지드), 6-클로로-3-(클로로메틸)-3,4-디히드로-2-메틸-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(메티클로티아지드), 3,4-디히드로-6-메틸-2H-1-벤조티오피란-7-설폰아미드 1,1-디옥사이드(메티크란), 7-클로로-1,2,3,4-테트라히드로-2-메틸-3-(2-메틸페닐)-4-옥소-6-퀴나졸린-설폰아미드(메토라존), 6-클로로-3-[(4-플루오로페닐)-메틸]-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(파라플루티지드), 6-클로로-3,4-디히드로-2-메틸-3-[[(2,2,2-트리플루오로에틸)티오]메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(폴리티아지드), 7-클로로-2-에틸-1,2,3,4-테트라히드로-4-옥소-6-퀴나졸린설폰아미드(퀴네타존), 6-클로로-3,4-디히드로-3-트리클로로메틸-2H-1,2,4-벤조타디아진-7-설폰아미드 1,1-디옥사이드(테클로티아지드), 6-클로로-3-(티클로로메틸)-3,4-디히드로-2H-1,2,4-벤조타디아진-7-설폰아미드 1,1- 디옥사이드(트리클로메티아지드);
(A7b):
3,7-디히드로-1,3-디메틸-7-(4-모포리닐메틸)-1H-푸린-2,6-디온(7-모포리노메틸테오필린), 3,7-디히드로-1-(2-히드록시프로필)-3,7-디메틸-1H-푸린-2,6-디온(프로테오브롬), 3,7-디히드로-3,7-디메틸-1H-푸린-2,6-디온(테오브롬);
(A7c):
6-아미노-3-에틸-1-(2-프로페닐)-2,4(1H,3H)-피리미딘디온(아미노메트라딘), 6-아미노-3-메틸-1-(2-메틸-2-프로페닐)-2,4(1H,3H)-피리미딘디온(아미소메트라딘);
(A7d):
N-페닐-1,3,5-트리아진-2,4-디아민(아마노진), 3,5-디아미노-N-(아미노이미노메틸)-6-클로로피라진카르복스아미드(아밀로라이드), N-(4-클로로페닐)-1,3,5-트리아진-2,4-디아민(클로라자닐), [3-메틸-4-옥소-5-(1-피페리디닐)-2-티아졸리디닐리덴]아세트산 에틸 에스테르(에토졸린), 6-히드라지노-3-피리다진카르복스아미드(히드라카르바진), 5-아미노-2[1-(3,4-디클로로페닐)에틸]-2,4-디히드로-3H-피라졸-3-원(무졸리민), 2-(2,2-디시클로헥실에틸)피페리딘(퍼헥실린), 6-페닐-2,4,7-프터리딘트리아민(트리암터렌), 3-(아미노설포닐)-5-(부틸아미노)-4-페녹시벤조산(부메타나이드), 5-(아미노설포닐)-4-클로로-2-[(2-푸라닐메틸)아미노]벤조산(푸로세미드), N-[[(1-메틸에틸)아미노]카르보닐]-4-[(3-메틸페닐)아미노]-3-피리딘설폰아미드(토라세미드);
클래스 (A8): 아포모핀
(Alb) 클래스에서 바람직한 화합물들은, 다음과 같다:
XAl= (IXa), RAl= CH2OH, RI Al= Cl, RⅢ Al= RⅣ Al= 자유원자가일 때, 식(Alb)의 이종고리의 4 및 5위치의 탄소원자들과 -CH=CH-이중결합을 형성하며, RⅡ Al= -(CH2)3-CH3, 로사탄잔기(Losartan residue);
로사탄에서와 같으나, 다만 RAl= -O 및 RⅢ Al자유원자가와, 식(Alb)의 이종고리의 5위치의 탄소원자와 결합하여 케톤기를 형성하기 위해, RⅣ Al및 이종고리의 4 위치의 탄소원자와 RI Al는, 5탄소원자들을 가지는 포화된 고리 (IXd)를 형성하기에 충분한, 이베사탄잔기(Irbesartan residue);
로사탄에서와 같으나, 다만 RⅡ Al= -O-CH2-CH3와, RI Al와 함께 RAl및 RⅣ Al및 RⅢ Al자유원자가들과 이종고리의 4 및 5 위치의 탄소원자들은, -COOH기를 함유하는 방향족라디칼 (IXc)을 형성하기에 충분한, 칸데사탄잔기(Candesartan residue);
로사탄에서와 같으나, 다만 XAl= -COOH와, RAl= (IXb), RI Al= H, RⅣ Al및 RⅢ Al자유원자가들은, 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자 사이에 이중결합을 형성하는, 에프로사탄잔기(Eprosartan residue).
A2 클래스의 바람직한 화합물들은 다음과 같다:
1-[[3-(4,7-디히드로-1-메틸-7-옥소-3-프로필-1H-피라졸[4,3-d]-피리미딘-5-일]-4-에톡시페닐]설포닐1-4-메틸-피페라진(실데나필), 2-(2-프로필옥시페닐)-8-아자푸린-6-원(자프리나스트).
(A3) 클래스의 바람직한 화합물들은 다음과 같다:
RI B1= H, RⅡ B1및 RⅢ B1= CH3, RⅤ B1= H, RⅥ B1= RⅦ B1= H, m = n = 1, XB1= -O-, RⅣ B1= (XIp)일 때, 여기서S1= S2= S4= H, S3= -CH2-CO-NH2, 아테노롤잔기(Atenolol residue);
아테노롤에서와 같으나, 다만 RⅣ B1= (XIs)인, 베푼노롤잔기(Befunolol residue);
아테노롤에서와 같으나, 다만 S3= S2= S4= H, S1= -CH2-CH=CH2인, 알프레노롤잔기(Alprenolol residue);
아테노롤에서와 같으나, 다만 S1= COCH3, S3= -NH-CO-(CH2)2-CH3, S2= S4= H인, 아세부토롤잔기(Acebutolol residue);
아테노롤에서와 같으나, 다만 S3= -CH2-CH2-O-CH2-(시클로프로필)인, 베타조롤잔기(Betaxolol residue);
아테노롤에서와 같으나, 다만 S3= -CH2-O-CH2-CH2-O-CH(CH3)2인, 비소프로롤잔기(Bisoprolol residue);
알프레노롤에서와 같으나, 다만 S1= (XIpⅡ) 및 RI B1= CH3인, 부페토롤잔기(Bufetolol residue);
부페토롤에서와 같으나, 다만 S1= -CN인, 부니트로롤잔기(Bunitrolol residue);
부페토롤에서와 같으나, 다만 S1= H, S4= Cl, S2= CH3인, 부프라노롤잔기(Bupranolol residue);
부페토롤에서와 같으나, 다만 S1= -CO-(CH2)2-CH3, S3= F인, 부토피로롤잔기(Butofilolol residue);
아테노롤에서와 같으나, 다만 RⅣ B1= (XIpⅧ)이고, 여기서 B = -NH-인, 카라조롤잔기(Carazolol residue);
부페토롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)이고, 여기서 A = -CH2-CH2-, B = -NH-, W1 = 자유원자가 및 1'위치의 탄소원자와 케톤기를 형성하는 W2 = -O인, 카테오롤잔기(Carteolol residue);
부페토롤에서와 같으나, 다만 S3= -NH-CO-N(C2H5)2, S1= -CO-CH3인, 셀리프로롤잔기(Celiprolol residue);
부페토롤에서와 같으나, 다만 S1= -O-CH2-CONH-CH3인, 세타모롤잔기(Cetamolol residue);
부프라노롤에서와 같으나, 다만 S2= Cl인, 클로라노롤잔기(Cloranolol residue);
아테노롤에서와 같으나, 다만 S3= -CH2-CH2-COOCH3인, 에스모롤잔기(Esmolol residue);
아테노롤에서와 같으나, 다만 RⅣ B1= (Xiu)인, 인데노롤잔기(Indenolol residue);
카테오롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)에서, A = -CH2-, B = -COCH2-, W1 = W2 = H인, 레보부노롤잔기(Levobunolol residue);
카테오롤에서와 같으나, 다만 RⅠ B1= H이고 RⅣ B1= (XIpⅧ)에서 A는 3차탄소원자이고 W1 자유원자가여서, A와 (XIpⅦ)의 1'위치의 탄소원자 사이에 -CH=CH-이중결합을 형성하고, W2 = CH3인, 메핀도롤잔기(Mepindolol residue);
아테노롤에서와 같으나, 다만 S3= -(CH2)2-OCH3인, 메토프로롤잔기(Metoprolol residue);
카테오롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)에서 A = -CH2-CH(OH)-, B = -CH2-, W2 = OH, W1 = H인, 나도롤잔기(Nadolol residue);
아테노롤에서와 같으나, 다만 S3= NO2인, 니페나롤잔기(Nifenalol residue);
메핀도롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)에서, A = -O-CH2-, B = -CH2-, W2 = -ONO2, W1 = H인, 니프라디롤잔기(Nipradilol residue);
알프레노롤에서와 같으나, 다만 S1= -O-CH2-CH=CH2인, 옥스프레노롤잔기(Oxprenolol residue);
부페토롤에서와 같으나, 다만 S1= 시클로펜틸인, 펜부토롤잔기(Penbutolol residue);
메핀도롤에서와 같으나, 다만 W2 = H인, 핀도롤잔기(Pindolol residue);
아테노롤에서와 같으나, 다만 S3= -NH-COCH3인, 프랙토롤잔기(Practolol residue);
부페토롤에서와 같으나, 다만 S1= H, S3=-NH-CO-NH-(시클로헥실)인, 탈리노롤잔기(Talinolol residue);
니프라디롤에서와 같으나, 다만 RⅠ B1= CH3, A = -S-CH2- 및 W2 = H인, 터타토롤잔기(Tertatolol residue);
터타토롤에서와 같으나, 다만 RⅣ B1= (XIn)인, 틸리소롤잔기(Tilisolol residue);
부페토롤에서와 같으나, 다만 RⅣ B1= (XIo)인, 티모롤잔기(Timolol residue);
부페토롤에서와 같으나, 다만 S1= S2= CH3인, 키벤노롤잔기(Xibenolol residue);
키벤노롤에서와 같으나, 다만 RⅠ B1= S1= H인, 톨리프로롤잔기(Toliprolol residue);
톨리프로롤에서와 같으나, 다만 RⅡ B1= H 및 RⅢ B1= (XIa)인, 베반토롤잔기(Bevantolol residue);
카라조롤에서와 같으나, 다만 RⅡ B1= H 및 RⅢ B1= (XIb)인, 카베디롤잔기(Carvedilol residue);
식(A3)에서 RⅠ B1= RⅡ B1= RⅢ B1= CH3, RⅤ B1= (XIh), n = m = 1, RⅥ B1= RⅦ B1= H, XB1= -O-, RⅣ B1= (XIg)일 때, 봅핀도롤잔기(Bopindolol residue);
부페토롤에서와 같으나, 다만 RⅣ B1= (XIt), 부큐모롤잔기(Bucumolol residue);
(A3) 식에서, m = n = 0 및 RⅣ B1= (XIz) RⅠ B1= RⅡ B1= RⅢ B1= CH3, RⅤ B1= H, 부푸라롤잔기(Bufuralol residue);
아테노롤에서와 같으나, 다만 YB1= H, n = m = 0, RⅣ B1= (XIi)와 RⅢ B1= (XIe)인, 부티드린잔기(Butidrine residue);
부티드린에서와 같으나, 다만 z = H, S3= OH 및 S2= CONH2, S1= S4= H인 RⅣ B1= (XIp)와 YB1= (XIf)와 RⅢ B1= (XIe)인, 딜레바롤잔기(Dilevalol residue);
베반토롤에서와 같으나, 다만 S2= H, S1= CN, RⅢ B1= (XIc)인, 에파노롤잔기(Epanolol residue);
부티드린에서와 같으나, 다만 RⅢ B1= CH3, RⅣ B1= (XIm)이고, 여기서 나프탈렌잔기는 -ORⅣ B1치환기를 가져오는 탄소원자에 2위치의 탄소원자에 의해 연결되어 있는, 프로네타롤잔기(Pronethalol residue);
프로네타롤에서와 같으나, 다만 m = 1 및 XB1= -O-와, 그리고 RⅣ B1은, XB1에 1위치의 탄소에 의해 연결된 나프탈렌잔기 (XIm)인 프로프라노롤잔기(Propranolol residue);
프로네타롤에서와 같으나, 다만 S1= S2= S4= H 및 S3= -NH-SO2-CH3와 RⅣ B1= (XIp)인, 소타롤잔기(Sotalol residue);
딜레바롤에서와 같으나, 다만 S2= -SOCH3와, 그리고 다른 방향족고리(식 XIf)에 대해 파라위치에서 Z = -OCH3인, 설피나롤잔기(Sulfinalol residue);
식 (A3)에서 RⅠ B1= RⅡ B1= H, t = 1인 RⅢ B1= (XId), RⅤ B1= H, n = m = 0, t = 0인 RⅣ B1= (XId)일 때, 네비보롤잔기(Nebivolol residue);
2-히드록시-5-[1-히드록시-2-[(1-메틸-3-페닐프로필)아미노]에틸]벤즈아미드(라베타롤), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-[(테트라히드로-2-푸라닐)카르보닐]피페라진(테라조신), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-(2-푸라닐카르보닐)피페라진(프라조신), 벤조니트릴, 2-[2-히드록시-3-[[2-(1H-인돌-3-일)-1,1-디메틸에틸]아미노]프로폭시(부신도롤).
(A4) 클래스에서 바람직한 화합물들은 다음과 같다:
(A4a):
(2S-시스)-3-(아세틸옥시)-5-[2-(디메틸아미노)에틸]-2,3-디히드로-2-(4-메톡시페닐)-1,5-벤조티아제핀-4(5H)-원(딜티아젬), α-[3-[[2-(3,4-디메톡시페닐)에틸]메틸아미노]프로필]-3,4-디메톡시-α-(1-메틸에틸)-벤젠아세토니트릴(베라파밀);
(A4b):
2-[(2-아미노에톡시)메틸]-4-(2-클로로페닐)-1,4-디히드로-6-메틸-3,5-피리딘디카르복실산 3-에틸 5-메틸에스테르(암로디핀), 4-(2,3-디클로로페닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 에틸 메틸 에스테르(페로디핀) 4-(4-벤조푸라자닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 5-메틸 3-(1-메틸)에틸에스테르(이스라디핀), 러칸니디핀, 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 2[메틸(페닐메틸)아미노]에틸에스테르(니카르디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 디메틸 에스테르(니페디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-메톡시에틸 1-메틸에틸 에스테르(니모디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 메틸 2-메틸-프로필 에트테르(니솔디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 에틸 메틸 에스테르(니트렌디핀);
(A4c):
(E)-1-[비스(4-플루오로페닐)메틸]4-(3-페닐-2-프로페닐)-피페라진(프루나리진).
클래스 (A7)에서 바람직한 화합물은 다음과 같다;
(A7a):
6-디클로로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(클로로티아지드), 2-클로로-5-(2,3-디히드로-1-히드록시-3-옥소-1H-이소인돌-1-일)벤제베설폰아미드(클로탈리돈), 6-클로로-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(히드로클로로티아지드), 3-(아미노설포닐)-4-클로로-N-(2,3-디히드로-2-메틸-1H-인돌-1-일)벤즈아미드(인다프아미드), 7-클로로-1,2,3,4-테트라히드로-2-메틸-3-(2-메틸페닐)-4-옥소-6-퀴나졸린설폰아미드(메토라존), 7-클로로-2-에틸-1,2,3,4-테트라히드로-4-옥소-6-퀴나졸린설폰아미드(퀴네타존);
(A7d):
3,5-디아미노-N-(아미노이미노메틸)-6-클로로피라진카르복스아미드(아밀로리드), 6-페닐-2,4,7-프테리딘트리아민(트리암테렌), 3-(아미노설포닐)-5-(부틸아미노)-4-펜녹시-벤조산(부메타니드), 5-(아미노설포닐)-4-클로로-2-[(2-푸라닐메틸)아미노]벤조산(푸로세미드), N-[[(1-메틸에틸)아미노]카르보닐]-4-[(3-메틸페닐)아미노]-3-피리딘설폰아미드(토라세미드).
본 발명에 따른 특히 바람직한 화합물들은 다음과 같다:
클래스 Alb): 로사탄;
클래스 A2): 실데나필, 자프리나스트;
클래스 A3): 아테노롤, 라베타롤, 티모롤, 프라조신, 테라조신, 프로프라노롤;
클래스 A4): 니카디핀, 니페디핀, 니모디핀;
클래스 A7): 클로로티아지드, 아밀로리드, 푸로세미드.
전술한 클래스들에 속하는 염들의 전구체들은, 여기에 참고문헌으로 결합되어 있는 "머크인덱스 12aEd."(1996)에 설명된 방법들에 따라 제조된다. 자프리나스트제조방법은, DE특허 2,162,096에 설명되어 있다. 부신도롤제조방법은 G.B.특허 2,001,633에 설명되어 있다.
본 발명에 따른 조성물들에서, 전술한 클래스들에 속하는 화합물들의 이성질체들도 사용될 수 있다. 이성질체들의 예는, 시스-, 트랜스-, 광학 이성질체 D 및L 또는 라세미, 에난시오머(enantiomer)이다. 일반적으로, 하나의 이성질체 형태는, 다른 형태에 대해 예를 들어 L형태에 대한 D형태 또는 그 반대의 경우 더 높은 활성을 가진다.
이들 클래스들에 속하는 화합물들의 염들은, 적어도 1 질산염이온몰/화합물몰을 함유한다. 바람직하게는, 질산이온몰과 전구체몰 사이의 비율은, 단일하다. 더 높은 몰비를 가지는 염들은, 분자에서 염화되기 충분한 기본 다른 아민기들이 존재할 때 얻어진다.
본 발명의 염들은, 통상의 부형제(excipients)와 함께 분야의 주지기술들에 따라 해당 약제 조성에서 퍼뮬레이트되는데, 예를 들어 "레밍톤의 제약학 15a Ed."책을 참조할 수 있다.
그들의 약제조성물들에서의 발명염들의 투여량은 동일하고, 일반적으로 언급된 클래스들의 전구체들의 투여량보다 낮다.
본 발명의 염들은 다음 방법들중 하나에 따라 얻어질 수 있다:
염화되는 물질이, 바람직하게는 히드록시기들을 함유하지 않는, 예를 들어 아세토니트릴, 에틸아세테이트, 테트라히드로푸란 등 유기용매에 용해가능한 자유염기 또는 해당 염으로 이용가능할 때, 염은 바람직하게 10% w/v와 같거나 더 높은 농도의 용매에서 물질을 용해하고, 화합물에 존재하는 염화가능한 아민기들의 몰에 해당하는 농축된 질산의 양을 첨가하여 제조될 수 있다. 질산은 동일용매에서 희석되는 것이 바람직하다. 바람직하게는 혼합물을 첨가하는 동안 또는 후에, 20℃ -0℃ 범위의 온도에서 냉각된다. 생성물은 일반적으로 여과에 의해 회수되고 용매로 세척된다.
반대로, 물질이 전술한 용매들에 거의 녹지 않거나, 용해성염으로 이용가능하지 않을 때, 히드록시화된 용매들과의 해당 혼합물들이 이용될 수 있다. 이런 용매들의 예들은, 메틸알콜, 에틸알콜 및 물이다. 그런 다음, 이렇게 얻어진 혼합물을 질산의 첨가후 비극성용매로 희석하여 침전이 촉진될 수 있다.
출발물질(starting product)이 염산으로 염화될 때, 화합물용액에 질산은을 직접 첨가하여 질산으로 염을 제조하는 것이 가능하다. 염화은을 여과한 후, 용액은 질산염을 회수하기 위해 농축되고 냉각된다.
출발물질이 염일때, 중탄산 또는 탄산 나트륨 또는 칼륨 포화용액, 또는 수산화 나트륨 또는 칼륨 희석용액으로 처리하여 해당염기를 유리할 수도 있다. 그런 다음, 염기는 적절한 유기용매(예를 들어, 할로겐화 용매들, 에스테르들, 에테르들)에 의해 추출되고, 그런 다음 건조된다. 유기용액은 증발되고, 그런 다음 아세토니트릴 또는 다른 전술한 용매들에 염기를 용해함으로 전술한 제조방법들에 따라 진행된다.
질산염들은, 여기에 참고문헌으로 결합되어 있는 출원인 이름의 유럽특허 제759,899호에서 설명된 대로 제조된 결합다리에 의해 분자에 -ONO2기 결합을 함유하는 상술된 클래스들의 전구체들을 이용하여서도 얻어질 수 있다.
다음 실시예들은, 단지 설명의 목적으로 제공된 것이고, 그 실시예들로 한정되는 것은 아니다.
실시예 1
티모롤질산염(Timolol nitrate salt) 제조
중탄산나트륨(100ml)의 포화수용액에 티모롤말레산염(7g)이 첨가된다. 혼합물은 에틸아세테이트(300ml)로 추출된다. 유기상은 황산나트륨으로 건조되고, 그런 다음 진공하에서 증발되어, 아세토니트릴(25ml)에 용해된 해당 티모롤염기(4.9g)이 얻어진다. 얼음으로 냉각된 용액은, 아세토니트릴(5ml)에서 65% 질산용액(1.08ml)으로 처리되고, 저온에서 30분동안 교반한 후, 여과되고, 에틸에테르로 세척되고 진공하에서 건조되는 고체를 제공하기 위해 에틸에테르(100ml)로 처리된다. m.p. 115℃-116℃의 티모롤질산염 4.6g이 얻어진다.1H-NMR(D2O) ppm : 4.34(1H,m), 3,76(4H,t), 3.39(4H,t), 3.23(2H,m), 3.04(2H,m), 1.29(9H,s).
원소분석(C13H25N5O6S):
계산(calc. %) C 41.15 H 6.64 N 18.46 S 8.45
습득(found %) C 41.24 H 6.61 N 18.38 S 8.31
실시예 2
프로프라노롤질산염 제조
중탄산나트륨(70ml)의 포화수용액에 프로프라노롤 히드로클로라이드염(5g)이 첨가된다. 혼합물은 에틸아세테이트(250ml)로 추출된다. 유기상은 황산나트륨으로 건조되고, 그런 다음 진공하에서 증발되어, 아세토니트릴/테트라히드로푸란 5/2(70ml)에 용해되는 해당 프로프라노롤염기(4.2g)가 얻어진다. 얼음으로 냉각된 용액은, 아세토니트릴(10ml)에서 65% 질산용액(1.13ml)으로 처리되고, 저온에서 30분동안 교반한 후, 여과되고, 에틸에테르로 세척되고 진공하에서 건조되는 고체를 제공하기 위해 에틸에테르(50ml)로 처리된다. m.p. 127℃-130℃의 프로프라노롤 질산염 5.1g이 얻어진다.
1H-NMR (D2O) ppm : 8.15(1H,m), 7.80(1H,m), 7.48-7.32(4H,m), 6.86(1H,d), 4.32(1H,m), 4.13(2H,d), 3,36(1H,m), 3.22(2H,d), 1.24(6H,d).
원소분석(C16H22N2O5):
계산(calc. %) C 59.62 H 6.88 N 8.69
습득(found %) C 59.99 H 6.97 N 8.65
실시예 3
실데나필질산염 제조
아세토니트릴(100ml) 및 테트라히드로푸란(40ml)의 혼합물에서 실데나필용액(7.7g, 16.3mmoles)은, 아세토니트릴(10ml)에 용해된 65% 질산(1.13ml)으로 처리된다. +4℃에서 30분후에, 감소된 압력에서 증발에 의해 적은 부피로 농축되고, 에틸에테르(100ml)가 서서히 첨가된다. 제조된 침전물은 여과되고, 에틸에테르로 세척되고, 진공하에서 건조된다. 흰색 아모퍼스고체(6.5g)이 얻어진다.
원소분석(C22H31N7O7S):
계산(calc. %) C 49.15 H 5.81 N 18.24 S 5.96
습득(found %) C 49.34 H 5.75 N 18.38 S 6.00
실시예 4
발사탄질산염 제조
발사탄용액(3.48g, 8mmoles)은 아세토니트릴(30ml) 및 테트라히드로푸란(10ml)의 혼합물에서 용해하여 제조된다. 아세토니트릴에 용해된 질산은 저온에서 첨가된다(아세토니트릴에서 65% 질산 2.7ml에 첨가하여 얻어지고, 최종부피 10ml가 되도록 하는 용액으로부터 취해진 2ml). 30분 후, 에틸에테르(100ml)은 동일온도(+4℃)에 서서히 첨가된다. 침전물은 여과되고, 에틸에테르로 세척되고 진공하에서 건조되어 제조된다. 흰색 아모퍼스고체(3.1g)가 얻어진다.
원소분석(C24H30N6O6):
계산(calc. %) C 57.82 H 6.07 N 16.86
습득(found %) C 58.02 H 6.02 N 16.77
실시예 5
히드랄라진질산염 제조
히드랄라진히드로클로라이드(3g)은 탄산칼륨 수용액(50ml)에 첨가된다. 그것은 에틸아세테이트(80ml)로 추출된다. 유기상은 물로 세척되고, 황산나트륨에의해 건조되고 진공하에서 증발된다. 잔여물(1g, 6.25mmoles)은 아세토니트릴(30ml) 및 메탄올(20ml)의 혼합물에 용해된다. 그것은 +4℃에서 냉각되고, 아세토니트릴(10ml)에서 65% 질산용액(0.6g, 6.24mmoles)이 첨가된다. 흰색 침전물은 제조되고, 여과되어 진공하에서 건조된다(1g, m.p. 237℃ - 243℃).
원소분석(C8H9N5O3):
계산(calc. %) C 43.05 H 4.06 N 31.38
습득(found %) C 43.32 H 4.03 N 31.22
실시예 6
니카디핀질산염 제조
아세토니트릴(20ml)에서 니카디핀히드로클로라이드(0.1g, 0.194mmoles)은 어둠에서 질산은(0.33g, 0.194mmoles)으로 처리된다. 30분동안 실온에서 계속 교반함으로서, 침전물이 흰색 고체로서 제조된다. 그것은 여과되고, 감소된 압력에서 부피가 반으로 될 때까지 농축되고, +4℃까지 냉각되고 에틸알콜로 처리된다. 침전물은 여과된다. 그것은 건조된다. 노란 고체가 얻어진다(0.05g, m.p. 193℃-198℃).
원소분석(C26H30N4O9):
계산(calc. %) C 57.56 H 5.57 N 10.33
습득(found %) C 57.44 H 5.63 N 10.44
실시예 7
베라파밀질산염 제조
아세토니트릴(50ml)과 테트라히드로푸란(15ml)의 혼합물에서 베라파밀 히드로클로라이드(3.44g, 7mmoles)는, 어둠에서 질산은(1.19g, 7mmoles)으로 처리된다. 용액은 한 시간동안 실온에서 계속 교반된다. 침전물이 서서히 제조되고, 마침내 여과된다. 용액은 부피가 반이 될 때까지 농축되고, +4℃에서 냉각되고, 제조된 침전물은 여과된다. 건조후, 흰색 아모포스고체가 얻어진다(2.8g).
원소분석(C27H39N3O7):
계산(calc. %) C 62.65 H 7.59 N 8.12
습득(found %) C 62.48 H 7.68 N 8.11
실시예 8
아밀로리드질산염 제조
메탄올(100ml)에서 아밀로리드히드로클로라이드용액(2g, 7.5mmoles)은, 어둠에서 질산은(1.28g, 7.5mmoles)으로 처리된다. 침전물은 신속히 제조된다. 그것은, 30분 동안 실온에서 교반상태로 둔다. 최종적으로, 고체는 여과되고, 용액은 감소된 압력하에서 초기부피의 반이 될 때까지 농축된다. 그것은 에틸에테르(50ml)로 처리되고, +4℃에서 냉각된 후, 얻어진 고체는 여과된다. 건조후, 고체는 분리된다(0.8g, m.p. > 280℃).
원소분석(C6H9ClN8O4):
계산(calc. %) C 24.63 H 3.10 N 38.29 Cl 12.11
습득(found %) C 24.75 H 3.03 N 38.19 Cl 12.24
실시예 9
기니아돼지에서 실험적 기관지협착에 대한 프로프라노롤, 프로프라노롤질산염, 티모롤 및 티모롤질산염의 효과연구
투여량 10mg/kg의 화합물과 해당 캐리어가, 연속 3일동안 복강내의 경로를 통해 기니아돼지들(각 6마리의 그룹들)에 투여되었다. 동물들은 델솔다토등의 J. 약리학적 방법 5 279 1981(Del Soldato et al. J. Pharmacol. Methods 5 279 1981)에 따라 준비되었다. 45분 후, 캅사이신염류용액(Capsaicin saline solution, 1㎍/Kg) 0.1ml이 정맥주사로 동물들에게 주사된다. 캅사이신투여 전 및 후에 주기적으로 변화하는 공기변동(tidal air variation)이, 전술한 참고문헌에서 설명된 대로 변형되고, 폴리그래픽시스템에 연결된 콘제트(Konzett) 기구에 의해 측정된다.
캅사이신주사에 의해 기니아돼지들에 유도된 실험적 기관지협착에 대한 화합물들과 그들의 해당 질산염들의 효과들이 표 1에 보고되어 있다.
표 1.
실시예 10
실데나필과 비교해서 실데나필질산염의 약리학적 활성
화합물들은 생리학적 용액에 투여된다. 대조군은 캐리어(생리학적 용액)만으로 처리된다.
실데나필질산염의 혈관-완화 활성은, 리베이로 등의 고혈압, 20, 298, 1992에 의해 설명된 것과 같이, NW-니트로-L-아르기닌-메틸-에스테르(L-NAME)으로 처리된 쥐들에서, 부최대(submaxium) 전기자극에 의해 유도된(D.A.Taylor et al., J.Pharmacol.Exp.Ther.224, 40-45 1983) 전립선 정관(deferent vessels)협착의 실험적모델을 이용해서 측정되었다. 6주동안 위스타 성체수컷쥐들(235-284g)은, 약 60mg/Kg의 일일 투여량에 해당하는 60-70mg/100ml농도의 L-NAME을 음료수로 받아들였다.
동물들은, 실데나필질산염, 실데나필 또는 캐리어 각각 10mg/kg을 일일투여량으로 피하경로를 통해 5일동안 받아들였다. 마지막 처치로부터 1시간 후, 동물들은 희생되었고, 정관의 전립선 부분은 제거되고, 37℃의 생리학적 용액에 담궈지고, 경벽자극(transmural stimulation)(최대자극의 95%, 0.2Hz)에 의해 수축되었다.
농도 10-6M의 시험물질의 추가로부터 5분이내에 결과인 신경성의 수축반응의 감소는, 혈관완화활성의 기준으로 받아들여진다.
표 2.
표로부터 명백한 바와 같이, 질산염의 근완화활성은, 전구체 대조화합물의 활성보다 크다.
해면상동맥(cavernous artery) 및 인간 해면체(cavernosum corpora)(말초수준에서의 혈관확장효과)의 완화효과에 대해서도 연구되었다. 외과수술을 받는 환자들로부터 나온 발기조직들을 사용하는 R.G.헴펠만(Hempelmann) 등의 약리학의 유럽저널 276,277-280(1995)에 설명된 기술이 이용되었다. 해면상동맥들은 주위 연결조직으로부터 분리되고 깨끗이 정돈되었다. 약 2mm 길이의 분절들이 얻어졌고 근운동기록장치에 고정되었다.
실험적 커브 직경/장력(diameter/tension)이 그려진 후, 표본들은 100mm Hg의 경관(transluminal)압력의 존재에서 도달되는 것의 90%에 해당하는 직경으로 조정되었고; 약 60분의 안정화기간 후, 수축은 아드레날린 3.10-6M에 의해 초래된다. 15분 후, 시험된 화합물의 각각 10-6M에 해당하는 투여량이 첨가되고, 완화퍼센티지가 기록되었다. 그 결과들은 표 3에 보고되어 있다.
실험의 제2시리즈는, 5-10mN장력하에서, 분리된 기관들용 용액기(bath)에 동일한 크기로 부유되어 있는 3 x 3 x 5mm 해면상조직의 분리된 스트립(strips)에 대해 동일한 프로토콜에 따라 실시되었다. 그 결과들은 표 4에 보고되어 있다.
표 3
표 4
상기 양 실험모델들에서, 실데나필처치 및 니트릭옥사이드 SIN-1 도너와의 처치 양자에 따른 아드레날린에 의해 유도된 수축에 대한 완화효과는 명백하다. 본 발명에 따른 유도체는, 전구체 실데나필 및 SIN-1 보다 더 높은 약리학적 효과를 보였다.
실시예 11
로사탄과 비교된 로사탄질산염의 항고혈압 및 항-안지오텐신활성에 대한 연구
화합물들은 생리학적 용액에 투여된다. 대조군은 캐리어(생리학적 용액)만으로 처리된다.
동맥고혈압에 대한 로사탄질산염의 저해효과는, 2개의 실험모델들을 이용하여 조사되었다: L-NAME에 의해 유도된 동맥고혈압(전술한 실시예 참조) 및 안지오텐신 II에 의해 초래된 근수축. 제1실험에서, 위스타 성체수컷쥐들(235-284g)은, 약 60mg/Kg의 일일 투여량에 해당하는 60-70mg/100ml농도로 L-NAME을 함유하는 음료수를 6주동안 받아들였다. 동물들은, 로사탄질산염, 로사탄 또는 캐리어 각각 10mg/kg을 일일투여량으로 피하경로를 통해 5일동안 받아들였다. 마지막 처치로부터 1시간 후, Zatz, Lab. Anim. Sci.,42,198,1990에 설명된 것과 같이, 카우달방법(caudal way)에 의해 전신동맥압이 측정되었다.
제2실험에서(안지오텐신 II에 의해 발생된 수축), P.C. Wong 등, 고혈압, 13, 489-497, 1989에 의해 설명된 방법은 다음과 같다. 기니아돼지들(300-350g)로부터 분리된 회장의 분절은, 안지오텐신 II(10mcg/ml), 안지오텐신 II + 로사탄질산염 10-6M, 및 안지오텐신 II + 로사탄 10-6M 각각을 함유하는 생리학적 용액에 담궈진다. 그 결과들은 표 5에 보고되어 있다.
표 5
표로부터, L-NAME에 의해 발생된 고혈압에 대한 질산염의 저해효과는 전구체대조화합물의 효과보다 크다는 것이 확인된다. 두개의 생성물들은, 안지오텐신 II에 의해 유도된 수축을 저해하기 때문에 근완화활성에 모두 효과적이지만, 본 발명에 따른 화합물은 더 높은 효능을 나타낸다.
실시예 12
미녹시딜과 비교된 미녹시딜질산염의 항고혈압 및 혈관-완화활성에 대한 연구
화합물들은 생리학적 용액에 투여된다. 대조군은 캐리어(생리학적 용액)만으로 처리된다.
동맥고혈압에 대한 미녹시딜질산염의 저해효과는, 2개의 실험모델들을 이용하여 조사되었다: L-NAME에 의해 유도된 동맥고혈압(실시예 10 참조) 및 전기자극에 의해 초래된 혈관수축. 제1약리학실험에서, 쥐들은, 실시예 11의 L-NAME 약리학실험에서 설명된 것과 같이 처리되었다. 제2실험에서, 테일러에 의해 설명된 방법(실시예 10 참조)은, 이전에 설명된 것에 따랐다. 쥐들(200-220g)의 분리된 정관의 전립선부분은 제거되고, 37℃의 생리학적 용액에 담궈졌고, 그런 다음 경벽자극(최대자극의 95%, 0.2Hz)에 의해 수축되었다.
혈관완화활성은, 수축신경성반응의 감소로서 표현되고, 10-6M농도에서 시험된 화합물의 첨가로부터 5분이내에 측정된다.
표 6
표 6으로부터 명백한 바와 같이, L-NAME에 의해 발생된 고혈압에 대한 미녹시딜질산염의 저해효과는, 대조화합물의 효과보다 크다. 혈관-완화활성에 대하여, 두개의 생성물들은, 전기자극에 의해 유도된 혈관수축을 저해하는데 모두 효과적이다.
실시예 13
티모롤과 비교된 티모롤질산염의 항고혈압 및 베타-항아드레날린활성에 대한 연구
두개의 실험모델들이 사용되었다: L-NAME에 의해 발생된 동맥고혈압 및 이소프레날린에 의해 초래된 근수축-정효과(inotropic-positive effect).
제1실험에서, 항고혈압활성은 실시예 11에서 설명된 실험모델에 따라 연구되었다.
제2실험에서는, 그로드진스키(Grodzinski)등의 Arch. Int. Phramacodyn., 191, 133-141, 1971에 설명된 방법을 따랐다. 기니아돼지들(300-350g)로부터 채취된 남겨진 심방표본들은, 칼슘이온의 농도가 1/3 낮아진 32℃의 생리학적 용액에서 보전되었고, 이소프레날린(10mcg/ml)에 의해 자극되었다. 베타-항아드레날린활성은, 10-6M 농도의 실험하에서 화합물의 첨가에 따른 근수축-정효과(심장근육수축의 증가)의 감소로서 표현된다.
표 7
표 7로부터 명백한 것과 같이, L-NAME에 의해 발생된 고혈압에 대한 티모롤질산염의 저해효과는 티모롤의 효과보다 크다. 항아드레날린활성에 대하여, 두개의 생성물들은 모두, 이소프레날린에 의해 초래된 근수축-정효과를 저해하는데 효과적이지만, 본 발명에 따른 것이 더 높은 효능을 나타낸다.
실시예 14
니카디핀과 비교된 니카디핀질산염의 항고혈압 및 칼슘길항제활성에 대한 연구
두개의 실험모델들이 사용되었다: L-NAME에 의해 유도된 동맥고혈압 및 염화칼슘에 의해 유도된 근수축.
제1실험에서, 항고혈압활성은 실시예 11에서 설명된 실험모델에 따라 연구되었다.
제2실험에서는, 적응된 실험모델은, M.J.스페딩(Spedding)의 J. 약리학 83, 211-220, 1984에 설명된 방법에 따른, 염화칼슘에 의해 초래된 회장수축실험이었다. 기니아돼지(300-350g)로부터 채취된 일레우스분절들은, 칼슘이온들을 함유하지 않는 생리학적 용액에서 37℃로 보전되었고, 그런 다음 염화칼슘첨가(최종농도 20mcg/ml)에 의해 자극되었다. 칼슘길항제활성은, 10-6M농도의 시험화합물들의 각각의 첨가에 따른 회장수축의 감소로 측정되었다.
표 8
표로부터 명백한 것과 같이, L-NAME에 의해 유도된 고혈압에 대한 질산염의 저해효과는 전구체 니카디핀의 효과보다 크다. 칼슘길항제활성에 대하여, 두개의 화합물들은, 정도에서는 차이가 있지만, 모두 칼슘-의존수축효과를 저해하는데 효과적인 것 같다.
실시예 15
아밀로리드와 비교된 아밀로리드질산염의쥐에서의 항고혈압 및 이뇨활성에 대한 연구
아밀로리드 약리학적 측면(profile)은, 다음 실험모델들을 이용해서 결정되었다: L-NAME에 의해 발생된 동맥고혈압 및 이뇨효과.
제1실험에서, 항고혈압활성은 실시예 11에서 설명된 실험모델에 따라 연구되었다.
제2실험에서는, 이뇨효과는, W.L.Lipschwitz 등의. J. 약리학. Exp. Ther. 79, 97-110, 1943에 설명된 방법에 따라서 연구되었다. 대사우리(metabolic cages)에 넣어둔 각각 6마리 쥐들(200-220g)의 3그룹은, 증류된 음료수(25ml/Kg p.o.)을 받아들였다. 그런 다음, 각 그룹은, 아밀로리드질산염(10mg/Kg), 아밀로리드(10mg/Kg) 또는 캐리어 각각을 피하로 주사된다. 소변량이, 투약후 6시간동안 수집되어 ml로 측정되었다. 이뇨효과는 캐리어로 처리된 그룹의 소변량에 대한 계산된 수집소변량의 퍼센트로서 표현된다.
표 9
표 9로부터 명백한 것과 같이, L-NAME에 의해 유도된 고혈압에 대한 아밀로리드질산염의 저해효과는, 아밀로리드의 효과에 비해 매우 크다. 혈관-완화활성에 대하여, 두개의 화합물들은, 유사한 이뇨활성을 보인다.
실시예 16
실데나필 및 자프리나스트염들의 급성독성에 대한 연구
두개의 생성물들은 카르복시메틸셀루로우즈 2%의 현탁액에 투여된다.
전술된 염들의 급성독성은, 각각 10마리 쥐로 이루어진 그룹들에 화합물을 증가하는 투여량으로 경구투여함으로서 평가되었다. 각 그룹은 단일의 투여량으로 투여된다.
동물들은, 14일동안 계속 관찰되었다. 치사률발생빈도(lethality incidence) 및 어떠한 독성징후도 평가되었다.
50mg/Kg 투여량의 투여후에도, 어떠한 명백한 독성의 징후도 나타나지 않았다. 모든 동물들이 살아남았다.
실시예 17
전구체들의 위에 대한 독성(gastric toxicity)과 비교하여 실데나필 및 자프리나스트염들의 위에 대한 독성의 연구
스프라그-도우리(Sprague-Dawley) 수컷쥐들(n=10)의 5 그룹들은, 24시간동안 금식되었다. 그런 다음, 4 그룹들은, 실데나필, 자프리나스트, 및 상기 약제들의 관련질산염들로 각각 i.p. 처치된다. 한 그룹은 처치되지 않아, 대조군이었다. 30분후, 물에 에탄올 50%의 1ml가 동물들에게 os에 의해 주어진다.
1시간후, 동물들은 희생되었다. 위는 제거되었고 위의 조직은 육안으로 검사되었다. 이 검사는 쥐들이 희생되기 전에 받은 처치를 알지 못하는 연구자에 의해 실행되었다. 병변들의 존부가 그레쩌 등(Gretzer et al. Br. J. Pharmacol. 123, 927,1998)에 의해 설명된 것과 같이 검사되었다.
그 결과들은 표 10에 보고되어 있다. 표에서, 발생빈도%로 나타난 위의 독성은, 위의 병변들을 나타내는 그룹의 쥐의 수이다.
표 10
표로부터 알 수 있듯이, 실데나필 또는 자프리나스트로 처치된 쥐들의 그룹에서 위의 병은 대조군에 대하여 악화되었다. 상기 약제의 해당 질산염들의 위의 독성은 대조군의 독성보다 낮았다.
실시예 18
퍼헥실린질산염 제조
질산 65%(0.75ml)은, 0℃로 냉각된 아세토니트릴 및 메탄올(10ml)에 퍼헥실린용액에 첨가된다.
얻어진 용액은 30분동안 0℃에서, 그런 다음 30분 더 실온에 계속하여 자력교반(magnetic stirring)된다. 용매는 감소된 압력하에서 증발되고, 초기생성물은 에틸에테르에서 현탁되고, 그런 다음 여과된다.
생성물(3.09g)이 녹는점 =151-155℃를 가지는 흰색 고체로서 얻어진다.
원소분석:
C H N
계산(calc. %) 67.00 10.65 8.26
습득(found %) 67.05 10.79 8.40
실시예 19
아포모핀질산염의 제조
질산은(2.72g, 16mmoles)은 아세토니트릴(70ml)에서 아포모핀히드로클로라이드(5g, 16mmoles)용액에 첨가되었고, 그 혼합물은, 30분동안 어두운 질소분위기하에서 교반되었다. 염화은은 여과되어지고, 용액은 디에틸에테르로 희석되었다. 침전물이 형성되어, 여과되고, 디에틸에테르로 세척되고 진공하에서 건조되었다. 4.3g이 회수되었다.
C, H, N 분석
계산(calc. %) C 61.81 H 5.49 N 8.48
습득(found %) C 61.84 H 5.45 N 8.51
실시예 20
자프리나스트질산염의 제조
질산용액65% 0.5ml/아세토니트릴(2.7ml/7.3ml)은, 아세토니트릴(10ml)에 자프리나스트(0.5g, 1.84mmoles)용액에 0℃에서 첨가되고, 얻어진 혼합물은 30분 동안 어두운 질소분위기하에서 교반되었다. 그런 다음, 용액은 디에틸에테르로 희석되고, 형성된 침전물은 여과되고, 디에틸에테르로 세척되고 진공하에서 건조되었다(0.4g).
C, H, N 분석
계산(calc. %) C 46.71 H 4.22 N 25.14
습득(found %) C 46.68 H 4.26 N 25.11
Claims (16)
- 다음 클래스들에서 선택되는 화합물들의 질산염들(nitrate salts).클래스(Alb):RⅢ Al자유원자가이면서 RAl= -O이어서, 5위치 탄소원자와 결합하여 케톤기를 형성하고,RⅣ Al및 RⅢ Al자유원자가들이면서, RI Al및 식(Alb)의 화합물에서 이종고리의 4 및 5위치의 탄소원자들과 RAl은, -COOH기를 함유하는 6탄소원자들을 가지는 방향족고리를 형성한다:RⅠ Al= H, Cl;RAl, RⅣ Al, RⅢ Al및 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들과 RⅠ Al은, COOH기를 함유하는 방향족고리 (IXc)를 형성하고,RⅣ Al및 식(Alb)의 이종고리의 4 위치의 탄소원자와 RⅠ Al는, 5 탄소원자들을 가지는 다음의 포화고리를 형성한다:RⅡ Al= -(CH2)3-CH3, -O-CH2-CH3;RⅢ Al= H, 자유원자가,RⅣ Al자유원자가와 RⅢ Al자유원자가는, 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들 사이에서 이중결합을 형성하고,RⅣ Al, RⅠ Al및 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들과 RⅢ Al은 -COOH기를 함유하는 방향족고리 (IXc)를 형성한다;RⅣ Al= 자유원자가, 식(Alb)의 이종고리의 4위치의 탄소원자와 RⅠ Al와 함께, RⅣ Al은, 5 탄소원자들을 가지는 포화고리 (IXd)를 형성하고,RⅢ Al, RⅠ Al및 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들과 RⅣ Al은 -COOH기를 함유하는 방향족고리 (IXc)를 형성하고,RⅢ Al와 RⅣ Al양 자유원자가들은, 식(Alb)의 이종고리의 4 및 5 위치의 탄소원자들 사이에서 이중결합을 형성하고;클래스 (Alc):클래스 (Alc) 전구체가 발사탄(Valsartan)으로 알려져 있고;클래스 (A2):1(2H)-프탈라지논 히드라존(히드랄라진); 6-(1-피페리디닐-1)-2,4-피리미딘디아민 3-옥사이드(미녹사이딜); 1-[[3-(4,7-디히드로-1-메틸-7-옥소-3-프로필-1H-피라졸[4,3-d]피리미딘-5-일)-4-에톡시페닐]설포닐1-4-메틸-피페라진(실데나필), 2-(2-프로필옥시페닐)-8-아자푸린-6-원(자프리나스트);클래스 (A3):서로 같거나 다른 RⅠ B1및 RⅡ B1은 H, CH3이고,식 (XId)에서 t = 0, 1.식 (XIe)에서 YB1은 다음 의미를 가질 수 있다:식 (XIf)에서 Z = H, -OCH3;식 (A3)에서:XBI= -O-, -S-;서로 같거나 다른 n 및 m은 0, 1이고;식 (XIp)에서:S1= H, CN, OCH3, CH3, -CH2-CH3, -O-CH2-CONH-CH3, -COCH3, -CO-(CH2)2-CH3, -O-CH2-CH=CH2, -CH2-CH=CH2, 시클로펜틸 또는S2= H, CH3, Cl, -SOCH3, -CONH2;S2및 동일한 라디칼 (XIp)의 C6방향족고리의 2 및 3 위치의 탄소원자들과 S1은, 다음의 고리를 형성한다:여기서:[식 XIpⅦ의 방향족고리에 인접한(*)원자]B = -CH2-, -NH-, -CH=CH-,(*)-CO-CH2-;A = -O-,(*)-CH2-CH(OH)-,(*)-O-CH2-,(*)-S-CH2, -CH2-CH2, -CH2-,A는 3차탄소원자이고, 동시에 W1은, A와 1'위치의 탄소원자 사이에 이중결합 -CH=CH-을 형성하기 위해서 자유원자가이고,5 원자들을 가지는 고리 (XIpⅦ)에서 A는, 치환기를 함유하는 3차탄소이기 때문에, 1'위치의 탄소원자 및 2개의 W1 또는 W2 라디칼들중 하나와, 자유원자가인다른 라디칼은, 다음 식에서 처럼 6탄소원자들을 가지는 방향족고리를 형성한다:W1 = H, 자유원자가, W1은 자유원자가이고 A는 상기에 규정된 대로 3차탄소원자일 때, A와 1'위치의 탄소원자 사이의 이중결합이 형성되고;W2, 1'위치의 탄소원자 및 치환기 A와 W1은, 6 탄소원자들을 가지는 방향족고리를 형성하고;W2 = 자유원자가, H, OH, -CH3, -ONO2, W1 = 자유원자가 및 1'위치의 탄소원자와는 케톤기를 형성하는 -O 이고,W1, 1'위치의 탄소원자 및 치환기 A와 W2는, 6 탄소원자들을 가지는 방향족고리를 형성하고;S3= H, F, Cl, OH, NO2, -CH2-CO-NH2, -(CH2)2-OCH3, -NH-COCH3, -CH2-O-CH2-CH2-O-CH(CH3)2, -CH2-CH2-COOCH3, -NH-CO-N(C2H5)2, -NH-CO-(CH2)2-CH3, -NH-SO2-CH3, -NH-CO-NH-[시클로헥실], -CH2-CH2-O-CH2-[시클로프로필];S4= H, Cl, -CH2-CH2- 이고, m = n = 1 및 RⅦ B1자유원자가인 동시에, 동일한 라디칼(XIp)의 방향족고리의 1 및 6 위치의 탄소원자들 및 산소인 식(A3)의 XB1와는, 다음의 고리를 형성한다:S4은 3차탄소원자이고, 라디칼 방향족고리(XIp)의 1 및 6 위치의 탄소원자 및 식 (A3)의 다음 구성요소(탄소원자 -|C|n- (n=1), 산소와 같은(m=1) 라디칼 XB1)및 RⅥ B1자유원자가와 RⅦ B1과는, 다음의 고리를 형성한다:RⅥ B1= H, 자유원자가;RⅦ B1= H, 자유원자가;및 그외에 다음 화합물들: 2-히드록시-5-[1-히드록시-2-[(1-메틸-3-페닐프로필)아미노]에틸]벤즈아미드(라베타롤), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-[(테트라히드로-2-푸라닐)카르보닐]피페라진(테라조신), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-(2-푸라닐카르보닐)피페라진(프라조신); 벤조니트릴, 2-[2-히드록시-3-[[2-(1H-인돌-3-일)-1, 1-디메틸에틸]아미노]프로폭시](부신도롤)클래스 (A4a):(A4a):β-[(2-메틸프로폭시)메틸]-N-페닐-N-(페닐메틸)-1-피롤리딘에타나민(베프리딜), (2S-시스)-3-(아세틸옥시)-8-클로로-5-[2-(디메틸아미노)에틸]-2,3-디히드로-2-(4-메톡시페닐)-1,5-벤조티아제핀-4(5H)-원(클렌티아젬), (2S-시스)-3-(아세틸옥시)-5-[2-(디메틸아미노)에틸]-2,3-디히드로-2-(4-메톡시페닐)-1,5-벤조티아제핀-4(5H)-1(딜티아젬), γ-페닐-N-(1-페닐에틸)벤젠-프로판아민(펜딜린), α-[3-[[2-(3,4-디메톡시페닐)에틸]메틸아미노]프로필]-3,4,5-트리메톡시-α-(1-메틸에틸)-벤젠아세토니트릴(갈로파밀), (1S-시스)메톡시아세트산2-[2[[3-(1H-벤즈이미다졸-2-일)프로필]메틸아미노]에틸]-6-플루오르-1,2,3,4-테트라히드로-1-(1-메틸에틸)-2-나프탈에닐 에스테르(미베프라딜), N-(1-메틸-2-페닐에틸)-γ-페닐벤젠프로판아민(프레닐아민), (R)-2-[2-[3-[[2-(1,3-베조디오솔-5-일옥시)에틸]메틸아미노]프로폭시]-5-메톡시페닐]-4-메틸-2H-1,4-벤조티아진-3(4H)-원(세모티아딜), N-(1,1,-디메틸에틸)-α-메틸-γ-페닐벤젠프로판아민(테로딜린), α-[3-[[2-(3,4-디메톡시페닐)에틸]메틸아미노]프로필]-3,4-디메톡시-α-(1-메틸에틸)-벤젠아세토니트릴(베라파밀);(A4b):2-[(2-아미노에톡시)메틸]-4-(2-클로로페닐)-1,4-디히드로-6-메틸-3,5-피리딘디카르복실산 3-에틸 5-메틸에스테르(암로디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 메틸 2-옥소프로필 에스테르(아라니디핀), [S-(R*,R*)]-±-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 1-(페닐메틸)-3-피롤리디닐 에스테르(바니디핀), (R*,R*)-±-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 1-(페닐메틸)-3-피페리디닐 에스테르(베니디핀), (E)-±-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-디메톡시에틸 3-페닐-2-프로페닐에스테르(실니디핀), 5-(5,5-디메틸-1,3,2-디옥사포스포리난-2-일)-1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3-피리딘-카르복실산 2-[페닐(페닐메틸)아미노]에틸 에스테르 P-옥사이드(에포니디핀), ±-4-(1,3-벤조디옥솔-4-일)-1,4-디히드로-2,6-디메틸-3,5-피니딘디카르복실산 2-[[(4-플루오로페닐)메틸]메틸아미노]에틸 1-메틸에틸 에스테르(엘고디핀), 4-(2,3-디클로로페닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 에틸 메틸 에스테르(펠로디핀), 4-(4-벤조푸라자닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 5-메틸 3-(1-메틸)에틸 에스테르(이스라디핀), (E)-4-[2-[3-(1,1-디메틸에톡시)-3-옥소-1-프로페닐]페닐]-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 디에틸 에스테르(라시디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-[(3,3-디페닐-프로필)메틸아미노]-1,1-디메틸에틸 메틸에스테르(레카니디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-[4-(디페닐메틸)-1-피페라지닐]에틸 메틸 에스테르(마니디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 2[메틸-페닐메틸)아미노]에틸 에스테르(니카디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 디메틸 에스테르(니페디핀), 2-시아노-1,4-디히드로-6-메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 3-메틸 5-(1-메틸에틸)에스테르(닐바디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-메톡시에틸 1-메틸에틸 에스테르(니모디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 메틸 2-메틸-프로필 에스테르(니솔디핀), 1,4-디히로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 에틸 메틸 에스테르(니트렌디핀);(A4c) :1-(디페닐메틸)-4-(3-페닐-2-프로페닐)피페라진(신나리진), (E)-1-[비스(4-플루오르페닐)메틸]4-(3-페닐-2-프로페닐) 피페라진(프루나리진), 4-[4,4-비스(4-플루오로페닐)부틸]-N-(2,6-디메틸페닐)-1-피페라진아세트아미드(리도프라진), 1-[비스(4-플루오로페닐)메틸]-4-[(2,3,4-트리메톡시페닐)메틸]피페라진(로메리진);(A4d):N,N-디메틸-3-[[1-(페닐메틸)-시클로헵틸]옥시]-1-프로판아민(벤즈시클란), 1-[2-[2-(디에틸아미노)에톡시]페닐]-3-페닐-1-프로파논(에타페논), 3,4-디메톡시-N-메틸-N-[3-[4-[[2-(1-메틸에틸)-1-인돌리지닐]설포닐]페녹시]프로필]벤젠에탄아민(판토파론);클래스 (A7):(A7a):6-클로로-3,4-디히드로-3-[(2-프로페닐티오)메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(알티아지드), 3,4-디히드로-3-(페닐메틸)-6-(트리플루오로메틸)-2H-1,2,4-벤조티아디아진-7-설폰아미드1,1-디옥사이드(벤드로플루메티아지드), (6-클로로-3-[[(페닐메틸)티오]메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(벤즈티아지드), 6-클로로-3,4-디히드로-3-(페닐메틸)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1,-디옥사이드(벤질히드로클로로티아지드), 6-클로로-3,4-디히드로-3-(2-메틸플로필)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(부티아지드), 6-클로로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(클로로티아지드), 2-클로로-5-(2,3-디히드로-1-히드록시-3-옥소-1H-이소인돌-1-일)벤즈베설폰아미드(클로탈리돈), 6-클로로-3-(시클로펜틸메틸)-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(시클로펜티아지드), 3-바이시클로[2.2.1]헵트-5-엔-2-일-6-클로로-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(시클로티아지드), 6-클로로-3,4-디히드로-3-[[(2,2,2-트리플루오로에틸)티오]메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(에피티아지드), 6-클로로-3-에틸-3,4-디-히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(에티아지드), 7-클로로-1,2,3,4-테트라히드로-4-옥소-2-페닐-6-퀴나졸린설폰아미드(펜퀴존), 3-(아미노설포닐)-4-클로로-N-(2,3-디히드로-2-메틸-1H-인돌-1-일)벤즈아미드(인다프아미드), 6-클로로-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(히드로클로로티아지드), 3,4-디히드로-6-(트리플루오로메틸)-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(히드로플루메티아지드), 6-클로로-3-(클로로메틸)-3,4-디히드로-2-메틸-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(메티클로티아지드), 3,4-디히드로-6-메틸-2H-1-벤조티오피란-7-설폰아미드 1,1-디옥사이드(메티크란), 7-클로로-1,2,3,4-테트라히드로-2-메틸-3-(2-메틸페닐)-4-옥소-6-퀴나졸린설폰아미드(메토라존), 6-클로로-3-[(4-플루오로페닐)-메틸]-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(파라플루티지드), 6-클로로-3,4-디히드로-2-메틸-3-[[(2,2,2-트리플루오로에틸)티오]메틸]-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(폴리티아지드), 7-클로로-2-에틸-1,2,3,4-테트라히드로-4-옥소-6-퀴나졸린설폰아미드(퀴네타존), 6-클로로-3,4-디히드로-3-트리클로로메틸-2H-1,2,4-벤조타디아진-7-설폰아미드 1,1-디옥사이드(테클로티아지드), 6-클로로-3-(티클로로메틸)-3,4-디히드로-2H-1,2,4-벤조티디아진-7-설폰아미드 1,1- 디옥사이드(트리클로메티아지드);(A7b):3,7-디히드로-1,3-디메틸-7-(4-모포리닐메틸)-1H-푸린-2,6-디온(7-모포리노메틸테오필린), 3,7-디히드로-1-(2-히드록시프로필)-3,7-디메틸-1H-푸린-2,6-디온(프로테오브롬), 3,7-디히드로-3,7-디메틸-1H-푸린-2,6-디온(테오브롬);(A7c):6-아미노-3-에틸-1-(2-프로페닐)-2,4(1H,3H)-피리미딘디온(아미노메트라딘), 6-아미노-3-메틸-1-(2-메틸-2-프로페닐)-2,4(1H,3H)-피리미딘디온(아미소메트라딘);(A7d):N-페닐-1,3,5-트리아진-2,4-디아민(아마노진), 3,5-디아미노-N-(아미노이미노메틸)-6-클로로피라진카르복스아미드(아밀로리드), N-(4-클로로페닐)-1,3,5-트리아진-2,4-디아민(클로라자닐), [3-메틸-4-옥소-5-(1-피페리디닐)-2-티아졸리디닐리덴]아세트산 에틸 에스테르(에토졸린), 6-히드라지노-3-피리다진카르복스아미드(히드라카바진), 5-아미노-2[1-(3,4-디클로로페닐)-에틸]-2,4-디히드로-3H-피라졸-3-원(무졸리민), 2-(2,2-디시클로헥실에틸)피페리딘(퍼헥실린), 6-페닐-2,4,7-프터리딘트리아민(트리암터렌), 3-(아미노설포닐)-5-(부틸아미노)-4-페녹시벤조산(부메타니드), 5-(아미노설포닐)-4-클로로-2-[(2-푸라닐메틸)아미노]벤조산(푸로세미드), N-[[(1-메틸에틸)아미노]카르보닐]-4-[(3-메틸페닐)아미노]-3-피리딘설폰아미드(토라세미드);클래스 (A8): 아포모핀
- 제1항에 있어서, 상기 클래스 (Alb)의 다음 화합물들의 질산염들:XAl= (IXa), RAl= CH2OH, RI Al= Cl, RⅢ Al= RⅣ Al= 자유원자가일 때, 식 (Alb)의 이종고리의 4 및 5위치의 탄소원자들과 -CH=CH-이중결합을 형성하며, RⅡ Al= -(CH2)3-CH3인, 로사탄잔기(Losartan residue);로사탄에서와 같으나, 다만 RAl= -O 및 RⅢ Al자유원자가와, 식 (Alb)의 이종고리의 5위치의 탄소원자와 결합하여 케톤기를 형성하기 위해, RⅣ Al및 이종고리의 4위치의 탄소원자와 RI Al는, 5탄소원자들을 가지는 포화된 고리 (IXd)를 형성하기에 충분한, 이베사탄잔기(Irbesartan residue);로사탄에서와 같으나, 다만 RⅡ Al= -O-CH2-CH3와, RI Al와 함께 RAl및 RⅣ Al및 RⅢ Al자유원자가들과 이종고리의 4 및 5 위치의 탄소원자들은, -COOH기를 함유하는 방향족라디칼 (IXc)을 형성하기에 충분한, 칸데사탄잔기(Candesartan residue);로사탄에서와 같으나, 다만 XAl= -COOH와, RAl= (IXb), RI Al= H, RⅣ Al및 RⅢ Al자유원자가들은, 식 (Alb)의 이종고리의 4 및 5 위치의 탄소원자들 사이에 이중결합을 형성하는, 에프로사탄잔기(Eprosartan residue).
- 제1항에 있어서, 클래스 (A3)의 다음 화합물들의 질산염들:RI B1= H, RⅡ B1및 RⅢ B1= CH3, RⅤ B1= H, RⅥ B1= RⅦ B1= H, m = n = 1, XB1= -O-, RⅣ B1= (XIp)일 때, 여기서S1= S2= S4= H, S3= -CH2-CO-NH2인, 아테노롤잔기(Atenolol residue);아테노롤에서와 같으나, 다만 RⅣ B1= (XIs)인, 베푼노롤잔기(Befunololresidue);아테노롤에서와 같으나, 다만 S3= S2= S4= H, S1= -CH2-CH=CH2인, 알프레노롤잔기(Alprenolol residue);아테노롤에서와 같으나, 다만 S1= COCH3, S3= -NH-CO-(CH2)2-CH3, S2= S4= H인, 아세부토롤잔기(Acebutolol residue);아테노롤에서와 같으나, 다만 S3= -CH2-CH2-O-CH2-(시클로프로필)인, 베타조롤잔기(Betaxolol residue);아테노롤에서와 같으나, 다만 S3= -CH2-O-CH2-CH2-O-CH(CH3)2인, 비소프로롤잔기(Bisoprolol residue);알프레노롤에서와 같으나, 다만 S1= (XIpⅡ) 및 RI B1= CH3인, 부페토롤잔기(Bufetolol residue);부페토롤에서와 같으나, 다만 S1= -CN인, 부니트로롤잔기(Bunitrolol residue);부페토롤에서와 같으나, 다만 S1= H, S4= Cl, S2= CH3인, 부프라노롤잔기(Bupranolol residue);부페토롤에서와 같으나, 다만 S1= -CO-(CH2)2-CH3, S3= F인, 부토피로롤잔기(Butofilolol residue);아테노롤에서와 같으나, 다만 RⅣ B1= (XIpⅧ)이고, 여기서 B = -NH-인, 카라조롤잔기(Carazolol residue);부페토롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)이고, 여기서 A = -CH2-CH2-, B = -NH-, W1 = 자유원자가 및 1'위치의 탄소원자와 케톤기를 형성하는 W2 = -O인, 카테오롤잔기(Carteolol residue);부페토롤에서와 같으나, 다만 S3= -NH-CO-N(C2H5)2, S1= -CO-CH3인, 셀리프로롤잔기(Celiprolol residue);부페토롤에서와 같으나, 다만 S1= -O-CH2-CONH-CH3인, 세타모롤잔기(Cetamolol residue);부프라노롤에서와 같으나, 다만 S2= Cl인, 클로라노롤잔기(Cloranolol residue);아테노롤에서와 같으나, 다만 S3= -CH2-CH2-COOCH3인, 에스모롤잔기(Esmolol residue);아테노롤에서와 같으나, 다만 RⅣ B1= (Xiu)인, 인데노롤잔기(Indenolol residue);카테오롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)에서, A = -CH2-, B = -COCH2-,W1 = W2 = H, 레보부노롤잔기(Levobunolol residue);카테오롤에서와 같으나, 다만 RⅠ B1= H이고 RⅣ B1= (XIpⅧ)에서 A는 3차탄소원자이고 W1 자유원자가여서, A와 (XIpⅦ)의 1'위치의 탄소원자 사이에 -CH=CH-이중결합을 형성하고, W2 = CH3인, 메핀도롤잔기(Mepindolol residue);아테노롤에서와 같으나, 다만 S3= -(CH2)2-OCH3인, 메토프로롤잔기(Metoprolol residue);카테오롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)에서 A = -CH2-CH(OH)-, B = -CH2-, W2 = OH, W1 = H인, 나도롤잔기(Nadolol residue);아테노롤에서와 같으나, 다만 S3= NO2인, 니페나롤잔기(Nifenalol residue);메핀도롤에서와 같으나, 다만 RⅣ B1= (XIpⅦ)에서, A = -O-CH2-, B = -CH2-, W2 = -ONO2, W1 = H인, 니프라디롤잔기(Nipradilol residue);알프레노롤에서와 같으나, 다만 S1= -O-CH2-CH=CH2인, 옥스프레노롤잔기(Oxprenolol residue);부페토롤에서와 같으나, 다만 S1= 시클로펜틸인, 펜부토롤잔기(Penbutolol residue);메핀도롤에서와 같으나, 다만 W2 = H인, 핀도롤잔기(Pindolol residue);아테노롤에서와 같으나, 다만 S3= -NH-COCH3인 프랙토롤잔기(Practolol residue);부페토롤에서와 같으나, 다만 S1= H, S3=-NH-CO-NH-(시클로헥실)인, 탈리노롤잔기(Talinolol residue);니프라디롤에서와 같으나, 다만 RⅠ B1= CH3, A = -S-CH2및 W2 = H인, 터타토롤잔기(Tertatolol residue);터타토롤에서와 같으나, 다만 RⅣ B1= (XIn)인, 틸리소롤잔기(Tilisolol residue);부페토롤에서와 같으나, 다만 RⅣ B1= (XIo)인, 티모롤잔기(Timolol residue);부페토롤에서와 같으나, 다만 S1= S2= CH3인, 키벤노롤잔기(Xibenolol residue);키벤노롤에서와 같으나, 다만 RⅠ B1= S1= H인, 톨리프로롤잔기(Toliprolol residue);톨리프로롤에서와 같으나, 다만 RⅡ B1= H 및 RⅢ B1= (XIa)인, 베반토롤잔기(Bevantolol residue);카라조롤에서와 같으나, 다만 RⅡ B1= H 및 RⅢ B1= (XIb)인, 카베디롤잔기(Carvedilol residue);식(A3)에서 RⅠ B1= RⅡ B1= RⅢ B1= CH3, RⅤ B1= (XIh), n = m = 1, RⅥ B1= RⅦ B1= H, XB1= -O-, RⅣ B1= (XIg)인, 봅핀도롤잔기(Bopindolol residue);부페토롤에서와 같으나, 다만 RⅣ B1= (XIt)인, 부큐모롤잔기(Bucumolol residue);식 (A3)에서, m = n = 0 및 RⅣ B1= (XIz) RⅠ B1= RⅡ B1= RⅢ B1= CH3, RⅤ B1= H인, 부푸라롤잔기(Bufuralol residue);아테노롤에서와 같으나, 다만 YB1= H, n = m = 0, RⅣ B1= (XIi)와 RⅢ B1= (XIe)인, 부티드린잔기(Butidrine residue);부티드린에서와 같으나, 다만 z = H, RⅣ B1= (XIp)와 YB1= (XIf)와 RⅢ B1= (XIe)이고, 여기서 S3= OH 및 S2= CONH2, S1= S4= H인, 딜레바롤잔기(Dilevalol residue);베반토롤에서와 같으나, 다만 S2= H, S1= CN, RⅢ B1= (XIc)인, 에파노롤잔기(Epanolol residue);부티드린에서와 같으나, 다만 RⅢ B1= CH3, RⅣ B1= (XIm)이고, 여기서 나프탈렌잔기는 -ORⅣ B1치환기를 가져오는 탄소원자에 2위치의 탄소원자에 의해 연결되어 있는, 프로네타롤잔기(Pronethalol residue);프로네타롤에서와 같으나, 다만 m = 1 및 XB1= -O-와, 그리고 RⅣ B1은, XB1에 1위치의 탄소에 의해 연결된 나프탈렌잔기 (XIm)인 프로프라노롤잔기(Propranolol residue);프로네타롤에서와 같으나, 다만 S1= S2= S4= H 및 S3= -NH-SO2-CH3와 RⅣ B1=(XIp)인, 소타롤잔기(Sotalol residue);딜레바롤에서와 같으나, 다만 S2= -SOCH3와 그리고 다른 방향족고리(식 XIf)에 대해 파라위치에서 Z = -OCH3인, 설피나롤잔기(Sulfinalol residue);식 (A3)에서 RⅠ B1= RⅡ B1= H, t = 1인 RⅢ B1= (XId), RⅤ B1= H, n = m = 0, t = 0인 RⅣ B1= (XId), 네비보롤잔기(Nebivolol residue);2-히드록시-5-[1-히드록시-2-[(1-메틸-3-페닐프로필)아미노]에틸]벤즈아미드(라베타롤), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-[(테트라히드로-2-푸라닐)카르보닐]피페라진(테라조신), 1-(4-아미노-6,7-디메톡시-2-퀴나졸리닐)-4-(2-푸라닐카르보닐)피페라진(프라조신).
- 제1항에 있어서, 클래스 (A4)의 다음 화합물들의 질산염들:(A4a):(2S-시스)-3-(아세틸옥시)-5-[2-(디메틸아미노)에틸]-2,3-디-히드로-2-(4-메톡시페닐)-1,5-벤조티아제핀-4(5H)-원(딜티아젬), α-[3-[[2-(3,4-디메톡시페닐)에틸]메틸아미노]프로필]-3,4-디메톡시-α-(1-메틸에틸)-벤젠아세토니트릴(베라파밀);(A4b):2-[(2-아미노에톡시)메틸]-4-(2-클로로페닐)-1,4-디-히드로-6-메틸-3,5-피리딘디카르복실산 3-에틸 5-메틸에스테르(암로디핀), 4-(2,3-디클로로페닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 에틸 메틸 에스테르(페로디핀) 4-(4-벤조푸라자닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘디카르복실산 5-메틸 3-(1-메틸)에틸에스테르(이스라디핀), 러칸니디핀, 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 메틸 2[메틸(페닐메틸)아미노]에틸에스테르(니카디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 디메틸 에스테르(니페디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 2-메톡시에틸 1-메틸에틸 에스테르(니모디핀), 1,4-디히드로-2,6-디메틸-4-(2-니트로페닐)-3,5-피리딘디카르복실산 메틸 2-메틸-프로필 에트테르(니솔디핀), 1,4-디히드로-2,6-디메틸-4-(3-니트로페닐)-3,5-피리딘디카르복실산 에틸 메틸 에스테르(니트렌디핀);(A4c):(E)-1-[비스(4-플루오로페닐)메틸]4-(3-페닐-2-프로페닐)-피페라진(프루나리진).
- 제1항에 있어서, 클래스 (A7)의 다음 화합물의 질산염들:(A7a):6-디클로로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(클로로티아지드), 2-클로로-5-(2,3-디히드로-1-히드록시-3-옥소-1H-이소인돌-1-일)벤제베설폰아미드(클로탈리돈), 6-클로로-3,4-디히드로-2H-1,2,4-벤조티아디아진-7-설폰아미드 1,1-디옥사이드(히드로클로로티아지드), 3-(아미노설포닐)-4-클로로-N-(2,3-디히드로-2-메틸-1H-인돌-1-일)벤즈아미드(인다프아미드), 7-클로로-1,2,3,4-테트라히드로-2-메틸-3-(2-메틸페닐)-4-옥소-6-퀴나졸린설폰아미드(메토라존), 7-클로로-2-에틸-1,2,3,4-테트라히드로-4-옥소-6-퀴나졸린설폰아미드(퀴네타존);(A7d):3,5-디아미노-N-(아미노이미노메틸)-6-클로로피라진카르복스아미드(아밀로리드), 6-페닐-2,4,7-프테리딘트리아민(트리암테렌), 3-(아미노설포닐)-5-(부틸아미노)-4-페녹시-벤조산(부메타니드), 5-(아미노설포닐)-4-클로로-2-[(2-푸라닐메틸)아미노]벤조산(푸로세미드), N-[[(1-메틸에틸)아미노]카르보닐]-4-[(3-메틸페닐)아미노]-3-피리딘설폰아미드(토라세미드).
- 제1항 내지 제5항에 있어서,클래스 Alb): 로사탄;클래스 A2): 실데나필, 자프리나스트;클래스 A3): 아테노롤, 라베타롤, 티모롤, 프라조신, 테라조신, 프로프라노롤;클래스 A4): 니카디핀, 니페디핀, 니모디핀;클래스 A7): 클로로티아지드, 아밀로리드, 푸로세미드인 질산염들.
- 제1항 내지 제6항에 있어서, 상기 화합물들의 하나 이상의 이성질체들을 함유하는 질산염들.
- 제1항 내지 제7항에 있어서, 상기 화합물들의 염들은 적어도 1질산염이온몰/화합물몰을 함유하는 질산염들.
- 제1항 내지 제8항에 따른 질산염들의 약제조성물들.
- 약물(medicament)로서 사용하기 위한 제1항 내지 제9항에 따른 질산염들 및 약제조성물들
- 고혈압치료용 약물들의 제조를 위한 제10항에 따른 염들 및 조성물들의 용도.
- 심혈관약제들(cardiovasculare medicines)로서 약물들의 제조를 위한 제11항에 따른 염들 및 조성물들의 용도.
- 염화될 수 있는 물질이, 히드록시기를 함유하지 않은 유기용매에 용해가능한 염기 또는 해당염으로서 이용가능할 때, 염은, 10%w/v이상의 농도에서 용매에 물질을 용해하고, 화합물에 존재하는 염화가능한 아민기들의 몰에 해당하는 농축된 질산의 양을 첨가하고, 20℃-0℃의 범위의 온도에서 첨가하는 동안 또는 첨가후에 냉각하고, 여과에 의해 생성물을 회수하여 제조되는 제1항 내지 제8항에 따른 질산염들의 제조방법.
- 제13항에 있어서, 물질이 잘 용해되지 않거나, 상기 언급한 용매들에서 잘 용해되지 않는 염으로서 이용가능할 때, 히드록시화된 용매들과의 해당 혼합물들이 사용되고, 침전은, 질산의 첨가후 이렇게 얻어진 혼합물을 비극성용매로 희석하여 촉진되는 질산염들의 제조방법.
- 제13항 및 제14항에 있어서, 출발물질이 염산으로 염화될 때, 질산염은 화합물용액에 질산은을 직접 첨가하고, 염화은을 여과하여 제조되고, 질산염을 회수하기 위해 용액이 농축되고 냉각되는 질산염들의 제조방법
- 출발물질이 염일때, 해당염기가 중탄산 또는 탄산 나트륨 또는 칼륨 포화용액, 또는 수산화 나트륨 또는 칼륨 희석용액 처리에 의해 유리되고, 적절한 유기용매에 의해 염기를 추출하고, 제13항 또는 제14항에서 지시된 질산염을 제조하기 위한 방법에 따르는 제1항 내지 제8항에 따른 질산염들의 제조방법.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ITMI98A001408 | 1998-06-19 | ||
IT1998MI001408A IT1301759B1 (it) | 1998-06-19 | 1998-06-19 | Sali nitrati di farmaci antiipertensivi |
Publications (2)
Publication Number | Publication Date |
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KR20010093631A true KR20010093631A (ko) | 2001-10-29 |
KR100460714B1 KR100460714B1 (ko) | 2004-12-09 |
Family
ID=11380283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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KR10-2000-7014179A KR100460714B1 (ko) | 1998-06-19 | 1999-06-15 | 항고혈압제의 질산염 |
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US (2) | US6645965B1 (ko) |
EP (1) | EP1087953B1 (ko) |
JP (1) | JP2002518492A (ko) |
KR (1) | KR100460714B1 (ko) |
CN (1) | CN1315945A (ko) |
AT (1) | ATE282600T1 (ko) |
AU (1) | AU770387B2 (ko) |
BR (1) | BR9911305A (ko) |
CA (1) | CA2335356A1 (ko) |
DE (1) | DE69922001T2 (ko) |
ES (1) | ES2234265T3 (ko) |
HU (1) | HUP0102719A3 (ko) |
IL (1) | IL139226A0 (ko) |
IT (1) | IT1301759B1 (ko) |
RU (1) | RU2235097C2 (ko) |
WO (1) | WO1999067231A1 (ko) |
ZA (1) | ZA200006136B (ko) |
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IT1318674B1 (it) * | 2000-08-08 | 2003-08-27 | Nicox Sa | Faramaci per l'incontinenza. |
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WO2005077374A1 (en) * | 2004-02-06 | 2005-08-25 | Becton, Dickinson And Company | Formulations of phosphodiesterase 5 inhibitors and methods of use |
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-
1998
- 1998-06-19 IT IT1998MI001408A patent/IT1301759B1/it active IP Right Grant
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1999
- 1999-06-15 RU RU2000131690/04A patent/RU2235097C2/ru not_active IP Right Cessation
- 1999-06-15 WO PCT/EP1999/004138 patent/WO1999067231A1/en active IP Right Grant
- 1999-06-15 EP EP99927990A patent/EP1087953B1/en not_active Expired - Lifetime
- 1999-06-15 IL IL13922699A patent/IL139226A0/xx unknown
- 1999-06-15 US US09/719,164 patent/US6645965B1/en not_active Expired - Fee Related
- 1999-06-15 KR KR10-2000-7014179A patent/KR100460714B1/ko not_active IP Right Cessation
- 1999-06-15 ES ES99927990T patent/ES2234265T3/es not_active Expired - Lifetime
- 1999-06-15 HU HU0102719A patent/HUP0102719A3/hu unknown
- 1999-06-15 CN CN99807516A patent/CN1315945A/zh active Pending
- 1999-06-15 DE DE69922001T patent/DE69922001T2/de not_active Expired - Fee Related
- 1999-06-15 AT AT99927990T patent/ATE282600T1/de not_active IP Right Cessation
- 1999-06-15 AU AU45139/99A patent/AU770387B2/en not_active Ceased
- 1999-06-15 CA CA002335356A patent/CA2335356A1/en not_active Abandoned
- 1999-06-15 JP JP2000555885A patent/JP2002518492A/ja active Pending
- 1999-06-15 BR BR9911305-8A patent/BR9911305A/pt not_active IP Right Cessation
-
2000
- 2000-10-30 ZA ZA200006136A patent/ZA200006136B/en unknown
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Also Published As
Publication number | Publication date |
---|---|
US6645965B1 (en) | 2003-11-11 |
WO1999067231A1 (en) | 1999-12-29 |
EP1087953B1 (en) | 2004-11-17 |
KR100460714B1 (ko) | 2004-12-09 |
AU4513999A (en) | 2000-01-10 |
HUP0102719A2 (hu) | 2001-12-28 |
US20040147575A1 (en) | 2004-07-29 |
IL139226A0 (en) | 2001-11-25 |
EP1087953A1 (en) | 2001-04-04 |
RU2235097C2 (ru) | 2004-08-27 |
IT1301759B1 (it) | 2000-07-07 |
AU770387B2 (en) | 2004-02-19 |
ITMI981408A1 (it) | 1999-12-19 |
HUP0102719A3 (en) | 2002-11-28 |
DE69922001T2 (de) | 2005-11-03 |
DE69922001D1 (de) | 2004-12-23 |
JP2002518492A (ja) | 2002-06-25 |
CN1315945A (zh) | 2001-10-03 |
CA2335356A1 (en) | 1999-12-29 |
ATE282600T1 (de) | 2004-12-15 |
ES2234265T3 (es) | 2005-06-16 |
BR9911305A (pt) | 2001-10-23 |
ZA200006136B (en) | 2002-01-30 |
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