KR20100054098A - Pharmaceutical composition for the treatment and prevention of cardiac diseases caused by ischemia or ischemic reperfusion - Google Patents
Pharmaceutical composition for the treatment and prevention of cardiac diseases caused by ischemia or ischemic reperfusion Download PDFInfo
- Publication number
- KR20100054098A KR20100054098A KR1020090108399A KR20090108399A KR20100054098A KR 20100054098 A KR20100054098 A KR 20100054098A KR 1020090108399 A KR1020090108399 A KR 1020090108399A KR 20090108399 A KR20090108399 A KR 20090108399A KR 20100054098 A KR20100054098 A KR 20100054098A
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- ischemia
- pharmaceutical composition
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 208000028867 ischemia Diseases 0.000 title claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 230000010410 reperfusion Effects 0.000 title claims abstract description 29
- 208000019622 heart disease Diseases 0.000 title claims abstract description 20
- 238000011282 treatment Methods 0.000 title claims abstract description 17
- 230000002265 prevention Effects 0.000 title claims abstract description 11
- 230000000302 ischemic effect Effects 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 239000003085 diluting agent Substances 0.000 claims abstract description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- 239000003937 drug carrier Substances 0.000 claims abstract description 6
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 206010003119 arrhythmia Diseases 0.000 claims description 11
- 230000006793 arrhythmia Effects 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 230000000747 cardiac effect Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 206010049993 Cardiac death Diseases 0.000 claims description 3
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 3
- 206010011906 Death Diseases 0.000 claims description 3
- 208000021908 Myocardial disease Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 208000019553 vascular disease Diseases 0.000 claims description 3
- 208000020446 Cardiac disease Diseases 0.000 claims description 2
- 208000001871 Tachycardia Diseases 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 230000004217 heart function Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000006794 tachycardia Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims 1
- -1 naphthoquinone compound Chemical class 0.000 description 16
- 206010047302 ventricular tachycardia Diseases 0.000 description 16
- 239000002253 acid Substances 0.000 description 14
- 238000007363 ring formation reaction Methods 0.000 description 14
- 208000003663 ventricular fibrillation Diseases 0.000 description 14
- 201000010099 disease Diseases 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 229930192627 Naphthoquinone Natural products 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 210000002216 heart Anatomy 0.000 description 8
- 208000031225 myocardial ischemia Diseases 0.000 description 8
- 210000001367 artery Anatomy 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000002861 ventricular Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 210000004351 coronary vessel Anatomy 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- CSFWPUWCSPOLJW-UHFFFAOYSA-N lawsone Chemical compound C1=CC=C2C(=O)C(O)=CC(=O)C2=C1 CSFWPUWCSPOLJW-UHFFFAOYSA-N 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 238000005698 Diels-Alder reaction Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000002791 naphthoquinones Chemical class 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QZPQTZZNNJUOLS-UHFFFAOYSA-N beta-lapachone Chemical compound C12=CC=CC=C2C(=O)C(=O)C2=C1OC(C)(C)CC2 QZPQTZZNNJUOLS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 206010058156 Reperfusion arrhythmia Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001345 alkine derivatives Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 231100000518 lethal Toxicity 0.000 description 3
- 230000001665 lethal effect Effects 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229960004889 salicylic acid Drugs 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- HARGZZNYNSYSGJ-UHFFFAOYSA-N 1,2 dihydrotanshinquinone Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)CO1 HARGZZNYNSYSGJ-UHFFFAOYSA-N 0.000 description 2
- KETQAJRQOHHATG-UHFFFAOYSA-N 1,2-naphthoquinone Chemical class C1=CC=C2C(=O)C(=O)C=CC2=C1 KETQAJRQOHHATG-UHFFFAOYSA-N 0.000 description 2
- OWRQRCNVZWAHAJ-UHFFFAOYSA-N 1-benzofuran-4,5-dione Chemical compound O=C1C(=O)C=CC2=C1C=CO2 OWRQRCNVZWAHAJ-UHFFFAOYSA-N 0.000 description 2
- XWPLFOWMVZGBOX-UHFFFAOYSA-N 2,3,3-trimethyl-2h-benzo[f][1]benzofuran-4,9-dione Chemical compound C1=CC=C2C(=O)C(OC(C3(C)C)C)=C3C(=O)C2=C1 XWPLFOWMVZGBOX-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 2
- YMSAOSLQCLYDGK-UHFFFAOYSA-N 3-methylidenenaphthalene-1,2,4-trione Chemical compound C1=CC=C2C(=O)C(=C)C(=O)C(=O)C2=C1 YMSAOSLQCLYDGK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- 238000005821 Claisen rearrangement reaction Methods 0.000 description 2
- GVKKJJOMQCNPGB-JTQLQIEISA-N Cryptotanshinone Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1[C@@H](C)CO2 GVKKJJOMQCNPGB-JTQLQIEISA-N 0.000 description 2
- GVKKJJOMQCNPGB-UHFFFAOYSA-N Cryptotanshinone Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)CO2 GVKKJJOMQCNPGB-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- WGENOABUKBFVAA-UHFFFAOYSA-N Dunnione Chemical compound C1=CC=C2C(OC(C3(C)C)C)=C3C(=O)C(=O)C2=C1 WGENOABUKBFVAA-UHFFFAOYSA-N 0.000 description 2
- 206010015856 Extrasystoles Diseases 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 208000009729 Ventricular Premature Complexes Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 238000007887 coronary angioplasty Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 230000000250 revascularization Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- SDRZFSPCVYEJTP-UHFFFAOYSA-N 1-ethenylcyclohexene Chemical class C=CC1=CCCCC1 SDRZFSPCVYEJTP-UHFFFAOYSA-N 0.000 description 1
- BMYZFVWZCNCJFG-UHFFFAOYSA-N 2-prop-2-enoxycyclohexa-2,5-diene-1,4-dione Chemical compound C=CCOC1=CC(=O)C=CC1=O BMYZFVWZCNCJFG-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- LCSKNASZPVZHEG-UHFFFAOYSA-N 3,6-dimethyl-1,4-dioxane-2,5-dione;1,4-dioxane-2,5-dione Chemical group O=C1COC(=O)CO1.CC1OC(=O)C(C)OC1=O LCSKNASZPVZHEG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YYVYAPXYZVYDHN-UHFFFAOYSA-N 9,10-phenanthroquinone Chemical compound C1=CC=C2C(=O)C(=O)C3=CC=CC=C3C2=C1 YYVYAPXYZVYDHN-UHFFFAOYSA-N 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 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 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 206010048858 Ischaemic cardiomyopathy Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 125000005631 S-sulfonamido group Chemical group 0.000 description 1
- 241000520680 Streptocarpus dunnii Species 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241001530102 Tabebuia Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229930187284 avellanedae Natural products 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 229950009941 chloralose Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- LDLDYFCCDKENPD-UHFFFAOYSA-N ethenylcyclohexane Chemical class C=CC1CCCCC1 LDLDYFCCDKENPD-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000876 intercostal muscle Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 1
- 229960003379 pancuronium bromide Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61P9/10—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)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
본 발명은 (a) 약리학적 유효량의 화학식 1 또는 2의 화합물, 약제학적으로 허용되는 그것의 염, 프로드럭, 용매화물 또는 이성질체, 및 (b) 약제학적으로 허용되는 담체, 희석제, 또는 부형제, 또는 이들의 조합을 포함하는, 허혈 또는 허혈 재관류에 의해 유발되는 심장질환의 치료 및 예방용 약제 조성물을 제공한다.The present invention provides a pharmaceutical composition comprising (a) a pharmaceutically effective amount of a compound of Formula 1 or 2, a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, and (b) a pharmaceutically acceptable carrier, diluent, or excipient, Or it provides a pharmaceutical composition for the treatment and prevention of heart disease caused by ischemia or ischemia reperfusion, including a combination thereof.
Description
본 발명은 허혈 또는 허혈 재관류에 의해 유발되는 심장질환의 치료 및 예방을 위한 약제 조성물에 관한 것으로서, (a) 약리학적 유효량의 나프토퀴논계 화합물, 약제학적으로 허용되는 그것의 염, 프로드럭, 용매화물 또는 이성질체, 및 (b) 약제학적으로 허용되는 담체, 희석제, 또는 부형제, 또는 이들의 조합을 통해 심장질환의 치료 및 예방에 우수한 효과를 나타낸다. The present invention relates to a pharmaceutical composition for the treatment and prevention of heart disease caused by ischemia or ischemia reperfusion, comprising: (a) a pharmacologically effective amount of a naphthoquinone compound, a pharmaceutically acceptable salt thereof, a prodrug, a solvent Cargoes or isomers, and (b) pharmaceutically acceptable carriers, diluents, or excipients, or combinations thereof, have excellent effects in the treatment and prevention of heart disease.
허혈 또는 허혈 재관류에 의해 유발되는 심장질환으로서는, 특히 심근경색이나 협심증 등의 급성 관질환에 의해 발생되는 심장질환 이벤트나 심장사가 알려져 있지만, 그 예후가 좋지 않은 경우가 적지 않다. 이들 질환에 대한 약물 치료는, 혈압 조절, 혈전 용해 등 혈행 동태의 조절이나 그 확보에 한정되고, 심장 혹은 심근을 보호하기 위한 근본적인 치료약이 없는 것이 현실이다. Heart diseases caused by ischemia or ischemia reperfusion are known as cardiac disease events or cardiac death caused by acute vascular diseases such as myocardial infarction and angina pectoris, but the prognosis is not good. Drug treatment for these diseases is limited to the regulation and securing of blood circulation dynamics such as blood pressure control and thrombolysis, and there is no fundamental therapeutic drug for protecting the heart or myocardium.
관동맥 질환은 해마다 증가하고 있고 이에 따라 허혈성 심질환에 대한 관혈행 재건방법도 다각도로 모색되고 있는데, 허혈성 심질환에 대한 관혈행 재건의 방 법에는 내과적 치료법인 경피적 관동맥 형성술 (PTCA)과 외과 수술에 의한 관동맥 바이패스술 (CABG)이 있다. 이들의 목적은 심근 경색에의 진전 및 돌연사의 예방, 생명 예후의 개선인데, PTCA에 의한 재관류 요법은 유효하다고 되어 있지만, 조기에 재협착, 재경색이 발현하는 것이 많다. 말기적 허혈성 심근증에 이르면 심장 이식이 적용되지만, 통상 이식은 매우 어렵고 세계적으로도 심장 이식에서의 기증자 부족은 심각한 상황이다. 특히, 동물실험이나 임상보고를 통해 여러 가지 형태로 알려진 바 있는 재관류 부정맥(reperfusion-induced arrhythmias)은 심장수술이나 관상동맥 성형술 및 혈전용해제를 이용한 치료방법이 개발, 임상 적용되는 사례가 증가하여 그 발생빈도가 현저히 증가할 뿐만 아니라, 관상동맥이 갑자기 수축하였다가 이완하는 경우 심실세동과 같은 치명적 부정맥에 의해 급사하는 경우도 있어 관심의 대상이 되고 있다. 따라서, 환자의 안전을 전제한 새로운 재관류 항부정맥제의 개발이 절실히 요구되고 있다.Coronary artery disease is increasing year by year, and thus, revascularization of ischemic heart disease is being sought from various angles. The method of revascularization of ischemic heart disease is based on the medical treatment of percutaneous coronary angioplasty (PTCA) and surgery. Coronary artery bypass surgery (CABG). Their purpose is to progress to myocardial infarction, to prevent sudden death, and to improve life prognosis. Although reperfusion therapy by PTCA is said to be effective, there are many cases of early restenosis and reinfarction. Although cardiac transplantation is applied to terminally ischemic cardiomyopathy, transplantation is usually very difficult and globally donor shortages in heart transplantation are a serious situation. In particular, reperfusion-induced arrhythmias, which have been known in various forms through animal experiments or clinical reports, have been developed due to the increasing number of clinical applications and treatments using cardiac surgery, coronary angioplasty and thrombolytics. In addition to a significant increase in frequency, when the coronary artery suddenly contracts and relaxes, it may be suddenly caused by fatal arrhythmias such as ventricular fibrillation. Therefore, there is an urgent need for the development of a new reperfusion antiarrhythmic agent on the premise of patient safety.
이에, 본 발명자들은 특정한 나프토퀴논계 화합물이 허혈 또는 허혈 재관류에 의해 유발되는 심장질환, 특히 허혈 또는 재관류로 인한 부정맥 및 심근경색과 관련하여 탁월한 예방 및 치료 효과를 발휘할 수 있음을 발견하였다.Accordingly, the present inventors have found that certain naphthoquinone compounds can exert excellent prophylactic and therapeutic effects in connection with cardiac diseases caused by ischemia or ischemia reperfusion, especially arrhythmia and myocardial infarction due to ischemia or reperfusion.
한편, 종래 나프토퀴논계 화합물들을 유효 성분으로 하는 약제 조성물은 일부 알려져 있는데, 그 중 β-lapachone은 남미에서 자생하는 라파초(laphacho) 나무(Tabebuia avellanedae)에서, dunnione과 α-dunnione 또한 남미에서 자생하는 Streptocarpus dunnii의 잎에서 얻어진다. 이들 천연의 tricyclic naphthoquinone 유도체들은 남미 지역에서는 오래 전부터 항암제를 비롯하여 남미 지역의 대표적인 풍토병인 샤가스병(Chagas disease)을 치료하기 위한 약으로 널리 사용되었고, 그 효과 또한 뛰어난 것으로 알려져 있다. 특히, 이들의 항암제로서의 약리 작용이 서방세계에 알려지기 시작하면서 사람들의 주목을 받기 시작했고, US 5,969,163에 개시되어 있는 바와 같이 이들 tricyclic naphtoquinone 유도체들은 실제로 다양한 연구 집단에 의해서 각종 항암제로 개발되고 있다.Meanwhile, some conventional pharmaceutical compositions containing naphthoquinone-based compounds as active ingredients are known, among which β-lapachone is grown in the Laphacho tree (Tabebuia avellanedae), which grows in South America, and dunnione and α-dunnione also grow in South America. Is obtained from the leaves of Streptocarpus dunnii. These natural tricyclic naphthoquinone derivatives have long been widely used in South America as a medicine for treating Chagas disease, which is a representative endemic disease in South America, including anticancer drugs. In particular, their pharmacological action as an anticancer agent began to be known in the West, and people began to attract attention, and as described in US Pat. No. 5,969,163, these tricyclic naphtoquinone derivatives are actually being developed into various anticancer agents by various research groups.
그러나, 각종 연구에도 불구하고 이들 나프토퀴논계 화합물들이 허혈 또는 허혈 재관류에 의해 유발되는 심장질환, 특히 허혈 또는 재관류로 인한 부정맥과 관련하여 탁월한 약리학적 효능을 가진다는 사실은 아직 알려져 있지 않은 실정이다. However, despite various studies, it is not known that these naphthoquinone compounds have excellent pharmacological efficacy in relation to cardiac diseases caused by ischemia or ischemia reperfusion, especially arrhythmias caused by ischemia or reperfusion.
본 출원의 발명자들은 다양한 연구와 실험을 거듭한 끝에, 소정의 나프토퀴논계 화합물이 허혈 및 허혈 재관류로 인한 심장질환의 치료 또는 예방에 사용될 수 있음을 새롭게 확인하고, 본 발명을 완성하였다.After various studies and experiments, the inventors of the present application newly confirmed that certain naphthoquinone-based compounds can be used for the treatment or prevention of heart disease due to ischemia and ischemia reperfusion, and completed the present invention.
따라서, 본 발명에 따른 허혈 또는 허혈 재관류에 의해 유발되는 심장질환의 치료 및 예방용 약제 조성물은, (a) 약리학적 유효량의 화학식 1 및 2 중에서 선택된 하나 또는 그 이상의 화합물, 약제학적으로 허용되는 그것의 염, 프로드럭, 용매화물 또는 이성질체, 및 (b) 약제학적으로 허용되는 담체, 희석제, 또는 부형제, 또는 이들의 조합을 포함하는 것으로 구성되어 있다.Accordingly, the pharmaceutical composition for the treatment and prevention of heart disease caused by ischemia or ischemia reperfusion according to the present invention comprises (a) a pharmacologically effective amount of one or more compounds selected from Formulas 1 and 2, pharmaceutically acceptable Salts, prodrugs, solvates or isomers thereof, and (b) pharmaceutically acceptable carriers, diluents, or excipients, or combinations thereof.
상기 식에서, Where
R1 및 R2는 각각 독립적으로 수소, 할로겐, 히드록시 또는 탄소수 1~6의 저급알킬 또는 알콕시이고, 또는 R1 및 R2가 상호 연결되어 치환 또는 비치환의 환구조를 이룰 수 있으며, 여기서 환형 구조는 포화 구조 또는 부분적 또는 전체적 불포화 구조일 수 있고;R 1 and R 2 are each independently hydrogen, halogen, hydroxy or lower alkyl or alkoxy having 1 to 6 carbon atoms, or R 1 and R 2 may be connected to each other to form a substituted or unsubstituted ring structure, wherein the cyclic The structure may be a saturated structure or a partially or fully unsaturated structure;
R3, R4, R5, R6, R7 및 R8는 각각 독립적으로 수소, 히드록시, 탄소수 1 ~ 20의 알킬, 알켄 또는 알콕시, 탄소수 4 ~ 20의 시클로알킬, 헤테로시클로알킬, 아릴 또는 헤테로아릴이고, 또는 이들 중 두 개의 치환기가 상호 결합에 의해 환형 구조를 이룰 수 있으며, 여기서 환형 구조는 포화 구조 또는 부분적 또는 전체적 불포화 구조일 수 있고;R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are Each independently hydrogen, hydroxy, alkyl having 1 to 20 carbon atoms, alkene or alkoxy, cycloalkyl having 4 to 20 carbon atoms, heterocycloalkyl, aryl or heteroaryl, or two of these substituents are cyclically bonded Wherein the cyclic structure can be a saturated structure or a partially or totally unsaturated structure;
X는 C(R)(R'), N(R"), O 및 S로 이루어진 군에서 선택되고, 바람직하게는 O 또는 S이고, 더욱 바람직하게는 O이며, 여기서 R, R' 및 R"는 각각 독립적으로 수소 또는 탄소수 1~6의 저급알킬이며;X is selected from the group consisting of C (R) (R '), N (R "), O and S, preferably O or S, more preferably O, where R, R' and R" Are each independently hydrogen or lower alkyl having 1 to 6 carbon atoms;
Y는 C, S 또는 N이고, 여기서 Y가 S인 경우 R7 및 R8는 어떠한 치환기도 아니며, N인 경우 R7은 수소 또는 탄소수 1 ~ 6의 저급알킬이고, R8은 어떠한 치환기도 아니며;Y is C, S or N, where R 7 and R 8 when Y is S No substituent, and when N, R 7 is hydrogen or lower alkyl of 1 to 6 carbon atoms, and R 8 is not any substituent;
n은 0 또는 1이고, n이 0인 경우에 그것의 인접 탄소원자들은 직접결합에 의해 환형 구조를 이룬다.n is 0 or 1, and when n is 0, its adjacent carbon atoms form a cyclic structure by direct bond.
본 발명에 따른 약제 조성물의 심장질환 치료 효과를 확인하기 위하여 본 발명자들이 수행한 실험에 따르면, 심장질환을 유도한 동물 실험에서 심실조기박동, 심실빈맥, 심실세동 등의 발생빈도를 현저히 줄이고, 관상동맥의 재관류에 의해 유발되는 치명적인 심실빈맥과 심실세동을 효과적으로 완화하여 재관류로 인한 부정맥 발생 빈도를 유의적으로 감소시킬 뿐만 아니라, 허혈성 심근경색에 효과적임을 입증함으로써, 허혈 또는 허혈 재관류에 의해 유발되는 심장질환에 유효한 치료효과가 있음을 확인하였다.According to experiments performed by the present inventors to confirm the therapeutic effect of the pharmaceutical composition of the present invention, significantly reduced the incidence of ventricular rhythm, ventricular tachycardia, ventricular fibrillation, etc. in animal experiments inducing heart disease, coronary Cardiac induced by ischemia or ischemia reperfusion by effectively alleviating lethal ventricular tachycardia and ventricular fibrillation caused by reperfusion of the arteries, which not only significantly reduces the incidence of arrhythmia due to reperfusion, but also proves effective for ischemic myocardial infarction. It was confirmed that there is an effective therapeutic effect on the disease.
용어 "약제학적으로 허용되는 염"이란 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는, 화합물의 제형을 의미한다. 상기 약제학적 염은, 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수고산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트 산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약제학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르지닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸)메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 화학식 1 및 2의 화합물은 통상적인 방법에 의해 그것의 염으로 전환시킬 수도 있다. The term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, tartaric acid, formic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like. Organic carbonic acid, such as citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Acid addition salts formed by sulfonic acids and the like, and the like. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N Organic salts such as -methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine and the like. The compounds of the formulas (1) and (2) according to the invention can also be converted to their salts by conventional methods.
용어 "프로드럭(prodrug)"이란 생체내에서 모 약제(parent drug)로 변형되는 물질을 의미한다. 프로드럭은 모 약제보다 투여하기 쉽기 때문에 종종 사용된다. 예를 들어, 이들은 구강 투여에 의해 생활성을 얻을 수 있음에 반하여, 모 약제는 그렇지 못할 수 있다. 프로드럭은 또한 모 약제보다 제약 조성물에서 향상된 용해도를 가질 수도 있다. 예를 들어, 프로드럭은, 수용해도가 이동성에 해가 되지만, 일단 수용해도가 이로운 세포에서는, 물질대사에 의해 활성체인 카르복실산으로 가수분해되는, 세포막의 통과를 용이하게 하는 에스테르("프로드럭")로서 투여되는 화합물일 것이다. 프로드럭의 또 다른 예는 펩티드가 활성 부위를 드러내도록 물질대사에 의해 변환되는 산기에 결합되어 있는 짧은 펩티드(폴리아미노 산)일 수 있다.The term "prodrug" refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. For example, prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, once the water solubility is detrimental to mobility, but once the water solubility is beneficial. Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism to reveal the active site.
이러한 프로드럭의 예로서, 본 발명에 따른 약제 조성물은 활성성분으로서 하기 화학식 1a의 프로드럭을 포함할 수 있다.As an example of such a prodrug, the pharmaceutical composition according to the present invention may include a prodrug of Formula 1a as an active ingredient.
상기 식에서,Where
R1, R2, R3, R4, R5, R6, R7, R8, X 및 n은 화학식 1에서와 동일하고;R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and n are the same as in formula (1);
R9 및 R10은 각각 독립적으로 -SO3 -Na+이거나 또는 하기 화학식 A로 표현되는 치환체 또는 이의 염이며, R 9 and R 10 are each independently a -SO 3 -, and the substituent or a salt thereof represented by the formula or Na + or A,
상기 식에서, Where
R11 및 R12는 각각 독립적으로 수소 또는 치환 또는 비치환의 선형 또는 가지형 C1~C20 알킬이고, R 11 and R 12 are each independently hydrogen or substituted or unsubstituted linear or branched C 1 -C 20 alkyl,
R13은 하기 치환체 i) 내지 viii)로 이루어진 군에서 선택되며,R 13 is selected from the group consisting of the following substituents i) to viii),
i) 수소;i) hydrogen;
ii) 치환 또는 비치환의 선형 또는 가지형 C1~C20 알킬;ii) substituted or unsubstituted linear or branched C 1 -C 20 alkyl;
iii) 치환 또는 비치환의 아민; iii) substituted or unsubstituted amines;
iv) 치환 또는 비치환의 C3~C10 시클로알킬 또는 C3~C10 헤테로시클로알킬; iv) substituted or unsubstituted C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl;
v) 치환 또는 비치환의 C4~C10 아릴 또는 C4~C10 헤테로아릴;v) substituted or unsubstituted C 4 -C 10 aryl or C 4 -C 10 heteroaryl;
vi) -(CRR'-NR"CO)l-R14, 여기서, R, R' 및 R"는 각각 독립적으로 수소 또는 치환 또는 비치환의 선형 또는 가지형의 C1~C20 알킬이고, R14는 수소, 치환 또는 비치환의 아민, 시클로알킬, 헤테로시클로알킬, 아릴 및 헤테로아릴로 이루어진 군에서 선택될 수 있고, l은 1~5 중에서 선택되며;vi)-(CRR'-NR "CO) l- R 14 , wherein R, R 'and R" are each independently hydrogen or substituted or unsubstituted linear or branched C 1 -C 20 alkyl, R 14 May be selected from the group consisting of hydrogen, substituted or unsubstituted amine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and l is selected from 1-5;
vii) 치환 또는 비치환의 카르복실;vii) substituted or unsubstituted carboxyl;
viii) -OSO3 -Na+;viii) -OSO 3 - Na + ;
k는 0~20 중에서 선택되고, k가 0인 경우, R11 및 R12는 존재하지 않고 R13은 카르보닐기에 직접 결합된다. k is selected from 0-20, and when k is 0, R <11> and R <12> does not exist and R <13> is couple | bonded directly with the carbonyl group.
용어 "용매화물(solvate)"이란, 비공유적 분자 사이의 힘(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric)인 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있으며, 상기 용매가 물인 경우 이는 수화 물(hydrate)을 의미한다.The term "solvate" includes a stoichiometric or non-stoichiometric amount of solvent bound by a non-covalent intermolecular force. Means a compound of the present invention or a salt thereof. Preferred solvents therein are solvents which are volatile, non-toxic, and / or suitable for administration to humans, when the solvent is water, meaning hydrate.
용어 "이성질체(isomer)"란, 동일한 화학식 또는 분자식을 가지지만 광학적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다.The term "isomer" means a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula, but which is optically or stericly different.
이하에서 별도의 설명이 없는 한, 용어 "화학식 1의 화합물"은, 화합물 그 자체, 약제학적으로 허용되는 그것의 염, 프로드럭, 용매화물 및 이성질체를 모두 포함하는 개념으로 사용되고 있다.Unless stated otherwise, the term "compound of formula 1" is used in the concept including the compound itself, pharmaceutically acceptable salts, prodrugs, solvates and isomers thereof.
용어 "알킬(alkyl)"은 지방족 탄화수소 그룹을 의미한다. 본 발명에서 알킬은 어떠한 알켄이나 알킨 부위를 포함하고 있지 않음을 의미하는 "포화 알킬(saturated alkyl)"과, 적어도 하나의 알켄 또는 알킨 부위를 포함하고 있음을 의미하는 "불포화 알킬(unsaturated alkyl)"을 모두 포함하는 개념으로 사용되고 있다. "알켄(alkene)" 부위는 적어도 두 개의 탄소원자가 적어도 하나의 탄소-탄소 이중 결합으로 이루어진 그룹을 의미하며, "알킨(alkyne)"은 부위는 적어도 두 개의 탄소원자가 적어도 하나의 탄소-탄소 삼중 결합으로 이루어진 그룹을 의미한다. 상기 알킬은 분지형, 직쇄형 또는 환형일 수 있으며, 치환 또는 비치환 구조일 수 있다.The term "alkyl" refers to an aliphatic hydrocarbon group. In the present invention, alkyl means "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety, and "unsaturated alkyl" means that it contains at least one alkene or alkyne moiety. It is used as a concept that includes all of them. "Alkene" moiety means a group of at least two carbon atoms consisting of at least one carbon-carbon double bond, and "alkyne" is a moiety wherein at least two carbon atoms contain at least one carbon-carbon triple bond Means a group consisting of. The alkyl may be branched, straight chain or cyclic, and may be substituted or unsubstituted.
용어 "헤테로시클로알킬(heterocycloalky)"은 환 탄소가 산소, 질소, 황 등으로 치환되어 있는 치환체로서, 예를 들어, 퓨란, 티오펜, 피롤, 피롤린, 피롤리딘, 옥사졸, 티아졸, 이미다졸, 이미다졸린, 이미다졸리딘, 피라졸, 피라졸린, 피라졸리딘, 이소티아졸, 트리아졸, 티아디아졸, 피란, 피리딘, 피퍼리딘, 모르포린, 티오모르포린, 피리다진, 피리미딘, 피라진, 피퍼라진, 트리아진 등을 들 수 있지 만, 이들만으로 한정되는 것은 아니다.The term "heterocycloalky" is a substituent in which the ring carbon is substituted with oxygen, nitrogen, sulfur, and the like, for example, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, Imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, Pyrimidine, pyrazine, piperazine, triazine, etc. are mentioned, but it is not limited to these.
용어 "아릴(aryl)"은 공유 파이 전자계를 가지고 있는 적어도 하나의 링을 가지고 있고 카르보시클릭 아릴(예를 들어, 페닐)과 헤테로시클릭 아릴기(예를 들어, 피리딘)를 포함하는 방향족치환체를 의미한다. 상기 용어는 모노시클릭 또는 융합 링 폴리시클릭(즉, 탄소원자들의 인접한 쌍들을 나눠 가지는 링들) 그룹들을 포함한다.The term "aryl" refers to an aromatic substituent having at least one ring having a shared pi electron system and comprising a carbocyclic aryl (eg phenyl) and a heterocyclic aryl group (eg pyridine) Means. The term includes monocyclic or fused ring polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups.
용어 "헤테로아릴(heteroaryl)"은 적어도 하나의 헤테로시클릭 환을 포함하고 있는 방향족 그룹을 의미한다. The term "heteroaryl" refers to an aromatic group containing at least one heterocyclic ring.
상기 아릴 또는 헤테로아릴의 예로는 페닐, 퓨란, 피란, 피리딜, 피리미딜, 트리아질 등을 들 수 있지만, 이들만으로 한정되는 것은 아니다.Examples of the aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, and the like.
본 발명에 따른 화학식 1에서 R1, R2, R3, R4, R5, R6, R7 및 R8는 임의적으로 치환된 구조일 수 있으며, 그러한 치환체들의 예로는 시클로알킬, 아릴, 헤테로아릴, 헤테로알리시클릭, 히드록시, 알콕시, 아릴옥시, 메르켑토, 알킬티오, 아릴티오, 시아노, 할로겐, 카르보닐, 티오카르보닐, O-카르바밀, N-카르바밀, O-티오카르바밀, N-티오카르바밀, C-아미도, N-아미도, S-술폰아미도, N-술폰아미도, C-카르복시, O-카르복시, 이소시아네이토, 티오시아네이토, 이소티오시아네이토, 니트로, 시릴, 트리할로메탄술포닐, 모노- 및 디-치환 아미노 그룹들을 포함한 아미노, 및 이들의 보호 유도체들로부터 개별적으로 그리고 독립적으로 선택된 하나 또는 그 이상의 치환체 등을 들 수 있다.In Formula 1 according to the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be an optionally substituted structure, and examples of such substituents include cycloalkyl, aryl, Heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thio Carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, iso One or more substituents individually and independently selected from thiocyanato, nitro, cyryl, trihalomethanesulfonyl, amino including mono- and di-substituted amino groups, and protective derivatives thereof, and the like. have.
상기 화학식 1의 화합물들 중 바람직한 예로는 하기 화학식 3 내지 5의 화합물일 수 있다.Preferred examples of the compound of Formula 1 may be a compound of Formulas 3 to 5.
하기 화학식 3의 화합물은 n이 0이면서 인접 탄소원자들이 직접 결합에 의해 환형 구조(furan 고리)를 형성하는 화합물로서, 이하에서는 때때로 '퓨란 화합물' 또는 'furano-o-naphthoquinone 유도체'로 칭하기도 한다.The compound of formula 3 is a compound in which n is 0 and adjacent carbon atoms form a cyclic structure (furan ring) by direct bonding, sometimes referred to as 'furan compound' or 'furano-o-naphthoquinone derivative' .
하기 화학식 4의 화합물은 n이 1인 화합물로서, 이하에서는 때때로 '피란(pyran) 화합물' 또는 'pyrano-o-naphthoquinone'로 칭하기도 한다.The compound of formula 4 is n is 1, hereinafter sometimes referred to as 'pyran compound' or 'pyrano-o-naphthoquinone'.
상기 화학식 4에서 R1 및 R2 는 특히 바람직하게는 각각 수소이다.In Formula 4, R 1 and R 2 are particularly preferably hydrogen.
상기 화학식 3의 퓨란 화합물들 중에서 특히 바람직한 예로는, R1, R2 및 R4가 각각 수소인 하기 화학식 3a의 화합물, 또는 R1, R2 및 R6가 각각 수소인 하기 화학식 3b의 화합물을 들 수 있다.Particularly preferred examples of the furan compounds of Formula 3 include a compound of Formula 3a, wherein R 1 , R 2, and R 4 are each hydrogen, or a compound of Formula 3b, wherein R 1 , R 2, and R 6 are each hydrogen: Can be mentioned.
또한, 상기 화학식 4의 피란 화합물들 중 특히 바람직한 예로는 R1, R2, R5, R6, R7 및 R8이 각각 수소인 하기 화학식 4a의 화합물을 들 수 있다.In addition, particularly preferred examples of the pyran compounds of the formula (4) include a compound of formula (4a) wherein R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each hydrogen.
또한, 상기 화학식 2의 화합물들 중 바람직한 예로는 하기 화학식 2a 및 2b의 화합물일 수 있으나 이것만으로 한정되는 것은 아니다.In addition, preferred examples of the compounds of Formula 2 may be, but are not limited to, compounds of Formulas 2a and 2b.
하기 화학식 2a의 화합물은 n이 0이면서 인접 탄소원자들이 직접 결합에 의해 환형 구조를 형성하고 Y가 C인 화합물이다. The compound of Formula 2a is a compound in which n is 0 and adjacent carbon atoms form a cyclic structure by direct bond, and Y is C.
하기 화학식 2b의 화합물은 화학식 2에서 n이 1이고 Y가 C인 화합물이다.The compound of Formula 2b is a compound wherein n is 1 and Y is C in Formula 2.
상기 식 2a 또는 2b에서, R1, R2, R3, R4, R5, R6, R7, R8 및 X는 화학식 2에서 정의된 바와 동일하다.In Formula 2a or 2b, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and X are the same as defined in Formula 2.
본 발명에서 심장질환의 치료 또는 예방에 약리학적 효과를 내는 유효 물질은 상기 언급된 화학식으로 표현된 화합물을 모두 포괄하는 것으로, 이하 '활물질'이라 약칭하기도 한다.In the present invention, an active substance that has a pharmacological effect on the treatment or prevention of heart disease encompasses all the compounds represented by the above-mentioned formula, and may be abbreviated as 'active substance'.
활물질의 제조Preparation of Active Material
본 발명에 따른 약제 조성물에서 상기 화학식 1 또는 2의 화합물들은, 이후 설명하는 바와 같이, 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있으며, 하기의 제조방법들은 일부 예시에 지나지 않으며, 그 이외의 방법들도 존재할 수 있음은 물론이다.In the pharmaceutical composition according to the present invention, the compounds of Formula 1 or 2 may be prepared by various methods based on known methods and / or techniques of organic synthesis, as described below. Are only some examples, and other methods may be present.
일반적으로 tricyclic naphthoquinone (pyrano-o-naphthoquinone 과 furano- o-naphthoquinone) 유도체들은 크게 두 가지 방법으로 합성할 수 있다. 첫 번째 방법은 하기의 β-lapachone의 합성방법과 같이 3-알릴-2-히드록시-1,4-나프토퀴논(3-allyl-2-hydroxy-1,4-naphthoquinone)을 사용하여 산을 촉매조건 에서 고리화 반응을 유도하는 방법이다.Generally, tricyclic naphthoquinone (pyrano-o-naphthoquinone and furano-o-naphthoquinone) derivatives can be synthesized in two ways. The first method uses 3-allyl-2-hydroxy-1,4-naphthoquinone (3-allyl-2-hydroxy-1,4-naphthoquinone) as described below for the synthesis of β-lapachone. It is a method of inducing a cyclization reaction under catalytic conditions.
즉, 2-알릴옥시-1,4-벤조퀴논을 스티렌(Styrene) 또는 1-비닐시클로헥산 유도체와 Diels-Alder 반응을 유도하고, 이때 생성된 중간체를 공기 중의 산소 또는 NaIO4, DDQ 등과 같은 산화제를 사용하여 탈수소화(dehydrogenation) 반응을 유도함으로써 3-알릴옥시-1,4-페난스렌퀴논을 얻을 수 있다. 이는 다시 가열함으로써 Claisen Rearrangement 반응을 통해서 Lapachole 형태의 2-알릴-3-히드록시-1,4-페난스렌퀴논을 얻을 수 있다.In other words, 2-allyloxy-1,4-benzoquinone is induced to react with a styrene or 1-vinylcyclohexane derivative and a Diels-Alder, and the intermediate formed therein is oxygen in air or an oxidizing agent such as NaIO 4 or DDQ. 3-allyloxy-1,4-phenansrenquinone can be obtained by inducing a dehydrogenation reaction using. It can be heated again to obtain Lapachole form 2-allyl-3-hydroxy-1,4-phenansrenquinone through Claisen Rearrangement reaction.
이렇게 얻은 2-알릴-3-히드록시-1,4-페난스렌퀴논은 최종적으로 산 촉매 조건에서 고리화 반응을 통해서 각종 3,4-페난스렌퀴논 또는 5,6,7,8-테트라히드로-3,4-나프토퀴논계 화합물을 합성할 수 있다. 이 때, 상기 반응식에 표현된 치환기(상기 반응식에서의 R21, R22, R23)의 종류에 따라서 5환 고리화 반응 또는 6환 고리화 반응이 진행될 뿐만 아니라 그에 상응하는 적절한 치환기(하기 반응식에서의 R11, R12, R13, R14, R15, R16)로 전환된다.Thus obtained 2-allyl-3-hydroxy-1,4-phenan srenquinone was finally subjected to various 3,4-phenan srenquinones or 5,6,7,8-tetrahydro- through cyclization under acid catalyzed conditions. A 3, 4- naphthoquinone type compound can be synthesize | combined. At this time, depending on the type of substituents (R 21 , R 22 , R 23 in the above reaction formula), the 5- or 6-membered cyclization reaction proceeds as well as the appropriate substituents corresponding thereto ( R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 in.
또한, 3-알릴옥시-1,4-페난스렌퀴논은 산(H+) 촉매 또는 알칼리(OH-) 촉매 조건하에서 3-옥시-1,4-페난스렌퀴논으로 가수분해되는데, 이를 각종 알릴 할라이드(Allyl halide)와 반응시킴으로써 C-알킬화(alkylation)에 의한 2-알릴-3-히드록시-1,4-페난스렌퀴논을 합성할 수 있다. 이렇게 얻어진 2-알릴-3-히드록시-1,4-페 난스렌퀴논 유도체는 산 촉매 조건에서 고리화 반응을 통해서 각종 3,4-페난스렌퀴논 또는 5,6,7,8-테트라히드로-3,4-나프토퀴논계 화합물을 합성할 수 있다. 이때, 상기 반응식에 표현된 치환기(상기 반응식에서의 R21, R22, R23, R24)의 종류에 따라서 5환 고리화 반응 혹은 6환 고리화 반응이 진행될 뿐만 아니라 그에 상응하는 적절한 치환기(하기 반응식에서의 R11, R12, R13, R14, R15, R16)로 전환된다.In addition, 3-allyloxy-1,4-phenan srenquinone is hydrolyzed to 3-oxy-1,4-phenan srenquinone under acid (H + ) catalyst or alkali (OH-) catalyst conditions. By reacting with (Allyl halide), 2-allyl-3-hydroxy-1,4-phenanthrenquinone by C-alkylation can be synthesized. The 2-allyl-3-hydroxy-1,4-phenan srenquinone derivatives thus obtained are various 3,4-phenan srenquinones or 5,6,7,8-tetrahydro- through cyclization under acid catalyzed conditions. A 3, 4- naphthoquinone type compound can be synthesize | combined. At this time, depending on the type of substituents (R 21 , R 22 , R 23 , R 24 in the scheme), the 5- or 6-membered cyclization reaction proceeds as well as the appropriate substituents corresponding thereto ( R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 ) in the following scheme.
그러나, 상기 반응식에서의 치환기인 R11과 R12이 동시에 수소인 화합물의 경우에는 산 촉매조건의 고리화 반응을 통해서는 얻을 수 없다. 이들 유도체는 J. K. Snyder (Tetrahedron Letters, 28, 3427~3430, 1987; Journal of Organic Chemistry, 55, 4995~5008, 1990) 가 보고한 방법에 따라, 먼저 고리화 반응을 통해서 퓨란(furan) 고리를 도입한 퓨라노벤조퀴논(furanobenzoquinone)을 먼저 얻고, 이를 1-Vinylcyclohexene 유도체와 고리화 반응을 통해서 tricyclic phenanthroquinone을 얻은 다음, 이를 수소 첨가 반응을 통해서 환원하여 얻었다. 이들 과정을 보다 일반적인 화학 반응식으로 정리하면 다음과 같다.However, in the case of a compound in which R 11 and R 12, which are substituents in the above reaction formula, are hydrogen at the same time, it cannot be obtained through an acid catalyzed cyclization reaction. These derivatives are described by JK Snyder (Tetrahedron Letters, 28, 3427-3430, 1987; Journal of Organic Chemistry, 55, 4995-5500, 1990), which first introduce a furan ring through a cyclization reaction. A furanobenzoquinone was first obtained, and tricyclic phenanthroquinone was obtained by cyclization with 1-Vinylcyclohexene derivative, and then reduced by hydrogenation. These processes can be summarized in more general chemical equations as follows.
상기 언급한 합성 방법 외에도, 본 발명에 따른 화학식 1에서 R1과 R2가 동시에 수소인 화합물의 경우에는 하기에 제시된 방법에 의해 합성될 수 있다. 첫째로, 산 촉매 고리화 반응에 의한 활성물질의 합성으로서 하기의 일반적인 화학 반응식으로 표현되는 반응에 의하여 얻을 수 있다.In addition to the synthetic methods mentioned above, in the case of compounds in which R 1 and R 2 are hydrogen at the same time according to the present invention, they may be synthesized by the method shown below. First, the synthesis of the active substance by the acid catalyzed cyclization reaction can be obtained by the reaction represented by the following general chemical formula.
즉, 2-hydroxy-1,4-naphthoquinone을 염기 존재 하에서 다양한 allylic bromide 또는 그 등가물과 반응시키면 C-alkylation(C-알킬화)과 O-alkylation(O-알킬화) 반응이 일어난 물질이 함께 얻어지는데, 반응 조건에 따라서는 한쪽 유도체만 합성하는 것도 가능하다. 여기서 O-알킬화된 유도체는 톨루엔이나 자일렌과 같은 용매를 사용하여 환류시킴으로써 Claisen Rearrangement 반응을 통해서 또 다른 유형의 C-알킬화된 유도체로 전환되기 때문에 다양한 유형의 3-substituted-2-hydroxy-1,4-naphthoquinone 유도체를 얻을 수 있다. 이렇게 얻어진 다양한 형태의 C-알킬화 유도체들은 황산을 촉매로 사용하여 고리화 반응을 유도함으로써, 상기 화합물들 중 pyrano-o-naphthoquinone 또는 furano-o-naphthoquinone 유도체들을 합성할 수 있다. That is, when 2-hydroxy-1,4-naphthoquinone is reacted with various allylic bromide or its equivalents in the presence of a base, a substance having C-alkylation and O-alkylation reactions is obtained together. Depending on the reaction conditions, it is also possible to synthesize only one derivative. Here, O-alkylated derivatives are converted to another type of C-alkylated derivative through the Claisen Rearrangement reaction by refluxing with a solvent such as toluene or xylene, so that various types of 3-substituted-2-hydroxy-1, 4-naphthoquinone derivatives can be obtained. The various types of C-alkylated derivatives thus obtained can synthesize pyrano-o-naphthoquinone or furano-o-naphthoquinone derivatives by inducing cyclization reaction using sulfuric acid as a catalyst.
두번째는 3-methylene-1,2,4-[3H]naphthalenetrione을 사용한 Diels-Alder 반응으로서, V. Nair 등 {Tetrahedron Lett. 42 (2001), 4549~4551}이 고지하고 있듯이, 2-hydroxy-1,4-naphthoquinone을 포름알데히드와 함께 가열할 때 생성되는 3-methylene-1,2,4-[3H]naphthalenetrione을 다양한 올레핀 화합물과의 Diels-Alder 반응을 유도함으로써 비교적 쉽게 다양한 pyrano-o-naphthoquinone 유도체를 합성할 수 있음을 보고하고 있다. 이 방법은 황산 촉매 조건에서의 고리화 반응을 유도하는 반응에 비해서 비교적 간단하게 다양한 형태의 pyrano-o-naphtho-quinone 유도체를 합성할 수 있는 장점이 있다.The second is Diels-Alder reaction using 3-methylene-1,2,4- [3H] naphthalenetrione, which is described in V. Nair et al. {Tetrahedron Lett. 42 (2001), 4549-4551}, it is known that 3-methylene-1,2,4- [3H] naphthalenetrione is produced by heating 2-hydroxy-1,4-naphthoquinone with formaldehyde. It has been reported that various pyrano-o-naphthoquinone derivatives can be synthesized relatively easily by inducing Diels-Alder reaction with compounds. This method has the advantage of being able to synthesize various types of pyrano-o-naphtho-quinone derivatives relatively simply compared to reactions that induce cyclization under sulfuric acid catalyst conditions.
세번째 방법은 Radical 반응에 의한 Haloakylation 및 고리화 반응으로서, 크립토탄신온(Cryptotanshinone), 15,16-디히드로탄신온(15,16-Dihydro- tanshinone) 등의 합성에 이용되었던 방법 또한 furano-o-naphthoquinone 유도체를 합성하는데 편리하게 사용할 수 있다. 즉, A. C. Baillie 등(J. Chem. Soc. (C) 1968, 48~52)이 고지하고 있듯이, 3-halopropanoic acid 또는4-halobutanoic acid 유도체로부터 유도한 2-haloethyl 또는 3-haloethyl radical 화학종을 2-hydroxy-1,4-naphthoquinone과 반응시킴으로 3-(2-haloethyl 또는 3-halopropyl)-2-hydroxy-1,4-naphthoquinone을 합성할 수 있는데, 이를 적절한 산성 촉매 조건에서 고리화 반응을 유도함으로써 다양한 pyrano-o-naphthoquinone 또는 furano-o- naphthoquinone 유도체를 합성할 수 있다. The third method is the haloakylation and cyclization reaction by the Radical reaction, which was used for the synthesis of Cryptotanshinone, 15,16-dihydrotanshinone, and furano-o- It can be conveniently used to synthesize naphthoquinone derivatives. In other words, as reported by AC Baillie et al. (J. Chem. Soc. (C) 1968, 48-52), 2-haloethyl or 3-haloethyl radical species derived from 3-halopropanoic acid or 4-halobutanoic acid derivatives are known. By reacting with 2-hydroxy-1,4-naphthoquinone, 3- (2-haloethyl or 3-halopropyl) -2-hydroxy-1,4-naphthoquinone can be synthesized, which induces cyclization under appropriate acidic catalytic conditions. Thus, various pyrano-o-naphthoquinone or furano-o-naphthoquinone derivatives can be synthesized.
네번째는 4,5-Benzofurandione의 Diels-Alder 반응에 의한 고리화 반응으로서, 크립토탄신온(Cryptotanshinone), 15,16-디히드로탄신온(15,16-Dihydro- tanshinone) 등의 합성에 이용되었던 또 다른 방법으로는 J. K. Snyder 등 (Tetrahedron Letters 28 (1987), 3427~3430) 이 고지하고 있는 방법이 있다. 이 방법은 4,5-Benzofurandione 유도체와 다양한 디엔(diene) 유도체와의 Diels-Alder 반응에 의한 Cycloaddition을 유도함으로써 furano-o-naphthoquinone 유도체를 합성할 수 있다.The fourth is a cyclization reaction by Diels-Alder reaction of 4,5-Benzofurandione, which was used for the synthesis of Cryptotanshinone, 15,16-Dihydrotanshinone, etc. Another method is reported by JK Snyder et al. (Tetrahedron Letters 28 (1987), 3427-3430). In this method, furano-o-naphthoquinone derivatives can be synthesized by inducing cycloaddition by Diels-Alder reaction between 4,5-Benzofurandione derivatives and various diene derivatives.
상기 방법들을 기초로 치환체의 종류에 따라 적절한 합성방법을 사용하여 다양한 유도체를 합성할 수 있다.Based on the above methods, various derivatives can be synthesized using an appropriate synthesis method according to the type of substituent.
본 발명에 따른 화합물들 중 특히 바람직한 예로는 하기 표 1의 것들을 들 수 있지만, 이들만으로 한정되는 것은 아니다. Particularly preferred examples of the compounds according to the invention include, but are not limited to, those of Table 1 below.
[표 1]TABLE 1
상기 "약제 조성물(pharmaceutical composition)"은 상기 화학식 1 또는 2의 화합물과 희석제 또는 담체와 같은 다른 화학 성분들의 혼합물을 의미한다. 약제 조성물은 생물체내로 화합물의 투여를 용이하게 한다. 화합물을 투여하는 다양한 기술들이 존재하며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 약제 조성물은 염산, 브롬산, 황산, 질산, 인산, 메탄술폰산, p-톨루엔술폰산, 살리실산 등과 같은 산 화합물들을 반응시켜서 얻어질 수도 있다.The "pharmaceutical composition" means a mixture of the compound of formula 1 or 2 with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering compounds, including but not limited to oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions may also be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
상기 "약리학적 유효량(therapeutically effective amount)"은 투여되는 화합물의 양이 치료하는 장애의 하나 또는 그 이상의 증상을 어느 정도 경감 또는 줄이거나, 예방을 요하는 질병의 임상학적 마커 또는 증상의 개시를 지연시키는데 유효한 활성성분의 양을 의미한다. 따라서, 약리학적 유효량은, (1) 질환의 진행 속도를 역전시키는 효과, (2) 질환의 그 이상의 진행을 어느 정도 금지시키는 효과, 및/또는 (3) 질환과 관련된 하나 또는 그 이상의 증상을 어느 정도 경감(바람직하 게는, 제거)하는 효과를 가지는 양을 의미한다. 약리학적 유효량은 치료를 요하는 질병에 대한 공지된 생채 내(in vivo) 및 생체 외(in vitro) 모델 시스템에서 화합물을 실험함으로써 경험적으로 결정될 수 있다.The “therapeutically effective amount” is to some extent alleviate or reduce one or more symptoms of the disorder being treated, or delay the onset of a clinical marker or symptom of a disease requiring prevention. It means the amount of active ingredient effective to. Thus, a pharmacologically effective amount can be used to determine (1) the effect of reversing the rate of progression of the disease, (2) the effect of inhibiting further progression of the disease to some extent, and / or (3) one or more symptoms associated with the disease. Means an amount that has the effect of reducing (preferably, removing) the degree. A pharmacologically effective amount can be determined empirically by experimenting with compounds in known in vivo and in vitro model systems for diseases in need of treatment.
본 발명에 따른 약제 조성물에서 상기 화학식 1의 화합물은, 앞서 자세히 설명한 바와 같이, 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있다.In the pharmaceutical composition according to the present invention, the compound of Formula 1 may be prepared by a variety of methods based on known methods and / or techniques of organic synthesis, as described above.
본 발명의 약제 조성물은, 예를 들어, 통상적인 혼합, 용해, 과립화, 당제-제조, 분말화, 에멀젼화, 캡슐화, 트래핑과 또는 동결건조 과정들의 수단에 의해, 공지 방식으로 제조될 수 있다.Pharmaceutical compositions of the present invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping and or lyophilizing processes. .
따라서, 본 발명에 따른 사용을 위한 약제 조성물은 약제학적으로 허용되는 담체, 희석제, 또는 부형제, 또는 이들의 조합을 추가적으로 포함할 수 있다. 즉, 약제학적으로 사용될 수 있는 제형으로의 활성 화합물의 처리를 용이하게 하는 부형제들 또는 보조제들을 포함하는 것으로 구성되어 있는 하나 또는 그 이상의 약리학적으로 허용되는 담체를 추가적으로 사용하여 통상적인 방법으로 제조될 수도 있다. 상기 약제 조성물은 생물체내로 화합물의 투여를 용이하게 한다.Thus, pharmaceutical compositions for use in accordance with the present invention may further comprise a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof. That is, it may be prepared in a conventional manner by additionally using one or more pharmaceutically acceptable carriers which comprise excipients or auxiliaries which facilitate the treatment of the active compound into a pharmaceutically usable formulation. It may be. The pharmaceutical composition facilitates administration of the compound into the organism.
상기 "담체(carrier)"는 세포 또는 조직 내부로의 화합물의 부가를 용이하게 하는 화합물로 정의된다. 예를 들어, 디메틸술폭사이드(DMSO)는 생물체의 세포 또는 조직 내부로의 많은 유기 화합물들의 투입을 용이하게 하는 통상 사용되는 담체이다.The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of an organism.
상기 "희석제(diluent)"는 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키게 되는 물에서 희석되는 화합물로 정의된다. 버퍼 용액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 버퍼 용액은 포스페이트 버퍼 식염수이며, 이는 인간 용액의 염 상태를 모방하고 있기 때문이다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형하는 일은 드물다.The term "diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.
여기에 사용된 화합물들은 인간 환자에게 그 자체로서, 또는 결합 요법에서와 같이 다른 활성 성분들과 함께 또는 적당한 담체나 부형제와 함께 혼합된 약제 조성물로서 투여될 수 있다. 적합한 제형은 선택된 투여 루트에 따라 죄우되며, 본 응용에서의 화합물의 제형 및 투여에 관한 기술은 "Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition, 1990"에서 확인할 수 있다.The compounds used herein may be administered to a human patient as such or as a pharmaceutical composition mixed with other active ingredients or with a suitable carrier or excipient, such as in a combination therapy. Suitable formulations are dictated by the route of administration chosen, and techniques for formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition, 1990".
활성성분을 인체에 투여하기 위해 약학적으로 제형화하는 다양한 기술들이 존재하며, 여기에는 경구, 주사, 에어로졸, 비경구, 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 경우에 따라서는, 염산, 브롬산, 황산, 질산, 인산, 메탄술폰산, p-톨루엔술폰산, 살리실산 등과 같은 산 화합물들을 반응시켜서 얻어질 수도 있다.There are a variety of techniques for pharmaceutically formulating the active ingredient for administration to the human body, including but not limited to oral, injection, aerosol, parenteral, topical administration, and the like. In some cases, it may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
약학적 제형화는 공지의 방법으로 수행할 수 있는 바, 예를 들어, 약제학적으로 가능한 경구, 외용, 경피, 경점막 제형 및 주사용 제형의 형태일 수 있다.Pharmaceutical formulations can be carried out by known methods, for example in the form of pharmaceutically possible oral, external, transdermal, transmucosal formulations and injectable formulations.
주사용 제형의 경우, 활성성분을 액상 용액으로, 바람직하게는 Hank 용액, Ringer 용액, 또는 생리 식염수와 같은 약리학적으로 적합한 버퍼로 제형화 할 수 있다. 점막 투과용 제형의 경우, 통과할 배리어에 적합한 비침투성제가 제형에 사용된다. 상기 비침투성제들은 당업계에 일반적으로 공지되어 있다.In the case of injectable formulations, the active ingredient may be formulated in a liquid solution, preferably in a pharmacologically suitable buffer such as Hank's solution, Ringer's solution, or physiological saline. For mucosal penetration formulations, non-penetrating agents suitable for the barrier to pass through are used in the formulation. Such non-invasive agents are generally known in the art.
본 발명에서 사용에 적합한 약제 조성물은 유효량의 활성성분들을 함유한 조성물을 포함한다. 더욱 구체적으로, 치료적 유효량은 치료될 객체의 생존을 연장하거나, 질환의 증상을 방지, 경감 또는 완화시키는데 유효한 화합물의 양을 의미한다. 치료적 유효량의 결정은, 특히 여기에 제공된 상세한 개시 내용 측면에서, 당업자의 능력 범위 내에 있다.Pharmaceutical compositions suitable for use in the present invention include compositions containing an effective amount of the active ingredients. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.
단위 용량 형태로 제형화하는 경우, 활성성분으로서 화학식 1 또는 2의 화합물은 약 0.1 내지 1,000 mg의 단위 용량으로 함유되는 것이 바람직하다. 상기 화합물의 투여량은 환자의 체중, 나이 및 질병의 특수한 성질과 심각성과 같은 요인에 따라 의사의 처방에 따른다. 그러나 성인 치료에 필요한 투여량은 투여의 빈도와 강도에 따라 하루에 약 1 내지 3000 mg 범위가 보통이다. 성인에게 근육내 또는 정맥내 투여시 일회 투여량으로 분리하여 하루에 보통 약 1 내지 500 mg의 전체 투여량이면 충분할 것이나, 일부 환자의 경우 더 높은 일일 투여량이 바람직할 수 있다.When formulated in unit dose form, it is preferred that the compound of formula 1 or 2 as the active ingredient is contained in a unit dose of about 0.1 to 1,000 mg. The dosage of the compound depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 3000 mg per day, depending on the frequency and intensity of administration. A total dosage of about 1 to 500 mg per day, usually separated by a single dose for intramuscular or intravenous administration to adults, will be sufficient, but for some patients a higher daily dosage may be desirable.
상기 허혈 또는 허혈 재관류에 의해 유발되는 심장질환은 심기능 장해 혹은 심근 장해로서, 빈맥세동, 부정맥, 심장질환 이벤트 또는 심장사 등을 들 수 있는데, 이들은 불안정, 협심증이나 심근경색 등의 급성 관질환에 의해 발생된다.Heart disease caused by ischemia or ischemia reperfusion is a cardiac dysfunction or myocardial disorder, such as tachycardia, arrhythmia, heart disease events or cardiac death, which are caused by acute vascular diseases such as instability, angina pectoris or myocardial infarction do.
본 발명은 또한 허혈 또는 허혈 재관류에 의해 유발되는 심장질환의 치료 또는 예방을 위한 약제의 제조에 화학식 1의 화합물을 사용하는 방법을 제공한다.The invention also provides a method of using the compound of formula 1 in the manufacture of a medicament for the treatment or prevention of heart disease caused by ischemia or ischemia reperfusion.
상기 "치료"란 발병 증상을 보이는 객체에 사용될 때 질환의 진행을 중단 또는 지연시키는 것을 의미하며, 상기 "예방"이란 발병 증상을 보이지는 않지만 그러한 위험성이 높은 객체에 사용될 때 발병 징후를 중단 또는 지연시키는 것을 의미한다. The term "treatment" means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms, and the "preventing" means stopping or delaying the manifestation of a disease when used in a subject who does not exhibit symptoms but is at high risk. It means to let.
이하 실험예들을 참조하여 본 발명의 내용을 상술하지만, 본 발명의 범주가 그것에 의해 한정되는 것은 아니다. The content of the present invention is described in detail below with reference to experimental examples, but the scope of the present invention is not limited thereto.
실험예 1: 고양이 심장의 허혈 및 재관류 손상 모델Experimental Example 1: Ischemia and Reperfusion Injury Model of Cat Heart
본 실험은 성숙한 숫 고양이(2.5 - 5 kg)를 대상으로 alpha-chloralose 60 mg/kg을 근육 내에 주사하여 마취한 뒤, 근육이완제 등을 정맥 내 주입하기 위하여 좌측상지전완정맥(antecubital vein)에 폴리에틸렌관을 삽입하였다. 개흉(thoracotomy) 시 나타나는 호흡곤란을 방지하기 위하여 모든 실험동물에 근육이완제(pancuronium bromide, 0.5 - 2 mg)를 주입하고, 기관절개술(tracheostomy)을 통해 인공호흡기를 사용하였다. 인공호흡기의 조절은 이산화탄소 측정기(capnometer, model 2200, TMM)로 측정한 호흡말기의 이산화탄소 분압이 29 - 36 mmHg가 되도록 하였다. 가슴 앞쪽의 가운데 피부를 절개한 뒤 왼쪽 제 4, 5 갈비뼈를 잘라내어 심장이 잘 보이도록 하였다. 노출된 심장의 심낭을 출혈이 없도록 자르고 좌전하행동맥을 주위의 신경을 손상시키지 않도록 조심하면서 주위조직으로부터 좌전하관상동맥(left anterior descending coronary artery, LAD)을 분리하였 다. 심전도는 생리기록기(physiograph, 7P4J, Grass)를 이용하여 Lead II를 기록하였다.In this study, anesthetized 60-mg / kg alpha-chloralose intramuscularly in mature male cats (2.5-5 kg), followed by polyethylene injection into the antecubital vein for intravenous injection of muscle relaxants. The tube was inserted. In order to prevent respiratory distress during thoracotomy, all animals were infused with pancuronium bromide (0.5-2 mg), and a ventilator was used through tracheostomy. Control of the ventilator was such that the partial pressure of carbon dioxide at the end of respiration measured by a carbon dioxide meter (capnometer, model 2200, TMM) was 29-36 mmHg. The skin was cut in the middle of the front of the chest, and the left 4th and 5th ribs were cut out so that the heart was clearly visible. The left anterior descending coronary artery (LAD) was isolated from the surrounding tissue while cutting the pericardium of the exposed heart free of bleeding and taking care not to damage the surrounding nerves. Electrocardiograms were recorded with Lead II using a physiological recorder (physiograph, 7P4J, Grass).
실험군은 좌전하행동맥을 6-0 silk로 20 분간 묶은 뒤 5 분간 재관류 시키되, 좌전하행동맥 결찰에 의한 허혈 유도 5 시간 전에 상기 표 1의 화합물 1(300 mg/kg)을 경구 투약하였다. 대조군은 실험군과 동일한 방법으로 실험을 진행하되, 화합물 1 대신 5 ml/kg의 vehicle (0.1% SDS)을 경구 투약하였다. 각 동물군의 심실 부정맥은 Lambeth convention의 정의에 따라 1) 심실조기박동(Pre-mature Ventricular beat, PVC)의 빈도, 2) 심실빈맥(Ventricular Tachycardia, VT)의 빈도, 3) 심실세동(Ventricular fibrillation, VF)의 빈도 및 사망여부를 허혈기(ischemic period)와 (결찰 후 10분경 관찰함), 재관류기(reperfusion period)에 각각 분석하였다.The experimental group was tied to the left anterior descending artery with 6-0 silk for 20 minutes and then reperfused for 5 minutes. Orally, the compound 1 (300 mg / kg) of Table 1 was orally administered 5 hours before induction of ischemia by left anterior descending artery ligation. As a control group, the experiment was conducted in the same manner as the experimental group, but 5 ml / kg vehicle (0.1% SDS) was orally administered instead of compound 1. Ventricular arrhythmias in each animal group are defined by the Lambeth convention: 1) frequency of pre-mature ventricular beat (PVC), 2) frequency of ventricular tachycardia (VT), and 3) ventricular fibrillation. , VF) frequency and mortality were analyzed during ischemic period (observed 10 minutes after ligation) and reperfusion period, respectively.
실험예 1-1: 10 분간 결찰에 의한 심근허혈에 대한 실험Experimental Example 1-1: Experiment for Myocardial Ischemia by ligation for 10 minutes
좌전하행동맥의 결찰로 유발된 10 분간의 심근허혈 시, 대조군의 총 29 마리 중에서 심실조기박동, 심실빈맥, 심실세동이 각각 27 마리 (93.1%), 14 마리 (48,3%), 4 마리(13,8%)에서 발생하였다. 관상동맥 결찰 5 시간 전에 화합물 1(300 mg/kg)을 경구 투여한 실험군 총 24 마리에 대한 실험 결과, 심실조기박동 75.0% (18 마리), 심실빈맥 12.5% (3 마리), 심실세동이 4.2% (1 마리)로 발생되어 대조군에 비해 현저히 발생률이 낮은 것으로 조사되었다. 이에 대한 결과를 도 1에 나타내었다. After 10 minutes of myocardial ischemia caused by ligation of the left anterior descending artery, 27 (93.1%), 14 (48,3%), and 4 ventricular pacing, ventricular tachycardia, and 4 of the control group (13,8%). Twenty four experimental groups orally administered Compound 1 (300 mg / kg) 5 hours prior to coronary artery ligation, ventricular pacing 75.0% (18), ventricular tachycardia 12.5% (3), ventricular fibrillation 4.2 The incidence of% (1) was significantly lower than that of the control group. The results are shown in FIG. 1.
실험예 1-2: 재관류성 부정맥에 대한 효과 실험Experimental Example 1-2: Effect Test on Reperfusion Arrhythmia
좌전하행동맥의 결찰로 유발된 20 분간의 심근허혈 후 재관류시킨 대조군 총 15 마리 모두에서 심실조기박동(100%) 및 심실빈맥(100%)이 발생하였으며, 14 마리가 심실세동(93.3%)으로 사망하였다. 관상동맥 결찰 5 시간 전에 화합물 1(300 mg/kg)을 경구 투여한 실험군 중에서 20 분간의 심근허혈 후 재관류의 대상이 된 총 16 마리 중 14 마리(87.5%)에서 심실조기박동이 관찰되었으며, 이는 대조군에 비해 크게 다르지 않은 결과이다. 반면에, 재관류성 심실빈맥과 심실세동은 각각 9 마리(56.3%, *P=0.007 vs. control group)와 8 마리(50.0%, *P=0.015 vs. control group)에서만 관찰되었는데, 그 발생률은 대조군에 비해 통계학적으로 현저히 낮은 것으로 확인되었다(Fisher Exact test). 이는 화합물 1이 관상동맥의 재관류에 의해 유발되는 치명적인 심실빈맥과 심실세동을 효과적으로 완화한 결과로 추측된다. 이에 대한 결과를 하기 표 2와 도 2에 나타내었다.Ventricular rhythm (100%) and ventricular tachycardia (100%) occurred in all 15 controls that were reperfused after 20 minutes of myocardial ischemia induced by ligation of the left anterior descending artery. 14 were ventricular fibrillation (93.3%). Died. Ventricular pacing was observed in 14 of the 16 subjects (87.5%) who were subjected to reperfusion after 20 minutes of myocardial ischemia in the experimental group orally administered Compound 1 (300 mg / kg) 5 hours before coronary artery ligation. This is not much different than the control group. On the other hand, reperfusion ventricular tachycardia and ventricular fibrillation were observed only in 9 (56.3%, * P = 0.007 vs. control group) and 8 (50.0%, * P = 0.015 vs. control group), respectively. It was found to be statistically significantly lower than the control group (Fisher Exact test). This is presumed to be a result of compound 1 effectively alleviating lethal ventricular tachycardia and ventricular fibrillation caused by reperfusion of coronary artery. The results are shown in Table 2 and FIG. 2.
[표 2] 마취된 고양이에서의 재관류 부정맥에 대한 약물의 효과 TABLE 2 Effect of drugs on reperfusion arrhythmias in anesthetized cats
이상의 결과에 의해, 화합물 1은 허혈성 부정맥 및 허혈 재관류성 부정맥, 특히 치명적인 심실빈맥과 심실세동을 효과적으로 완화하는 것으로 확인되었다.From the above results, it was confirmed that Compound 1 effectively alleviates ischemic arrhythmias and ischemic reperfusion arrhythmias, particularly lethal ventricular tachycardia and ventricular fibrillation.
실험예 2: 허혈성 심근경색에 대한 효과Experimental Example 2: Effect on Ischemic Myocardial Infarction
허혈성 심근경색에 대한 실험은 다음과 같이 수행하였다. C57BL/6 mice 수컷에 액상 마취제 (keta mine:xylazine=20:1)를 kg/ml로 복강내 주사하여 마취시키고, trachea에 22-gauge IV chatheter needle을 넣어 Ventilator(Harvard Apparatus)를 연결하여 강제호흡을 유지시켰으며, 흉부를 절개하여 심장을 노출시켰다. 이후 심외막을 조심스럽게 분리해 내고 좌심실의 위치를 확인하였다. 좌전하 동맥이 포함되도록 7-0 polypropene silk (round cut)로 좌심의 1 mm 아래쪽을 결찰하였다. 허혈상태의 심장에 색과 수축력을 관찰하였다. 결찰하여 허혈을 유발시킨 후에, 늑간 사이근, 배곧은근의 흉부부분, 얕은 흉부근 순서로 4-0 vicryl (polygalatin)로 봉합하고 마지막으로 5-0 black silk로 피부를 봉합하였다. 이후 삽관을 위한 절개부위를 봉합하고 인공호흡기를 제거한 후 회복을 위해 마우스를 따뜻하게 유지시켰다.Experiments on ischemic myocardial infarction were performed as follows. C57BL / 6 mice were anesthetized by intraperitoneal injection of liquid anesthetic (keta mine: xylazine = 20: 1) at kg / ml, and forced breathing by connecting a 22-gauge IV chatheter needle to trachea using a Ventilator (Harvard Apparatus). The thoracic incision was made to expose the heart. Then, the epicardium was carefully removed and the position of the left ventricle was confirmed. 7-0 polypropene silk (round cut) was ligated 1 mm below the left heart to include the left anterior artery. Color and contractile force were observed in the ischemic heart. After ligation to induce ischemia, the intercostal muscles, the rectus abdominal thorax and the shallow thoracic muscles were closed with 4-0 vicryl (polygalatin) and finally the skin was closed with 5-0 black silk. The incision was then closed for intubation, the ventilator removed and the mouse kept warm for recovery.
화합물 1의 150 mg/kg를 0.1% SLS solution 상태로 경구투여 하였으며, 시술 하루 전부터 투여하여 시술 후 4 주간 투여하였다. 대조군은 실험군과 동일한 방법으로 실험을 진행하되 0.1% SLS (1 mg/kg)을 동일하게 경구 투여하였다. 150 mg / kg of Compound 1 was orally administered in the state of 0.1% SLS solution, and administered one day before the procedure and then administered for 4 weeks after the procedure. As a control group, the experiment was conducted in the same manner as the experimental group, but 0.1% SLS (1 mg / kg) was orally administered in the same manner.
약물의 허혈성 심근경색의 효과 확인 실험을 위하여 심전도 측정기 (Physiograph, 7P4J, Grass)를 이용하여 LeadII를 기록하여 부정맥, 심실세동 등을 측정하였다. 또한 심초음파 실험을 통해 좌심 확장기, 좌심 수축기 등을 측정, 심근 기능의 중요한 지표인 FS (Fractional shortening)을 측정하였다.In order to confirm the effect of ischemic myocardial infarction of the drug, the lead II was recorded using an electrocardiogram (Physiograph, 7P4J, Grass) to measure arrhythmia and ventricular fibrillation. In addition, echocardiography was performed to measure left ventricular diastolic and left ventricular systolic, and to measure FS (Fractional shortening), an important indicator of myocardial function.
그 결과가 도 3에 개시되어 있는 바, 도 3에서 보는 바와 같이, 화합물 1을 투여한 경우 FS가 control에 비하여 증가함을 관찰할 수 있었으며, 심근경색후 약물 투여시 심장 기능이 회복되는 것을 확인하였다. As shown in FIG. 3, the results showed that FS increased as compared to the control when Compound 1 was administered, and that the cardiac function was restored upon administration of the drug after myocardial infarction. It was.
이상 설명한 바와 같이, 본 발명에 따른 약제 조성물은 허혈 또는 허혈 재관류에 의해 유발되는 심장질환의 예방 및 치료에 탁월한 효과를 나타낸다.As described above, the pharmaceutical composition according to the present invention has an excellent effect on the prevention and treatment of heart disease caused by ischemia or ischemia reperfusion.
본 발명이 속한 분야에서 통상의 지식을 가진 자라면, 상기 내용을 바탕으로 본 발명의 범주내에서 다양한 응용 및 변형을 행하는 것이 가능할 것이다.Those skilled in the art to which the present invention pertains will be able to make various applications and modifications within the scope of the present invention based on the above contents.
도 1 은 실험예 1-1의 실험에서 심근허혈 초기 10분간의 부정맥 발생률을 나타낸다. (P=0.013 vs. Control group (Chi-square test). VPBs: ventricular premature beats (심실조기박동), VT: ventricular tachycardia (심실빈맥), VF: ventricular fibrillation (심실세동)). Figure 1 shows the incidence of arrhythmias in the initial 10 minutes of myocardial ischemia in the experiment of Experimental Example 1-1. (P = 0.013 vs. Control group (Chi-square test) .VPBs: ventricular premature beats), VT: ventricular tachycardia (ventricular tachycardia), VF: ventricular fibrillation (ventricular fibrillation).
도 2는 실험예 1-2의 좌전하행동맥 결찰로 인한 20분간의 심근허혈 후 재관류 시 대조군(Cont)과 화합물 1의 투여군(Exp)에서의 부정맥 발생률을 나타낸다. (VPBs: ventricular premature beats (심실조기박동), VT: ventricular tachycardia (심실빈맥), VF: ventricular fibrillation (심실세동)).Figure 2 shows the incidence of arrhythmias in the control group (Cont) and the compound 1 administration group (Exp) during reperfusion after myocardial ischemia for 20 minutes due to left anterior descending artery ligation of Experimental Example 1-2. (VPBs: ventricular premature beats), VT: ventricular tachycardia (ventricular tachycardia), VF: ventricular fibrillation (ventricular fibrillation).
도 3은 실험예 2의 심근경색 모델에서의 개선된 F.S 수치를 나타낸다. 3 shows improved F.S values in myocardial infarction model of Experimental Example 2. FIG.
Claims (11)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020080112784 | 2008-11-13 | ||
| KR20080112784 | 2008-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20100054098A true KR20100054098A (en) | 2010-05-24 |
Family
ID=42170516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020090108399A Withdrawn KR20100054098A (en) | 2008-11-13 | 2009-11-11 | Pharmaceutical composition for the treatment and prevention of cardiac diseases caused by ischemia or ischemic reperfusion |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20100054098A (en) |
| WO (1) | WO2010056041A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101401253B1 (en) * | 2012-03-06 | 2014-05-29 | 연세대학교 산학협력단 | Composition for increasing the amount of the LDL receptor by inhibition of the expression of PCSK9 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| US9394285B2 (en) | 2013-03-15 | 2016-07-19 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08113555A (en) * | 1994-10-14 | 1996-05-07 | Japan Tobacco Inc | 2-amino-3-halogeno-1,4-naphthoquinone derivative and its use for medicine |
| US5824700A (en) * | 1996-02-20 | 1998-10-20 | Wisconsin Alumni Research Foundation | Ortho-quinone derivatives novel synthesis therefor and their use in the inhibition of neoplastic cell growth |
| WO2006088315A1 (en) * | 2005-02-16 | 2006-08-24 | Md Bioalpha Co., Ltd. | Pharmaceutical composition for the treatment or prevention of diseases involving obesity, diabetes, metabolic syndrome, neuro-degenerative diseases and mitochondria dysfunction diseases |
| WO2007094632A1 (en) * | 2006-02-15 | 2007-08-23 | Md Bioalpha Co., Ltd. | Method for controlling nad(p)/nad(p)h ratio by oxidoreductase |
| WO2008136642A1 (en) * | 2007-05-07 | 2008-11-13 | Mazence Inc. | Naphthoquinone-based pharmaceutical composition for treatment or prevention of diseases involving obesity, diabetes, metabolic syndrome, neuro-degenerative diseases and mitochondria dysfunction diseases |
| KR20090073381A (en) * | 2007-12-31 | 2009-07-03 | 주식회사 머젠스 | Pharmaceutical composition for the treatment and prevention of heart disease |
-
2009
- 2009-11-11 KR KR1020090108399A patent/KR20100054098A/en not_active Withdrawn
- 2009-11-11 WO PCT/KR2009/006622 patent/WO2010056041A2/en not_active Ceased
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101401253B1 (en) * | 2012-03-06 | 2014-05-29 | 연세대학교 산학협력단 | Composition for increasing the amount of the LDL receptor by inhibition of the expression of PCSK9 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010056041A2 (en) | 2010-05-20 |
| WO2010056041A3 (en) | 2010-08-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20040033991A1 (en) | Treating of cardiovascular and related pathologies | |
| RU2373934C1 (en) | Application of glutaric acid derivatives or their pharmaceutically acceptable salts as antiarrhythmic drug | |
| WO1994003171A1 (en) | Cardiac protective | |
| US20030119794A1 (en) | Novel bretylium compositions and kits and their use in preventing and treating cardiovascular conditions | |
| KR100372243B1 (en) | Anti-arrhythmic composition and method of treatment | |
| US6482811B1 (en) | Bretylium compositions and kits, and their use in preventing and treating cardio-vascular conditions | |
| EP0633777B1 (en) | Parenteral solutions containing 3-dialkylaminoethoxybenzoyl-benzofurans | |
| KR20100054098A (en) | Pharmaceutical composition for the treatment and prevention of cardiac diseases caused by ischemia or ischemic reperfusion | |
| JPH02108688A (en) | Quinoline compound | |
| CN112209834B (en) | A kind of organic nitrite radical donor and its preparation method and medical application | |
| TWI225397B (en) | Uses of thaliporphine or its derivatives in treatment of cardiac diseases and preparation of the same | |
| CN108774220B (en) | Compounds for treating myocardial ischemia and uses thereof | |
| HU190355B (en) | Process for producing pharmaceutical compositions for treating coronaria-diseases and hypertonia | |
| CN109180712B (en) | 2-arrowhead alcohol arylboronic acid ester derivatives and application thereof | |
| RU2414893C1 (en) | Quaternary ammonium derivative of novocain, which possesses anti-arrhythmic activity, and method of its obtaining | |
| RU2338538C1 (en) | Antiantihypertensive | |
| CN118359663B (en) | Mitochondrial targeting genistein derivative and application thereof in preparation of medicines for resisting myocardial ischemia reperfusion injury | |
| KR20050110681A (en) | 2-(butyl-1-sulfonylamino)-n-[1(r)-(6-methoxypyridin-3-yl)-propyl]-benzamide, the use thereof in the form of drug and pharmaceutical preparations containing said compound | |
| ES2483940T3 (en) | A new dosage regimen for ionic channel modulating compounds for the treatment of acute atrial fibrillation in a human being | |
| RU2458690C1 (en) | 3-(2,2,2-trimethylhydrazinium) propionate-5-bromnicotinate 3-(2,2,2-trimethylhydrazinium) potassium propionate derivative exhibiting antiischemic activity | |
| CN114835675A (en) | Medicine for treating myocardial ischemia and application thereof | |
| Shamsi et al. | Correlation of Chemical Structure of Pheno-Thiazines with their Coronary Dilator and Antiarrhythmic Activities | |
| WO2024037564A1 (en) | Phenothiazine compound and use thereof | |
| HU212502B (en) | Process for producing pharmaceutical preparative containing n-methyl-2-(3-pyridyl)-tetrahydrothiopyrane-2-carbothioamide-1-oxide applicable for treating insufficiency of coronary arteries | |
| KR20060125849A (en) | Erectile Dysfunction Treatment Methods |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0109 | Patent application |
Patent event code: PA01091R01D Comment text: Patent Application Patent event date: 20091111 |
|
| PG1501 | Laying open of application | ||
| PC1203 | Withdrawal of no request for examination | ||
| WITN | Application deemed withdrawn, e.g. because no request for examination was filed or no examination fee was paid |