CN102552272B - Method for treating sepsis - Google Patents
Method for treating sepsis Download PDFInfo
- Publication number
- CN102552272B CN102552272B CN201110412182.XA CN201110412182A CN102552272B CN 102552272 B CN102552272 B CN 102552272B CN 201110412182 A CN201110412182 A CN 201110412182A CN 102552272 B CN102552272 B CN 102552272B
- Authority
- CN
- China
- Prior art keywords
- terazosin
- compound
- alkyl
- thf
- purposes
- 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.)
- Active
Links
- 206010040047 Sepsis Diseases 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 238000002360 preparation method Methods 0.000 claims abstract description 79
- 239000003814 drug Substances 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 claims description 146
- 229960001693 terazosin Drugs 0.000 claims description 145
- 208000013223 septicemia Diseases 0.000 claims description 46
- 239000004599 antimicrobial Substances 0.000 claims description 44
- 229960003022 amoxicillin Drugs 0.000 claims description 24
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 24
- 229940038649 clavulanate potassium Drugs 0.000 claims description 24
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 24
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 claims description 24
- -1 2-4thiazolinyl- Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229930182555 Penicillin Natural products 0.000 claims description 14
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 14
- 229940049954 penicillin Drugs 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 229960000723 ampicillin Drugs 0.000 claims description 11
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 11
- 230000000844 anti-bacterial effect Effects 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims description 7
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 claims description 7
- 229930195708 Penicillin V Natural products 0.000 claims description 7
- 229960003623 azlocillin Drugs 0.000 claims description 7
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 claims description 7
- 229960003644 aztreonam Drugs 0.000 claims description 7
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 7
- 229960003326 cloxacillin Drugs 0.000 claims description 7
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 claims description 7
- 229960004273 floxacillin Drugs 0.000 claims description 7
- 229960002260 meropenem Drugs 0.000 claims description 7
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims description 7
- 229940056367 penicillin v Drugs 0.000 claims description 7
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 claims description 7
- 229960002292 piperacillin Drugs 0.000 claims description 7
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims description 7
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims description 7
- 229960005256 sulbactam Drugs 0.000 claims description 7
- OPYGFNJSCUDTBT-PMLPCWDUSA-N sultamicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(=O)OCOC(=O)[C@H]2C(S(=O)(=O)[C@H]3N2C(C3)=O)(C)C)(C)C)=CC=CC=C1 OPYGFNJSCUDTBT-PMLPCWDUSA-N 0.000 claims description 7
- 229960001326 sultamicillin Drugs 0.000 claims description 7
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims description 7
- 229960003865 tazobactam Drugs 0.000 claims description 7
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000012453 solvate Substances 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 6
- 150000002148 esters Chemical class 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 104
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 96
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 68
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 64
- 101150079312 pgk1 gene Proteins 0.000 description 48
- 239000000243 solution Substances 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 47
- 230000006907 apoptotic process Effects 0.000 description 46
- 238000002425 crystallisation Methods 0.000 description 42
- 230000008025 crystallization Effects 0.000 description 42
- 238000010992 reflux Methods 0.000 description 37
- 241000699670 Mus sp. Species 0.000 description 34
- 238000004364 calculation method Methods 0.000 description 34
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 34
- 238000005406 washing Methods 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 229910052786 argon Inorganic materials 0.000 description 32
- 239000013078 crystal Substances 0.000 description 32
- 238000004896 high resolution mass spectrometry Methods 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 230000000694 effects Effects 0.000 description 29
- 239000002158 endotoxin Substances 0.000 description 28
- 229920006008 lipopolysaccharide Polymers 0.000 description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 201000010099 disease Diseases 0.000 description 24
- 235000013399 edible fruits Nutrition 0.000 description 23
- 230000003115 biocidal effect Effects 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
- 230000004083 survival effect Effects 0.000 description 21
- 238000011282 treatment Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 15
- 229940088872 Apoptosis inhibitor Drugs 0.000 description 14
- 241000588724 Escherichia coli Species 0.000 description 14
- 239000000158 apoptosis inhibitor Substances 0.000 description 14
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 239000012190 activator Substances 0.000 description 12
- 125000002837 carbocyclic group Chemical group 0.000 description 12
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 241000252983 Caecum Species 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 210000004534 cecum Anatomy 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 238000002156 mixing Methods 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- 231100000331 toxic Toxicity 0.000 description 10
- 230000002588 toxic effect Effects 0.000 description 10
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 230000001640 apoptogenic effect Effects 0.000 description 9
- 239000012472 biological sample Substances 0.000 description 9
- 238000007912 intraperitoneal administration Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 102000003952 Caspase 3 Human genes 0.000 description 8
- 108090000397 Caspase 3 Proteins 0.000 description 8
- 206010008132 Cerebral thrombosis Diseases 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 238000003771 laboratory diagnosis Methods 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 230000035939 shock Effects 0.000 description 7
- 0 COc1cc2nc(Cl)nc(NCC=C)c2cc1* Chemical compound COc1cc2nc(Cl)nc(NCC=C)c2cc1* 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 125000005239 aroylamino group Chemical group 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 6
- 238000004422 calculation algorithm Methods 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 238000002493 microarray Methods 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 5
- 208000014644 Brain disease Diseases 0.000 description 5
- 208000031229 Cardiomyopathies Diseases 0.000 description 5
- 206010007882 Cellulitis Diseases 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 5
- 208000032274 Encephalopathy Diseases 0.000 description 5
- 206010021333 Ileus paralytic Diseases 0.000 description 5
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 5
- 201000009906 Meningitis Diseases 0.000 description 5
- 206010031252 Osteomyelitis Diseases 0.000 description 5
- 206010035664 Pneumonia Diseases 0.000 description 5
- 206010037596 Pyelonephritis Diseases 0.000 description 5
- 208000001647 Renal Insufficiency Diseases 0.000 description 5
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 5
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 5
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 239000003781 beta lactamase inhibitor Substances 0.000 description 5
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 5
- 208000015294 blood coagulation disease Diseases 0.000 description 5
- 229940124587 cephalosporin Drugs 0.000 description 5
- 150000001780 cephalosporins Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 201000001421 hyperglycemia Diseases 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 201000006370 kidney failure Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 208000019423 liver disease Diseases 0.000 description 5
- 201000003453 lung abscess Diseases 0.000 description 5
- 239000003120 macrolide antibiotic agent Substances 0.000 description 5
- 201000007620 paralytic ileus Diseases 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 150000007660 quinolones Chemical class 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 201000004193 respiratory failure Diseases 0.000 description 5
- 229940124530 sulfonamide Drugs 0.000 description 5
- 150000003456 sulfonamides Chemical class 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 229940072172 tetracycline antibiotic Drugs 0.000 description 5
- 210000001541 thymus gland Anatomy 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical class COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 5
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- 102000004121 Annexin A5 Human genes 0.000 description 4
- 108090000672 Annexin A5 Proteins 0.000 description 4
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 3
- 208000007204 Brain death Diseases 0.000 description 3
- 241000288673 Chiroptera Species 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- UKESBLFBQANJHH-UHFFFAOYSA-N O=C(C1OCCC1)N1CCNCC1 Chemical compound O=C(C1OCCC1)N1CCNCC1 UKESBLFBQANJHH-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000013611 chromosomal DNA Substances 0.000 description 3
- 150000004683 dihydrates Chemical class 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 238000000018 DNA microarray Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241001433703 Escherichia coli O111:B4 Species 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102100028251 Phosphoglycerate kinase 1 Human genes 0.000 description 2
- 101710139464 Phosphoglycerate kinase 1 Proteins 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 125000005251 aryl acyl group Chemical group 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- KKCIOUWDFWQUBT-UHFFFAOYSA-N thyronine Chemical compound C1=CC(CC(N)C(O)=O)=CC=C1OC1=CC=C(O)C=C1 KKCIOUWDFWQUBT-UHFFFAOYSA-N 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- OSJPPGNTCRNQQC-UHFFFAOYSA-N 3-phosphoglyceric acid Chemical compound OC(=O)C(O)COP(O)(O)=O OSJPPGNTCRNQQC-UHFFFAOYSA-N 0.000 description 1
- TYYCNSUODPEVQP-UHFFFAOYSA-N 8-[(4-fluorophenyl)sulfonylamino]-4-(3-pyridin-3-ylpropyl)octanoic acid Chemical compound C=1C=CN=CC=1CCCC(CCC(=O)O)CCCCNS(=O)(=O)C1=CC=C(F)C=C1 TYYCNSUODPEVQP-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000051485 Bcl-2 family Human genes 0.000 description 1
- 108700038897 Bcl-2 family Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PYOZJKUCOBUBMY-UHFFFAOYSA-N CCCc1cc2nc(Cl)nc(N)c2cc1OC Chemical compound CCCc1cc2nc(Cl)nc(N)c2cc1OC PYOZJKUCOBUBMY-UHFFFAOYSA-N 0.000 description 1
- NQNKQLCWMSODEZ-UHFFFAOYSA-N CCCc1cc2nc(N(CC3)CCN3C(C3OCCC3)=O)nc(N)c2cc1OC Chemical compound CCCc1cc2nc(N(CC3)CCN3C(C3OCCC3)=O)nc(N)c2cc1OC NQNKQLCWMSODEZ-UHFFFAOYSA-N 0.000 description 1
- DGHKCBSVAZXEPP-UHFFFAOYSA-N COc(cc1c(Cl)nc(Cl)nc1c1)c1OC Chemical compound COc(cc1c(Cl)nc(Cl)nc1c1)c1OC DGHKCBSVAZXEPP-UHFFFAOYSA-N 0.000 description 1
- HWIIAAVGRHKSOJ-UHFFFAOYSA-N COc(cc1c(N)nc(Cl)nc1c1)c1OC Chemical compound COc(cc1c(N)nc(Cl)nc1c1)c1OC HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 244000176261 Viburnum cassinoides Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 238000007622 bioinformatic analysis Methods 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- RDZWDNLPNSFDPR-UHFFFAOYSA-N bis(oxolan-2-yl)methanone Chemical compound C1CCOC1C(=O)C1CCCO1 RDZWDNLPNSFDPR-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000005986 heart dysfunction Effects 0.000 description 1
- 206010019847 hepatosplenomegaly Diseases 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000010553 multiple abscesses Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 206010034754 petechiae Diseases 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960001909 terazosin hydrochloride Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for treating sepsis, in particular to application of compounds in a formula I and pharmaceutically acceptable salts, solvates, esters and prodrugs of the compounds in preparation of medicines for treating and/or preventing sepsis and complications thereof. In the formula, substituent groups are described in the specifications.
Description
Technical field
The present invention relates to treat septicemic cemia method, particularly for example terazosin of quinazoline derivant and quinazoline derivant treats and/or prevents the purposes in the medicine of septicemia and complication thereof in preparation.
Background technology
Septicemia (Sepsis) is first cause dead in global intensive care unit.Septicemia it is believed that the abnormal adjusting (Bone et al., 1996) of the inflammation that is a kind of complexity.But many clinical trials of cytokine or antiinflammatory specificity medicament fail significantly to improve septicemia patient's survival, rethink that the septicemic cemia strategy for the treatment of is necessary.Although effect is limited, antibiotic therapy is the septicemic cemia important channel for the treatment of.Basic research shows, inhibited apoptosis is blocking test septicemia effectively.In septicemia patient, the apoptosis of immunocyte can further weaken immunne response.In addition, blocking-up apoptosis has been proved to be a kind of septicemic cemia Critical policies (Braun et al., 1999 of giving treatment to; Hotchkiss et al., 2000; Chung et al., 2001; Weaver et al., 2004; Wesche-Soldato et al., 2005).
Apoptosis is the basic biological phenomena of the one of cell, multicellular organism remove in unwanted or abnormal cell, play a part necessary.It plays an important role in the growth of stable and multiple systems of the evolution of organism, interior environment.Apoptosis is not only a kind of special cell death type, and has important biological significance and complicated the Molecular Biology Mechanism.Apoptosis is the strict process of controlling of polygenes.These genes are very conservative between kind, if Bcl-2 family, caspase family, oncogene are as C-myc, antioncogene P53 etc., along with the development of Protocols in Molecular Biology has had suitable understanding to the process of apoptosis of many kinds, but apoptotic process precise mechanism still imperfectly understands up to now.And the disorder of apoptotic process may be direct or indirect with having of numerous disease relation.People understand the brain death causing due to cerebral thrombosis also with apoptosis-related.In addition the activation that, it is believed that PGK 1 (phosphoglycerate kinase 1, referred to as pgk1) contributes to for example treatment or the prevention relevant to apoptosis of some diseases.
Terazosin (Terazosin) is used for clinical conventionally with its hydrochlorate, the specification of gone on the market tablet or capsule has 1mg, 2mg and 5mg.Terazosin hydrochloride can be used for treating benign prostate hyperplasia, also can be used for treating hypertension, can be used alone or share as diuretic or Alpha 1 adrenergic blocking agent with other antihypertensive drug.For existing clinical indication, terazosin is 1～10mg for the daily dose usual range of being grown up.Terazosin is used for the treatment of benign prostatic hyperplasia (BPH), and after medication, benign prostate hyperplasia shape alleviates that to block caused smooth muscle loosening relevant with urine flow velocity improvement and the alpha 1 adrenergic receptor in neck of bladder and prostate.Because there is relatively few alpha 1 adrenergic receptor in body of bladder, therefore terazosin can alleviate the obstruction of bladder outlet and not affect the contraction of bladder.In addition, thus terazosin makes Blood pressure drop by reducing total peripheral vascular resistance.It is mainly caused by alpha 1 adrenergic receptor blocking-up that the vasodilation of terazosin, Blood pressure drop effect seem.
Up to now, still lack clinically effective apoptosis inhibitor, the novel anti-apoptotic compound of exploitation is for for example treating and/or preventing septicemia and complication thereof, and apoplexy septicemia and complication thereof are noticeable goals in research.
Summary of the invention
The object of this invention is to provide the new method and the novel targets that treat and/or prevent septicemia and complication thereof.The inventor is surprisingly found out that, a class quinazoline derivant for example clinical for benign prostate hyperplasia and hypertensive medicine terazosin separately or can effectively treat and/or prevent septicemia and complication thereof with antibiotic combinations.The present invention is based on this discovery and be accomplished.
Summary of the invention
First aspect present invention relates to formula I compound,
Or the acceptable salt of its pharmacy, solvate, ester, prodrug, wherein
R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl-, C
1-6alkyl acyl-, aryl-acyl-, C
6-10aryl-, C
5-6cycloalkyl-, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 5-or 6-ring, wherein said alkyl is optionally selected from following substituent group by 1-3 and replaces: hydroxyl, halogen;
R
2and R
3be selected from independently of one another H, halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, CN, NO
2, NH
2, OH, C
1-6alkoxyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6alkyl acyl-, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit's carbocyclic ring or heterocycle;
R
4and R
5be selected from independently of one another H, halogen, CN, NO
2, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclyloxy base-, C
1-6alkyl acyl.
Second aspect present invention relate to formula I compound for example terazosin preparation as the purposes in the medicine of apoptosis inhibitor, for example terazosin is in preparation as the purposes in the medicine of pgk1 activator for formula I compound, or for example terazosin of formula I compound treats and/or prevents the purposes in the medicine of septicemia and complication thereof in preparation.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises for example terazosin of formula I compound or the acceptable salt of its pharmacy or the solvate that treat and/or prevent effective dose, and optional pharmaceutically acceptable carrier.
Fourth aspect present invention provides a kind of medicine box product, comprising for example terazosin of formula I compound or the acceptable salt of its pharmacy or the solvate that treat and/or prevent effective dose, and at least one antimicrobial agents.
Fifth aspect present invention relates in the method that has inhibited apoptosis in the experimenter of needs or biological sample, activate the method for pgk1 having in the experimenter that needs or biological sample, or there being the method that treats and/or prevents septicemia and complication thereof in the experimenter who needs.
Sixth aspect present invention relates to as apoptosis inhibitor, as pgk1 activator or as the such as terazosin of formula I compound that treats and/or prevents septicemia and complication thereof.
Brief description of the drawings
Fig. 1 has described induction HS-Gal4 and has expressed the 1-3 hour survival rate of apoptosis HS > rpr fruit bat afterwards.Each point represents meansigma methods+SE.Test n=6.
Fig. 2 is the compound list using in drug screening.These compounds are selected based on Cmap.Divide into groups according to the positive correlation of their apoptotic micro-array chip technology or negative correlation.
Fig. 3 has described with apoptosis fruit bat model discrimination medicine.Apoptosis fruit bat represents with average+SE the survival rate of every kind of medicine.Contrast (not giving medicine) shows with white rod.Giving different medicines represents with white or black rod respectively.Test n=5.
Fig. 4 has described terazosin (4 μ g/ml) and can significantly stop due to the apoptosis due to LPS and IFN γ toxicity.What dyeed by Annexin V is apoptotic cell.The statistical result showed terazosin apoptosis capable of inhibiting cell that test obtains.Every group of cell number is counted as 200-250 cell.
In Fig. 5, Fig. 5 a has described the survival rate curve of terazosin (0.4mg/kg) to septicemic cemia LPS modelling effect.Check and carry out survival rate tracing analysis by Kaplan-Merier with Log Rank algorithm.The number of mice and the p value that use are shown in this figure.Fig. 5 b has described agarose gel and has shown LPS treatment DNA break afterwards.Every band represents the genomic DNA from a thymus for mice.The processing method of each mice is marked on the top of every band.
Fig. 6 has described mice and has used the survival rate after terazosin (0.04mg/kg) at lps injection (13.5mg/kg) after 12 hours.Check and analyze by Kaplan-Merier with Log Rank algorithm.The number of mice and the p value that use are shown in this figure, and in figure, T represents terazosin.
Fig. 7 has described the survival rate curve of septicemic cemia escherichia coli model.Escherichia coli injection was injected terazosin (0.4mg/kg) after 1.5 hours.Check and analyze by Kaplan-Merier with Log Rank algorithm.The number of mice and the p value that use are shown in this figure.
Fig. 8 has described the impact of terazosin on Escherichia coli Growth.After using terazosin 24 hours, compare it and the effect of ampicillin to bacterial growth by inhibition zone.In figure, result shows, do not add the contrast (control) of medicine and the terazosin of various dose (0.2 μ gT, 2 μ gT, 200 μ gT, 2mgT) and all can not suppress Escherichia coli Growth, and ampicillin (2mg Amp) shows inhibition Escherichia coli Growth.
Fig. 9 has described the survival rate curve of terazosin to the effect of septicemic cemia CLP model.After CLP, passed through twice terazosin of subcutaneous injection in 1.5 and 24 hours with 0.08mg/kg.Use separately antibiotic Co-Am to have the increase phenomena of mortality to CLP model.And the combination of terazosin and antibiotic Co-Am has protective effect to septicemic cemia CLP model.Check and analyze by Kaplan-Merier with LogRank algorithm.Quantity and the p value of the mice using are shown in this figure.In figure, T represents terazosin, and Co-Am represents the mixture that the weight ratio of amoxicillin and clavulanate potassium is 4: 1.
Figure 10 has described the Western blotting of the activity form of caspase-3 3 in Raw 264.7 cells of LPS and IFN γ processing.Albumen applied sample amount in the group of three different disposal is identical.
Figure 11 has described terazosin chemical modification and has produced the chemical process that Affi-gel connects.
In Figure 12, figure a has described to angle albumen to obtain a protein band obviously only occurring (at the band with arrow labelling between 43kd to 55kd) in experimental group by terazosin agarose beads.Be accredited as Pgk1 through protein spectrum.Figure b has described to pass through terazosin agarose beads albumen post with the Pgk1 of vivoexpression, has still obtained Pkg1 band, illustrates that terazosin and Pgk1 are directly combinations.
The impact of the terazosin that Figure 13 has described variable concentrations on Pgk1 activity.
Figure 14 has described to express Raw 264.7 cells of Pgk1 can antagonism apoptosis.There is the cell membrane phospholipid acyl serine of apoptosis by rollover in adipose membrane laterally.Annexin V and phospholipids incorporate, thereby the cell of labelling apoptosis.
Figure 15 has described, after mouse infection Pgk1 slow virus, in CLP model, to show protective effect.Every injected in mice 1x10
7the virus of individual active unit, tested after one week.
Figure 16 has described the effect of terazosin reduction mouse blood sugar
Figure 17 has described the effect of the anti-cerebral thrombosis of terazosin
Detailed description of the invention
First aspect present invention relates to formula I compound,
Or the acceptable salt of its pharmacy, solvate, ester, prodrug, wherein
R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl-, C
1-6alkyl acyl-, aryl-acyl-, C
6-10aryl-, C
5-6cycloalkyl, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 5-or 6-ring, wherein said alkyl is optionally selected from following substituent group by 1-3 and replaces: hydroxyl, halogen;
R
2and R
3be selected from independently of one another H, halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, CN, NO
2, NH
2, OH, C
1-6alkoxyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6alkyl acyl-, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit's carbocyclic ring or heterocycle;
R
4and R
5be selected from independently of one another H, halogen, CN, NO
2, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclyloxy base-, C
1-6alkyl acyl.
According to the compound of first aspect present invention, wherein R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-4alkoxy-C
1-4alkyl-, C
2-4thiazolinyl-, C
2-4alkynyl-, C
1-4alkoxyl-, C
1-4alkyl acyl-, phenyl acyl group-, phenyl-, C
5-6cycloalkyl, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 5-or 6-ring, wherein said alkyl is optionally selected from following substituent group by 1-3 and replaces: hydroxyl, halogen.In one embodiment, described R
1aand R
1bbe selected from independently of one another H ,-NH
2,-OH, CH
3c (O)-,-(CH
2)
2-O-(CH
2)
2-OH ,-CH
2-CH=CH
2,-CH
2-C ≡ CH ,-(CH
2)
5cH
3,-(CH
2)
4-CF
3, cyclohexyl ,-CH
2-(CH
2)
3-CH
2-,-(CH
2)
2o (CH
2)
2-OH ,-Ph, CH
3,-C (O)-CF
3,-C (O)-Ph.
According to the compound of first aspect present invention, wherein R
2and R
3be selected from independently of one another H, halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
1-6alkoxyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit's carbocyclic ring or heterocycle.In one embodiment, described R
2and R
3be selected from independently of one another H, CH
3o-,-CH
2-O-CH
2-,-O (CH
2)
2oC
2h
5,-OC (O) CH
3,-F ,-CF
3,
and 1,2-pyridine ring ,-NHCOCH
3,-(CH
2)
2cH
3,-NHCOPh,
According to the compound of first aspect present invention, wherein R
4and R
5be selected from independently of one another H, halogen, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, halo C
1-6alkyl-, C
1-6alkoxyl-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclyloxy base.In one embodiment, described R
4and R
5be selected from independently of one another H ,-O (CH
2)
2oC
2h
5,-OC (O) CH
3,-OCH
3,
-CF
3,-F ,-NHCOCH
3,-(CH
2)
3cH
3,-NHCOPh,
According to the compound of first aspect present invention, wherein said alkyl, thiazolinyl and alkynyl are straight chain or side chain.In one embodiment, described C
1-6alkyl is selected from C
1-5alkyl, C
1-4alkyl, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group.In one embodiment, described C
2-6thiazolinyl is selected from C
2-5thiazolinyl, C
2-4thiazolinyl, for example vinyl, acrylic, pi-allyl.In one embodiment, described C
2-6alkynyl is selected from C
2-5alkynyl, C
2-4alkynyl.
According to the compound of first aspect present invention, wherein said C
5-6cycloalkyl is selected from cyclopenta and cyclohexyl.
According to the compound of first aspect present invention, wherein said aryl is selected from phenyl, naphthyl, preferably phenyl.
According to the compound of first aspect present invention, wherein said halogen is selected from fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
According to the compound of first aspect present invention, it is the compound (their structure is as described in compound preparation example part) that is selected from the following Co.1 to Co.33 of being numbered:
Note: active * represents that each compound tests under 0.02 μ g/ml concentration, activates the multiple of Pgk1 activity.
Second aspect present invention relate to formula I compound for example terazosin preparation as the purposes in the medicine of apoptosis inhibitor.
Second aspect present invention also relate to formula I compound for example terazosin preparation as the purposes in the medicine of pgk1 activator.
Second aspect present invention also relates to for example terazosin of formula I compound and treats and/or prevents the purposes in the medicine of septicemia and complication thereof in preparation.
Second aspect present invention also relates to for example terazosin of formula I compound and treats and/or prevents the purposes in the medicine of hyperglycemia, cerebral thrombosis and complication thereof in preparation.
According to the purposes of second aspect present invention, wherein said apoptosis inhibitor treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the purposes of second aspect present invention, wherein said pgk1 activator treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the purposes of second aspect present invention, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.
According to the purposes of second aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the purposes of second aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every daily dose of human or animal (mammal), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
According to the purposes of second aspect present invention, wherein said formula I compound is terazosin.
According to the purposes of second aspect present invention, wherein terazosin is the acceptable salt of pharmacy or its solvate of terazosin.
According to the purposes of second aspect present invention, wherein said terazosin is the hydrochlorate of terazosin.
According to the purposes of second aspect present invention, wherein said terazosin is the hydrate of terazosin hydrochlorate.In one embodiment, terazosin is the dihydrate of terazosin hydrochlorate.
According to the purposes of second aspect present invention, in wherein said medicine, also comprise at least one antimicrobial agents.
According to the purposes of second aspect present invention, in wherein said medicine, also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
According to the purposes of second aspect present invention, in wherein said medicine, also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, also comprise at least one antimicrobial agents in described medicine, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, in described medicine, also comprise amoxicillin and clavulanate potassium.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises for example terazosin of formula I compound or the acceptable salt of its pharmacy or the solvate that treat and/or prevent effective dose, and optional pharmaceutically acceptable carrier.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least one antimicrobial agents.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, also comprise at least one antimicrobial agents in described pharmaceutical composition, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, in described pharmaceutical composition, also comprise amoxicillin and clavulanate potassium.
According to the pharmaceutical composition of third aspect present invention, it is for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the pharmaceutical composition of third aspect present invention, it is as pgk1 activator.In one embodiment, wherein said pgk1 activator treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the pharmaceutical composition of third aspect present invention, it is be used for the treatment of and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.In one embodiment, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the pharmaceutical composition of third aspect present invention, it is be used for the treatment of and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
According to the pharmaceutical composition of third aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every daily dose of human or animal (mammal), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
Fourth aspect present invention provides a kind of medicine box product, comprising for example terazosin of formula I compound or the acceptable salt of its pharmacy or the solvate that treat and/or prevent effective dose, and at least one antimicrobial agents.
According to the medicine box product of fourth aspect present invention, for example terazosin of wherein said formula I compound or the acceptable salt of its pharmacy or solvate are in same compositions or in the compositions separating with described at least one antimicrobial agents.
According to the medicine box product of fourth aspect present invention, for example terazosin of wherein said formula I compound or the acceptable salt of its pharmacy or solvate are in the compositions separating with described at least one antimicrobial agents.
According to the medicine box product of fourth aspect present invention, comprising the first compositions being separated from each other and the second compositions, described the first compositions comprises for example terazosin of formula I compound or the acceptable salt of its pharmacy or solvate and the optional pharmaceutically acceptable carrier that treat and/or prevent effective dose, and described the second compositions comprises and treats and/or prevents the antimicrobial agents of effective dose and optional pharmaceutically acceptable carrier.
According to the medicine box product of fourth aspect present invention, wherein said antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
According to the medicine box product of fourth aspect present invention, wherein said antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, described antimicrobial agents comprises amoxicillin and clavulanate potassium.
According to the medicine box product of fourth aspect present invention, it is for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the medicine box product of fourth aspect present invention, it is as pgk1 activator.In one embodiment, wherein said pgk1 activator treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the medicine box product of fourth aspect present invention, it is be used for the treatment of and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.In one embodiment, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the medicine box product of fourth aspect present invention, it is be used for the treatment of and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
According to the medicine box product of fourth aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every daily dose of human or animal (mammal), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
Fifth aspect present invention relates in the method that has inhibited apoptosis in the experimenter of needs or biological sample, and the method comprises the such as terazosin of formula I compound of using effective dose to described experimenter or biological sample.
Fifth aspect present invention also relates to the method that activates pgk1 in the experimenter of needs or biological sample having, and the method comprises the such as terazosin of formula I compound of using effective dose to described experimenter or biological sample.
Fifth aspect present invention also relates to the method that treats and/or prevents septicemia and complication thereof in the experimenter who has needs, and the method comprises the such as terazosin of formula I compound of using effective dose to described experimenter.
Fifth aspect present invention also relates to the method that treats and/or prevents hyperglycemia, cerebral thrombosis and complication disease thereof in the experimenter who has needs, and the method comprises the such as terazosin of formula I compound of using effective dose to described experimenter.
According to the method for fifth aspect present invention, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.
According to the method for fifth aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the method for fifth aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every daily dose of human or animal (mammal), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
According to the method for fifth aspect present invention, wherein said formula I compound is terazosin.
According to the method for fifth aspect present invention, wherein terazosin is the acceptable salt of pharmacy or its solvate of terazosin.
According to the method for fifth aspect present invention, wherein said terazosin is the hydrochlorate of terazosin.
According to the method for fifth aspect present invention, wherein said terazosin is the hydrate of terazosin hydrochlorate.In one embodiment, terazosin is the dihydrate of terazosin hydrochlorate.
According to the method for fifth aspect present invention, wherein also comprise at least one antimicrobial agents of using effective dose to described experimenter or biological sample.
According to the method for fifth aspect present invention, wherein also comprise at least one antimicrobial agents of using effective dose to described experimenter or biological sample, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
According to the method for fifth aspect present invention, wherein also comprise at least one antimicrobial agents of using effective dose to described experimenter or biological sample, described antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, described antimicrobial is amoxicillin and clavulanate potassium.
Sixth aspect present invention relates to the such as terazosin of formula I compound as apoptosis inhibitor.
Sixth aspect present invention also relates to the such as terazosin of formula I compound as pgk1 activator.
Sixth aspect present invention also relates to as the such as terazosin of formula I compound that treats and/or prevents septicemia and complication thereof.
Sixth aspect present invention also relates to as the such as terazosin of formula I compound that treats and/or prevents hyperglycemia, cerebral thrombosis and complication thereof.
According to the formula I compound of sixth aspect present invention, wherein said apoptosis inhibitor treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the formula I compound of sixth aspect present invention, wherein said pgk1 activator treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the formula I compound of sixth aspect present invention, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.
According to the formula I compound of sixth aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the formula I compound of sixth aspect present invention, wherein said formula I compound for example, is 0.001～5mg/kg for every daily dose of human or animal (mammal), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
According to the formula I compound of sixth aspect present invention, it is terazosin.
According to the formula I compound of sixth aspect present invention, it is the acceptable salt of pharmacy or its solvate of terazosin.
According to the formula I compound of sixth aspect present invention, it is the hydrochlorate of terazosin.
According to the formula I compound of sixth aspect present invention, it is the hydrate of terazosin hydrochlorate, for example the dihydrate of terazosin hydrochlorate.
According to the formula I compound of sixth aspect present invention, it also combines with at least one antimicrobial agents.
According to the formula I compound of sixth aspect present invention, it also combines with at least one antimicrobial agents, and described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
According to the formula I compound of sixth aspect present invention, it also combines with at least one antimicrobial agents, and described antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, described antimicrobial agents is amoxicillin and clavulanate potassium.
The either side according to the present invention, the use amount of wherein said for example terazosin of formula I compound can be with reference to existing clinical medicine dose.For example, when for human therapy and/or prevention septicemia and complication thereof, the using dosage of terazosin can be at present clinically this medicine for example, for 0.01～100 times of the dosage of Other diseases (hypertension), preferably 0.02～80 times, preferably 0.05～20 times, preferably 0.1～10 times, preferably 0.1～5 times, preferably 0.2～5 times, preferably 0.2～2 times.
The either side according to the present invention, the use amount of wherein said antimicrobial agents can be with reference to existing clinical medicine dose.For example, when for human therapy and/or prevention septicemia and complication thereof, its using dosage can be at present clinically this antimicrobial agents for example, for 0.01～100 times of the dosage of Other diseases (infection), preferably 0.02～80 times, preferably 0.05～20 times, preferably 0.1～10 times, preferably 0.2～5 times.
The either side according to the present invention, wherein said amoxicillin and/or the use amount of clavulanate potassium can be with reference to existing clinical medicine doses.For example, when for human therapy and/or prevention septicemia and complication thereof, its using dosage can be at present clinically this amoxicillin and/or clavulanate potassium for example, for 0.01～100 times of the dosage of Other diseases (infection), preferably 0.02～80 times, preferably 0.05～20 times, preferably 0.1～10 times, preferably 0.2～5 times.
In some embodiments of either side of the present invention, described formula I compound does not comprise the compound of numbering Co.33.
The feature that arbitrary embodiment of either side of the present invention or this either side has is equally applicable to arbitrary embodiment of other either side or this other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
As described herein, term " septicemia " is also called " septicemia ", it has conventionally known implication of those skilled in the art, and typically refer to a kind of because antibacterial and/or other microorganism enter blood circulation, and therein growth and breeding, produce toxin and the general severe infections that causes.Clinical manifestation is increased etc. for heating, serious toxemic symptoms, erythra petechia, hepatosplenomegaly and leukocyte count.Gram positive coccus septicemia is easily migrated focus; The easy concurrent infection shock of gram-negative bacteria septicemia.When septicemia is called pyaemia septica or is called sepsis during with multiple abscess.
As described herein, term " pgk1 activator " refers to PGK 1 (phosphoglycerate kinase 1, referred to as pgk1) activator, its can activate pgk1 and therefore those skilled in the art understand its treatment that can be used for relevant disease or disease, prevent, alleviate and/or alleviate.
Term " about " used herein, it typically refers to the range of error that comprises that this area allows, for example ± 10%, for example ± 5%, for example ± 2%.
As described herein, term " effective dose " refers to the dosage that can realize treatment in experimenter, prevent, alleviate and/or alleviate disease of the present invention or disease.
As described herein, term " pharmaceutical composition ", it can exchange and use with " compositions ", refers to be used in experimenter to realize the material for the treatment of, prevent, alleviate and/or alleviate disease of the present invention, disease, symptom.
As described herein, term " experimenter " or " patient ", can refer to accept the present composition and extract to treat, to prevent, to alleviate and/or to alleviate the animal of disease of the present invention, disease, symptom, particularly mammal, such as people, Canis familiaris L., monkey, cattle, horse etc.
As described herein, term " disease or symptom " refers to a kind of condition of described experimenter, and this condition is relevant with disease of the present invention or symptom.
As described herein, " % ", as do not specialize, while being solid for total material, generally refer to the percentage ratio of w/w, while being liquid for total material, generally refer to the percentage ratio of weight/volume.Certainly, be liquid and solute while being liquid for total material, the percentage ratio that characterizes this liquid solute generally refers to the percentage ratio of volume/volume.
Terazosin (Terazosin, (4-(4-amido-6,7-dimethoxy quinazoline-2-yl) piperazine-1-yl) (oxolane-2-yl) ketone, C
19h
25n
5o
4), it has following chemical structural formula:
In the present invention, in the time mentioning terazosin, it not only comprises the compound shown in above structure, also comprises the acceptable salt of pharmacy (for example hydrochlorate) of said structure compound, and such as hydrate of the solvate of said structure compound and salt thereof.In a preferred embodiment of the invention, described terazosin refers to terazosin hydrochloride dihydrate.The present invention is below used as the terazosin of formula I compound typical case to carry out large quantity research to show the beat all effect of the present invention; Below testing particularly in biological test, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The present invention attempts screening apoptosis inhibitor from clinical medicine.First, the present invention uses the model of cell apoptosis of fruit bat by the gene expression of micro-array chip technical Analysis.Then, the present invention uses contact figure (connectivity map, Cmap) to determine candidate's apoptosis blocker by bioinformatic analysis decision.Then, the present invention has screened the apoptotic drug candidate of inhibition dipteral insect fruit bat (Drosophila).As a result, the present invention has determined terazosin, and it is for alleviating hypertensive clinical application.In addition, the present invention finds that terazosin can suppress the apoptosis being mediated by bacterial endotoxin (lipopolysaccharide, LPS, 2 μ g/ml) and interferon gamma (IFN γ, 50U/ml) in macrophage.In addition, the present invention's discovery, in septicemic cemia three test models, terazosin can reduce the mortality rate of mice greatly.What is interesting is, compared with independent use antibiotic, make terazosin and antibiotic combinations can produce better protective effect.Result of the present invention shows, terazosin is a kind of new apoptosis inhibitor.It can be used for combining with antibiotic therapy.
Fruit bat is the important animal model system of screening of medicaments.The apoptosis pathway of caspase-3 (caspase) in addition ,-mediation is fully conservative between dipteral insect and people.For example Reaper (rpr) brings into play Main Function (White et al., 1994) in the apoptosis of fruit bat.Although, can cause abnormal cell apoptosis and the organic death (White et al., 1996) of extensive distribution from the rpr expression of heat shock promoter.Whether the present invention has studied the present invention program can screen apoptosis blocker with fruit bat Apoptosis Model.HS-Gal4 (a kind of whole body expression and heat activated promoter), can impel 5 ' any genetically modified expression repeating that contains UAS (upstream activating sequence).When make this HS-Gal4 fruit bat and UAS-Reaper drosophila hybrid (referred to as HS > rpr) at 18 DEG C time, female descendant is normal development from start to finish.But, at 37 DEG C, give heat shock 2-3 hour, approximately the offspring of 50-70% after 14-24 hour dead (Fig. 1).The present invention has selected 25 kinds of compounds (Fig. 2) that rank is forward, and the impact of their fatality rate on HS > rpr is determined in the pacing of going forward side by side.The present invention finds only have terazosin can improve significantly the survival (Fig. 3) of HS > rpr fruit bat.
In order to test whether also inhibited apoptosis in the mammalian cell of cultivating of terazosin, the present invention is by LPS and IFN γ cell death inducing in macrophage RAW264.7 cell, and this LPS and IFN γ bring out apoptotic known medicament in cultured cell.The present invention is by the observation of cell apoptosis (Fig. 4) that dyes with Annexin V.Inventor's discovery, the cell that LPS (2 μ g/ml) and IFN γ (50U/ml) process causes cell membrane damage, turns up, thereby is dyeed by Annexin V.This is a kind of apoptosis pattern of classics.And application terazosin (4 μ g/ml) can reduce by 50% apoptosis (Fig. 4).Importantly, the present invention finds unexpectedly effectively inhibited apoptosis and can be further used for treating and/or preventing septicemia and complication thereof of terazosin.
In order further to study the effect of terazosin in septicemic cemia mammal model, the present invention has studied the mice of accepting LPS treatment.The present invention's discovery, at injection LPS (13.5mg/kg, i.p.) the 1.5 hours remarkable increase of injection terazosin (0.4mg/kg i.p) meeting mouse survivals afterwards, (Fig. 5 a).In order to confirm that terazosin is to apoptotic effect, the present invention has detected apoptotic label DNA break.As the organ that produces immunocyte, during septicemia, thymus is responsive (Ayala et al., 1998) to apoptosis.Therefore, the present invention has compared the genomic DNA and the genomic DNA of mouse thymus that adds terazosin treatment with LPS of the mouse thymus of the LPS treatment of using by oneself.Result shows, in the mice of processing at LPS, obvious DNA ladder type has occurred, but in the mice with terazosin treatment, greatly reduces that (Fig. 5 b).Whether can play a role in the septicemic cemia later stage in order to test terazosin, the present invention is 12 hours injection terazosins after using LPS.Result demonstration, terazosin still has satisfied effect (Fig. 6).
Then, in the septicemia model of Escherichia Coli Injection, tested terazosin.Result shows, the death (Fig. 7) that terazosin can protect mice to be induced by escherichia coli.In order to measure potential antibacterial effect, the inventor has detected the Escherichia coli Growth situation under terazosin exists.Result demonstration, with respect to ampicillin, terazosin can not suppress Escherichia coli Growth (Fig. 8).
Because LPS and escherichia coli model only can be simulated gram-negative bacteria and infected, the present invention has further tested terazosin in caecum ligation and puncture (CLP) model, this model it is believed that it is tentative septicemic cemia goldstandard model (Parker and Watkins, 2001; Wichterman et al., 1980).First, bolt of the present invention is surveyed the terazosin (for the identical concentration of LPS model) of 0.4mg/kg.But, at initial 5 days, not faster (data do not show) that the mice of injection terazosin is more dead than matched group.The present invention infers that this may be because the serious heart dysfunction and the hypotension that are caused by CLP cause.Therefore the function that, medicine reduces blood pressure may have been covered the effect of its anti-apoptosis.For head it off, terazosin concentration is reduced to 0.08mg/kg by the present invention, and the inventor has measured the impact of this concentration of injected in mice on blood pressure, finds that mice blood pressure is completely normal.This result is used in it in rat, can not reduce blood pressure consistent (Kyncl et al., 1985).What is interesting is, in the time within 1.5 hours and 24 hours after operation, injecting 2 times, terazosin has significantly promoted the survival (Fig. 9) of CLP model small mouse.Secondly, the present invention has tested terazosin and antibiotic combinations, in the present invention, antibiotic amoxicillin and clavulanate potassium (Co-Am are selected, the weight ratio of amoxicillin and clavulanate potassium is 4: 1, in the time that other place of the present invention is mentioned in the mode of concrete example or example, also refer to the proportioning of this 4: 1.Those skilled in the art understand, in the time making a general reference the combination of amoxicillin and clavulanate potassium, the weight ratio of amoxicillin and clavulanate potassium can be 1: 1 to 10: 1, particularly 1: 1 to 7: 1, for example approximately 1: 1, approximately 4: 1, approximately 7: 1) with terazosin combination.The present invention's discovery, terazosin combines with Co-Am the Co-Am in independent comparing and demonstrates stronger protective effect (Fig. 9).In addition, this combination therapy has still proved the therapeutic effect of CLP administration in 6 hours afterwards.
Whether relevant with its function as α 1-adrenoceptor inhibitor in order to test the protection effect of terazosin; the present invention has checked Minidress (0.4mg/kg; i.p.), it is another kind of α 1-adrenoceptor blocker (Cavero et al., 1977).The present invention finds that septicemia that Minidress causes LPS is without any curative effect.These results show, terazosin can significantly increase the septicemic cemia survival rate that suppresses LPS-mediation, and its function is likely by apoptotic inhibitory action instead of targeting α 1-adrenoceptor.
Block apoptotic Biological Mechanism in order to study terazosin, the present invention has sought its latent effect to inhibited apoptosis protease, realizing due to the apoptosis in fruit bat is mainly the caspase-3 activation (McCall and Steller, 1997) by inherent.But western blot analysis of the present invention shows, the activity form (homologous genes of Dpc-1 and drICE in fruit bat) of carrying out daughter cell apoptotic proteins enzyme 3 reduces (Figure 10) because of terazosin.The present invention infers, the upstream target of terazosin scalable caspase-3 3.For sldh gene, the present invention links terazosin in agarose beads, and Figure 11 has shown its chemosynthesis approach.Then in Raw 264.7 cell extracts, angle albumen, found that (Figure 12 a) to have more a band with respect to blank and medicine competition matched group.Through Mass Spectrometric Identification, this band is Pgk1.For whether the combination of determining terazosin and Pgk1 is direct relation, the inventor has expressed also purification in the antibacterial Pgk1 albumen of mice, found that terazosin can be external directly in conjunction with Pgk1 albumen, (Figure 12 b).Because cross expression Pgk1 apoptosis capable of inhibiting cell (Mazzoni et al., 2009) in yeast, the inventor guesses that terazosin may activate the enzymatic activity of Pgk1.In order to prove this conjecture, the inventor has detected Pgk1 vitro enzyme activity.Found that, the terazosin of 0.05 μ M can activate nearly 3 times of the enzymatic activity of Pgk1, can reduce the activation (Figure 13) to enzymatic activity and increase terazosin concentration to 0.4 μ M.If Pgk1 enzymatic activity is the reason of inhibited apoptosis, crossing expression Pkg1 just should inhibited apoptosis.The inventor's experimental result shows, by the RAW264.7 cell line of expressing the foundation of Pgk1 slow virus, has significantly reduced LPS and IFN γ apoptosis after treatment; And there is not change (Figure 14) in the apoptosis of excessively expressing EGFP.Further, the inventor has expressed Pgk1 with subcutaneous injection slow virus or EGFP contrasts in mice.After one week, do CLP operation, found that, with respect to the one group of mice that infects green fluorescent protein, the mice of injection Pgk1 virus has significantly been improved survival rate (Figure 15).The present invention is not subject to the constraint of any particular theory, and the inventor thinks that Pgk1 is the target spot that terazosin is new.
Research of the present invention shows, terazosin can easily be converted in clinical practice, and without the existing antibiotic therapy program of amendment.Below biological test of the present invention is elaborated.
embodiment
a, compound preparation example part
Following preparation example has exemplarily been prepared segment bounds I compound of the present invention, and each compound represents with Co.1 to Co.32 respectively, and Co.33 represents terazosin.In the reaction process of following preparation example, " reflux " represents to reflux, and " 1-pentanol " represents 1-amylalcohol.
the preparation of preparation example 1:Co.1
Step 1: pass into ammonia to being dissolved with in the 200mL tetrahydrofuran solution of compound 1a (50mmol), reaction is carried out 36 hours at 25 DEG C.In system, there are a large amount of white solids to separate out, filter after gained white solid oxolane washs and obtain final products 1f.Productive rate is: 63%.
Step 2: add 15mL acetic anhydride to compound 1f (10mmol), reaction refluxes 2 hours.Cool to room temperature, has a large amount of white solids to separate out in system, filter after gained white solid oxolane washs and obtain final products 1g.Productive rate is: 63%.
Step 3: the in the situation that of argon atmospher, add 1h (2mmol) to being dissolved with in the solution of 1-amylalcohol of 1g (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.1 with obtaining final products 1i after ether/recrystallizing methanol.Productive rate is: 60%.
1H NMR (300MHz, CDCl
3): 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), d 2.61 (s, 3H, CH
3), 3.47-4.07 (m, 11H, thf-H, pip-H and CH2CH2O), 3.93 (s, 3H, OCH
3), 3.97 (s, 3H, OCH3), 4.82 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 430.20928 (M+H) (value of calculation: 430.20904); Elementary analysis: (C, 58.74; H, 6.34; N, 16.30; O, 18.63); Value of calculation: (C, 58.73; H, 6.34; N, 16.31; O, 18.63).
the preparation of preparation example 2:Co.2
Step 1: add compound 1b (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 4 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 1c after petrol ether/ethyl acetate recrystallization.Productive rate is: 41%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 1c (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.2 with obtaining final products 1e after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 14H, thf-H, pip-H and CH
2cH
2o), 3.84 (s, 3H, OCH
3), 3.87 (s, 3H, OCH
3), 4.73 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); 13C NMR (DMSO-d6): d 25.2,27.9,40.9,44.1,44.6,55.8,56.2,60.1,68.1,68.2,72.1,74.9,102.4,104.4,106.9,146.2,154.4,154.2,158.6,169.6; HR-MS (ESI-positivity): 476.25120 (M+H) (value of calculation: 476.25091); Elementary analysis: C, 58.08; H, 7.00; N, 14.73; O, 20.19; Value of calculation: (C, 58.09; H, 6.99; N, 14.73; O, 20.19).
the preparation of preparation example 3:Co.3
Step 1: add hydrazine hydrate (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 4 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 3a after petrol ether/ethyl acetate recrystallization.Productive rate is: 61%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 3a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.3 with obtaining final products 3b after ether/recrystallizing methanol.Productive rate is: 31%.
1H NMR (300MHz, DMSO-d6): d 1.87 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.43-4.07 (m, 6H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.63 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 403.20938 (M+H) (value of calculation: 403.20946).
the preparation of preparation example 4:Co.4
Step 1: add hydration oxyammonia (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 3 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 4a after petrol ether/ethyl acetate recrystallization.Productive rate is: 88%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 4a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.4 with obtaining final products 4b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, DMSO-d6): 1.81 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 6H, thf-H, pip-H), 3.87 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.43 (m, 1H, thf-2H), 7.26 (s, 1H, Ar-5H), 7.74 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 404.19339 (M+H) (value of calculation: 404.19341).
the preparation of preparation example 5:Co.5
Step 1: add allyl amine (22mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 8 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 5a after petrol ether/ethyl acetate recrystallization.Productive rate is: 31%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 4a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.5 with obtaining final products 5b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, DMSO-d6): 1.82 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 6H, thf-H, pip-H), 3.87 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.04 (d, 2H), 4.43 (m, 1H, thf-2H), 5.19-5.23 (m, 2H), 5.82-5.88 (m, 1H), 7.26 (s, 1H, Ar-5H), 7.74 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 428.22978 (M+H) (value of calculation: 428.22986).
the preparation of preparation example 6:Co.6
Step 1: add allyl amine (28mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 10 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 6a after petrol ether/ethyl acetate recrystallization.Productive rate is: 44%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 4a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.6 with obtaining final products 6b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, DMSO-d6): 1.82 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 6H, thf-H, pip-H), 3.80 (s, 2H), 3.87 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.04 (d, 2H), 4.43 (m, 1H, thf-2H), 7.26 (s, 1H, Ar-5H), 7.74 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 426.21413 (M+H) (value of calculation: 426.21408).
the preparation of preparation example 7:Co.7
Step 1: add compound 7a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 3 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 7b after petrol ether/ethyl acetate recrystallization.Productive rate is: 61%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 7b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.7 with obtaining final products 7c after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 0.86-1.62 (m, 11H), 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.46-4.07 (m, 8H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.83 (s, 3H, OCH
3), 4.75 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 472.29238 (M+H) (value of calculation: 472.29229).
the preparation of preparation example 8:Co.8
Step 1: add compound 8a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 1.5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 8b after petrol ether/ethyl acetate recrystallization.Productive rate is: 71%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 8b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.8 with obtaining final products 8c after ether/recrystallizing methanol.Productive rate is: 42%.
1H NMR (300MHz, DMSO-d6): 1.22-1.72 (m, 11H), 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.05 (m, 8H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.73 (s, 3H, OCH
3), 4.43 (m, 1H, thf-2H), 7.54 (s, 1H, Ar-5H), 7.86 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 512.24846 (M+H) (value of calculation: 512.24859).
the preparation of preparation example 9:Co.9
Step 1: add compound 9a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 2.5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 9b after petrol ether/ethyl acetate recrystallization.Productive rate is: 21%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 9b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.9 with obtaining final products 9c after ether/recrystallizing methanol.Productive rate is: 43%.
1H NMR (300MHz, DMSO-d6): 1.32-1.52 (m, 10H), 1.86 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 9H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.79 (s, 3H, OCH
3), 4.46 (m, 1H, thf-2H), 7.33 (s, 1H, Ar-5H), 7.78 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 470.27673 (M+H) (value of calculation: 470.27658).
the preparation of preparation example 10:Co.10
Step 1: add compound 10a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 9b after petrol ether/ethyl acetate recrystallization.Productive rate is: 36%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 9b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.10 with obtaining final products 10c after ether/recrystallizing methanol.Productive rate is: 43%.
1H NMR (300MHz, DMSO-d6): 1.33-1.47 (m, 6H), 1.86 (m, 2H, thf-H), 2.04 (m, 2H, thf-H), 3.57-4.09 (m, 12H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.77 (s, 3H, OCH
3), 4.48 (m, 1H, thf-2H), 7.37 (s, 1H, Ar-5H), 7.79 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 456.26108 (M+H) (value of calculation: 456.26119).
the preparation of preparation example 11:Co.11
Step 1: add compound 11b (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining final products 11c after petrol ether/ethyl acetate recrystallization.Productive rate is: 41%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 11b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.11 with obtaining final products 11c after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 1.79 (m, 2H, thf-H), 2.06 (m, 2H, thf-H), 3.27-4.08 (m, 17H, thf-H, pip-H and CH
2cH
2o), 3.85 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.73 (m, 1H, thf-2H), 7.26 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 490.26656 (M+H) (value of calculation: 490.26658).
the preparation of preparation example 12:Co.12
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 12a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.12 with obtaining final products 12b after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 1.79 (m, 2H, thf-H), 2.06 (m, 2H, thf-H), 3.47-4.08 (m, 11H, thf-H, pip-H), 3.85 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.73 (m, 1H, thf-2H), 6.86-7.62 (m, 7H, Ar-H); HR-MS (ESI-positivity): 464.22978 (M+H) (value of calculation: 464.22996).
the preparation of preparation example 13:Co.13
Step 1: add 20mL13a to compound 1f (10mmol), reaction refluxes 2 hours.Cool to room temperature, has a large amount of white solids to separate out in system, filter after gained white solid oxolane washs and obtain final products 13b.Productive rate is: 82%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 13b (2mmol).After reaction system refluxes 5.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.13 with obtaining final products 13c after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, CDCl
3): 1.80 (m, 2H, thf-H), 2.06 (m, 2H, thf-H), 3.47-4.07 (m, 13H, thf-H, pip-H), 3.93 (s, 3H, OCH
3), 3.97 (s, 3H, OCH3), 4.82 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 484.18078 (M+H) (value of calculation: 484.18084).
the preparation of preparation example 14:Co.14
Step 1: add 22mL14a to compound 1f (10mmol), reaction refluxes 2 hours.Cool to room temperature, has a large amount of white solids to separate out in system, filter after gained white solid oxolane washs and obtain final products 14b.Productive rate is: 55%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 14b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.14 with obtaining final products 14c after ether/recrystallizing methanol.Productive rate is: 48%.
1H NMR (300MHz, CDCl
3): d 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.45-4.47 (m, 13H, thf-H, pip-H), 3.93 (s, 3H, OCH
3), 3.97 (s, 3H, OCH
3), 4.82 (m, 1H, thf-2H), 6.89-7.72 (m, 7H, Ar-H); HR-MS (ESI-positivity): 492.22469 (M+H) (value of calculation: 492.22478).
the preparation of preparation example 15:Co.15
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 15b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.15 with obtaining final products 15c after ether/recrystallizing methanol.Productive rate is: 55%.
1H NMR (300MHz, CDCl
3): 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.49-4.27 (m, 13H, thf-H, pip-H), 4.82 (m, 1H, thf-2H), 6.07 (s, 2H, CH
2oCH
2) 7.27 (s, 1H, Ar-5H), 7.68 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 372.16718 (M+H) (value of calculation: 372.16726).
the preparation of preparation example 16:Co.16
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 16a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.16 with obtaining final products 16a after ether/recrystallizing methanol.Productive rate is: 45%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (t, 6H, CH
3-H) 1.87 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.45-4.17 (m, 25H, thf-H, pip-H), 4.79 (m, 1H, thf-2H), 7.27 (s, 1H, Ar-5H), 7.68 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 504.28215 (M+H) (value of calculation: 504.28221).
the preparation of preparation example 17:Co.17
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 17a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.17 with obtaining final products 17a after ether/recrystallizing methanol.Productive rate is: 55%.
1H NMR (300MHz, CDCl
3): 1.83 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), d 2.61 (s, 3H, CH
3), 3.47-4.07 (m, 11H, thf-H, pip-H and CH2CH2O), 3.94 (s, 3H, OCH
3), 4.82 (m, 1H, thf-2H), 7.18 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 416.19344 (M+H) (value of calculation: 416.19339).
the preparation of preparation example 18:Co.18
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 18a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.18 with obtaining final products 18b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, CDCl
3): 1.80 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.80 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 376.17853 (M+H) (value of calculation: 376.17849).
the preparation of preparation example 19:Co.19
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 19a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.19 with obtaining final products 19b after ether/recrystallizing methanol.Productive rate is: 54%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (m, 6H), 1.89 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.07-4.07 (m, 15H, thf-H, pip-H), (4.85 m, 1H, thf-2H), (7.63 s, 1H, Ar-5H), (7.89 s, 1H, Ar-8H); HR-MS (ESI-positivity): 479.23836 (M+H) (value of calculation: 479.23823).
the preparation of preparation example 20:Co.20
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 20a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.20 with obtaining final products 20b after ether/recrystallizing methanol.Productive rate is: 54%.
1H NMR (300MHz, CDCl
3): 1.83 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.07-4.07 (m, 11H, thf-H, pip-H), 4.88 (m, 1H, thf-2H), 7.58 (m, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 8.38 (d, 1H, Ar-H) 8.83 (d, 1H, Ar-H); HR-MS (ESI-positivity): 379.18833 (M+H) (value of calculation: 379.18825).
the preparation of preparation example 21:Co.21
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 21a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.21 with obtaining final products 21b after ether/recrystallizing methanol.Productive rate is: 54%.
1H NMR (300MHz, CDCl
3): 1.86 (m, 2H, thf-H), 2.01 (m, 2H, thf-H), 2.62 (s, 3H, CH
3), 3.17-4.07 (m, 11H, thf-H, pip-H), 3.97 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.89 (s, 1H, Ar-H), 8.83 (d, 1H, Ar-H); HR-MS (ESI-positivity): 379.18833 (M+H) (value of calculation: 379.18825).
the preparation of preparation example 22:Co.22
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 22a (2mmol).After reaction system refluxes 5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.22 with obtaining final products 22b after ether/recrystallizing methanol.Productive rate is: 61%.
1H NMR (300MHz, CDCl
3): 0.88-0.93 (t, 3H), 1.62 (m, 2H), 1.88 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 2.64 (t, 2H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 400.23464 (M+H) (value of calculation: 400.23486).
the preparation of preparation example 23:Co.23
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 23a (2mmol).After reaction system refluxes 5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.23 with obtaining final products 23b after ether/recrystallizing methanol.Productive rate is: 48%.
1H NMR (300MHz, CDCl
3): 1.87 (m, 2H, thf-H), 2.01 (m, 2H, thf-H), 3.17-4.07 (m, 11H, thf-H, pip-H), 3.97 (s, 3H, OCH
3), 4.87 (m, 1H, thf-2H), 6.86-7.62 (m, 7H, Ar-H); HR-MS (ESI-positivity): 477.22497 (M+H) (value of calculation: 477.22503).
the preparation of preparation example 24:Co.24
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 25a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.25 with obtaining final products 25b after ether/recrystallizing methanol.Productive rate is: 24%.
1H NMR (300MHz, CDCl
3): 1.86 (m, 2H, thf-H), 1.94-2.58 (m, 8H), 3.17-4.07 (m, 12H, thf-H, pip-H), 3.97 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 5.56 (m, 2H), 7.15 (s, 1H, Ar-5H), 7.71 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 454.24499 (M+H) (value of calculation: 454.24543).
the preparation of preparation example 25:Co.25
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 25a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.25 with obtaining final products 25b after ether/recrystallizing methanol.Productive rate is: 45%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (t, 6H, CH
3-H) 1.88 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.44-4.17 (m, 25H, thf-H, pip-H), 3.85 (s, 3H, OCH
3), 3.87 (s, 3H, OCH
3), 4.87 (m, 1H, thf-2H), 7.27 (s, 1H, Ar-5H), 7.68 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 564.30330 (M+H) (value of calculation: 564.30334).
the preparation of preparation example 26:Co.26
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 26a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.17 with obtaining final products 26a after ether/recrystallizing methanol.Productive rate is: 55%.
1H NMR (300MHz, CDCl
3): 1.86 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), d 2.61 (s, 3H, CH
3), 3.47-4.07 (m, 11H, thf-H, pip-H and CH2CH2O), 3.91 (s, 3H, OCH
3), 3.95 (s, 3H, OCH
3), 3.99 (s, 3H, OCH
3), 4.82 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 476.21445 (M+H) (value of calculation: 476.21452).
the preparation of preparation example 27:Co.27
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 27a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.27 with obtaining final products 27b after ether/recrystallizing methanol.Productive rate is: 53%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (m, 6H), 1.88 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.07-4.07 (m, 15H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.63 (s, 1H, Ar-5H), 7.89 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 539.25942 (M+H) (value of calculation: 539.25936).
the preparation of preparation example 28:Co.28
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 28a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.28 with obtaining final products 28b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, CDCl
3): 1.78 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 436.19955 (M+H) (value of calculation: 436.19962).
the preparation of preparation example 29:Co.29
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 29a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.29 with obtaining final products 29b after ether/recrystallizing methanol.Productive rate is: 44%.
1H NMR (300MHz, CDCl
3): 1.84 (m, 2H, thf-H), 2.01 (m, 2H, thf-H), 2.62 (s, 3H, CH
3), 3.17-4.07 (m, 11H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.85 (s, 3H, OCH
3), 3.97 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.89 (s, 1H, Ar-H), 8.83 (d, 1H, Ar-H); HR-MS (ESI-positivity): 475.23050 (M+H) (value of calculation: 475.23051).
the preparation of preparation example 30:Co.30
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 30a (2mmol).After reaction system refluxes 5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.30 with obtaining final products 30b after ether/recrystallizing methanol.Productive rate is: 65%.
1H NMR (300MHz, CDCl
3): 0.88-0.93 (t, 3H), 1.62 (m, 2H), 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 2.64 (t, 2H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.71 (s, 3H, OCH
3), 3.76 (s, 3H, OCH
3), 3.91 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 400.23464 (M+H) (value of calculation: 474.27164).
the preparation of preparation example 31:Co.31
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 31a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.31 with obtaining final products 31b after ether/recrystallizing methanol.Productive rate is: 24%.
1H NMR (300MHz, CDCl
3): 1.864 (m, 2H, thf-H), 1.93-2.58 (m, 8H), 3.17-4.07 (m, 12H, thf-H, pip-H), 3.80 (s, 3H, OCH
3), 3.83 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 5.56 (m, 2H), 7.15 (s, 1H, Ar-5H), 7.71 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 536.25085 (M+H) (value of calculation: 536.25091).
the preparation of preparation example 32:Co.32
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 32a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.32 with obtaining final products 32b after ether/recrystallizing methanol.Productive rate is: 45%.
1H NMR (300MHz, CDCl
3): 1.860 (m, 2H, thf-H), 1.95-2.58 (m, 8H), 3.17-4.07 (m, 12H, thf-H, pip-H), 3.80 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 3.93 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 5.56 (m, 2H), 7.15 (s, 1H, Ar-5H), 7.71 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 514.26655 (M+H) (value of calculation: 514.26656).
B, biological test example part
1, the raising of fruit bat and screening compound
UAS-rpr and HS-Gal4 fruit bat are purchased from U.S. Bloomington storage center.The F1 filial generation (HS > rpr) of these two kinds of germline hybridization is for screening of medicaments.These filial generation fruit bats are brought up at 18 DEG C.Various medicines are dissolved in 5% glucose solution with the concentration using in the cell culture in cmap.By drug solution, (150 μ l) are placed on three layers of filter paper plate in tubule.Then, adult 20 1-3 ages in days HS > rpr fruit bat is placed in this bottle and reaches 1 day.For cell death inducing, make these fruit bats heat shock 2 hours at 37 DEG C.After heat shock 12 hours, calculate survival rate.
2, micro-array chip technical finesse and data analysis
The fruit bat (genetic background mates with control series) that 10 bottles of 1-3 ages in days are prepared in the filial generation of the hs-Gal4 of hybridizing from hs > rpr with yw67c23.In every bottle, contain 35 female fruit bats.This fruit bat (time is 0 hour) and heat shock before heat shock are refrigerated in liquid nitrogen for 1,2,3,4,5,6,7,8 and 12 hours.Prepare total RNA by RNeasy mini test kit (Quiagen, Inc).Be for further processing to remove the chromosomal DNA in sample with TURBO DNase test kit (Ambion, Inc).The quality of RNA sample detection and micro-array chip technical finesse step are to carry out according to Affymetrix DNA microarray chip technology standard scheme.Use the fruit bat 2.0 DNA microarray chip technologies (Affymetrix, Inc) from Affymetrix.Process these arrays affects to reduce between different batches simultaneously.Use Arrayassist 5.0 (Affymetrix, Inc) software to carry out data analysis.The algorithm of " RMA " is for analytical data.Because each time point is only collected an experimental data point, three adjacent time points are analyzed jointly, and the intermediate value of this each time point is regarded as the data of this group.The for example time 0,1 and 2 is called " time 1 " in result.The present invention has designed micro-array chip technical data to increase the instantaneous resolution of changes in gene expression in this process.The present invention infers and in transcribing, shown variation as fruit gene, and it can be reflected in adjacent time point.For functional gene enrichment, usage data of the present invention storehouse instrument (http://david.abcc.ncifcrf.gov/).
3, by contact graph discovery candidate compound
The present invention is transformed into mammal homologous genes (www.affymetrix.com) by the upper mediation down-regulated gene from fruit bat micro-array chip technology by data base.Then the scheme, providing based on cmap generates signal file (Lamb et al., 2006).After this, obtain the compound of positive correlation and negative correlation.These medicines are purchased from Sigma-Aldrich.
4, cell culture and apoptosis induction
RAW 264.7 cells are cultivated in DMEM culture medium (Gibco), in this culture medium, be supplemented with 10%FBS (Gibco), 0.1g/L streptomycin and 0.06g/L penicillin (Amresco).For cell death inducing, the RAW of 90% fusion 264.7 cells are being contained to 2 μ g/ml lipopolysaccharide (LPS; Escherichia coli O111:B4, Sigma) DMEM (10%FBS) in cultivate 24 hours.
5, Hoechst dyeing
First use Carnoy fixative (75% ethanol, 25% acetic acid) fixed cell, then use Hoechst 33342 (10 μ g/ml, Sigma) dyeing 10min.After ice-cold PBS washing 3 times, by confocal microscope (TCS SP5, Leica) observation of cell.
6, septicemic cemia mouse model
Male BALB/C (20 ± 3g) mice purchased from Vital River (Beijing company of dimension tonneau China, China) is raised the animal center in Peking University.All tests are by Peking University's animal maintenance and use committee (Peking University Institutional Animal Care and Use Committee) approval.For septicemic cemia LPS model, by injected in mice LPS (13.5mg/kg, i.p.) once.For septicemic cemia escherichia coli model, each injected in mice (i.p.) 1x10
8the antibacterial of CFU.For drug test, 1.5 hours injection (i.p.) terazosins (0.4mg/kg or 0.04mg/kg) or solvent buffer after giving LPS.Every 12 hour record mice fatality rate 7 days.
For septicemic cemia caecum ligation and puncture (CLP) model, with chloral hydrate (300mg/kg, i.p.) anesthetized mice.Ventrimeson cuts 1.5-2.0cm, exposes caecum.Separate after arteria ileocaeca, caecum is punctured once by No. 22 standard needle, and carrying out ligation from 5mm place, caecum top.Then make abdominal part sealing by continous suture.Finally, by injecting (37 DEG C of the normal saline of pre-temperature; 5ml/100g, s.c.) animal is recovered.For antibiotic therapy, give Co-Am (southern Shandong pharmacy group company, Shandong, China) (30mg/kg) by administration by gavage.Observe mouse survival rate every 12 hours and reach 7 days.
7, Western blotting
For Western blotting, the antibody test caspase-3 3 of the caspase-3 3 (#9664, Cell Signaling) activating by identification, the antibody of actin is purchased from Wuhan doctor's moral company.
8, DNA fragmentation fractional analysis
After lps injection 24 hours, take out a thymus from the mice of accepting different treatments.Then extract chromosomal DNA by chromosomal DNA purification kit (Biofuture, Beijing, China).Evaluate DNA fragmentation degree by DNA agarose gel.
9, the analysis of bacteriostatic activity
Utilize Oxford cup to analyze the potential antibiotic activity of terazosin.The terazosin of different quality is added in the cup of Oxford, put into the LB culture dish that is paved with escherichia coli (Escherichia coli O111:B4), after 24 hours, observe terazosin and the impact of ampicillin on Escherichia coli Growth.
10, the analysis of terazosin target
The present invention is upper by terazosin being connected to Affi-gel, then mixes with the protein extract of RAW 264.7 cells, washes off in connection with the foreign protein on Affi-gel.With the combining albumen eluting of sample-loading buffer, after 96 degree heating, run glue (albumin glue of 15% concentration).Special protein band is cut, carry out Mass Spectrometric Identification.
11, the impact of terazosin on Pgk1 activity
At the Pgk1 of expression in escherichia coli mice recombiant protein (His-Pgk1), then use ni-sepharose purification His-Pgk1.Purifying protein is diluted to every milliliter of 0.15 unit, adds the terazosin of gradient concentration, detect the activity of Pgk1.
12, the research of terazosin and Pgk1 affinity
With the Affi-gel of different disposal and the His-Pgk1 of purification hatching, after 4 hours, wash away the albumen of non-specific binding, with the combining albumen eluting of sample-loading buffer, after 96 degree heating, run glue (albumin glue of 15% concentration).
13, statistical analysis
For survival rate analysis, under Log Rank algorithm, use Kaplan-Meier inspection.For group relatively, use one-sided ANOVA inspection.In order to compare two data sets, the present invention uses student-t inspection.
According to the present invention, have been found that the new performance of terazosin, particularly it can be used as apoptosis inhibitor, and is used for the treatment of and/or prevents septicemia and complication thereof.
14, Pgk1 is active detects
Utilize the composition of Colorimetric GAPDH Assay Kit (ScienCell), and the GAPDH solution of buying and preparing, HEPES solution, MgSO4 solution.Then at reactant liquor (30mM Hepes, 3mM ATP, 0.22mMNADH, 10mM MgSO4,10mM 3-PGA, the GAPDH of 3-4U/ml, pH 7.5) in add certain density formula I compound, at 25 DEG C with spectrophotometer (340nm) detect absorb.According to the variation of absorption value in 1-10 minute, calculate Pgk1 relative activity.Change sooner, activity is larger.Notice that experimental group will deduct the absorption at 340nm with isocyatic compound simultaneously.
The activity of formula I compound represents to activate the multiple of Pgk1, and wherein 0.02 μ g/ml terazosin can activate active 2.9 times of Pgk1; O.1, Compound C is tested under 0.02 μ g/ml concentration to Co.32, and the multiple that activates Pgk1 activity sees above respectively, and the multiple that for example Co.1 and Co.2 activate Pgk1 activity is respectively 2.9 and 2.3.
15, apoptosis-inducing and detection
By RAW 264.7 cell culture (Gibco) in DMEM culture medium, add 5% hyclone and dual anti-(streptomycin of 0.1mg/ml and the penicillin of 0.06mg/ml).Add lipopolysaccharide and the (LPS of 2 μ g/ml; Escherichia coliO111:B4, Sigma-Aldrich) gamma interferon (Peprotech) of 50U/ml is apoptosis-induced.Add certain density compound simultaneously.Assess apoptosis by the method for western blot, antibody is the activity form antibody (#9661, Cell Signaling) of Caspase 3.And taking β-Actin as internal reference (Boster).Assess with the value of Caspase 3/ β-Actin the degree that apoptosis occurs.
16, the hypoglycemic activity of terazosin
Give mice shot terazosin (0.4mg/kg i.p.), after 18 hours, measure mouse blood sugar, find that blood glucose has reduced nearly 30% left and right (t-inspection, P < 0.01); And unknown significance difference while simultaneously giving saline.The results are shown in Figure 16.In identical test method, other exemplary compounds of the present invention for example Co.1, Co.3, Co.7, Co.9, Co.13, Co.16, Co.19, Co.24, Co.27, Co.32 all show can make blood glucose reduce by 20% to 50%.
17, the effect of the anti-cerebral thrombosis of terazosin
Make mouse brain thrombus model, after mice is because of thrombosis death, cerebral tissue is dyeed, result is presented at brain sheet middle part and presents white (it is the typical phenomenon of brain death); When shot terazosin (0.4mg/kg i.p.), can obviously reduce thanatogenic tissue's area.Result is added up, taking % thanatogenic tissue=white portion area/gross area as investigating index, mice quantity=6 under every kind of condition.Through t-inspection, P < 0.05.The results are shown in Figure 17, result from figure, terazosin can obviously reduce the area of brain death tissue.In identical test method, other exemplary compounds of the present invention for example Co.1, Co.4, Co.7, Co.8, Co.13-14, Co.16, Co.19, Co.24-27, Co.29, Co.31-32 all show can obviously reduce thanatogenic tissue's area, P < 0.05.
18, anti-septicemia effect
BALB/C mice (20 grams of left and right) intraperitoneal injection of LPS (13.5mg/kg), injects certain density medicine after one and a half hours, within every 12 hours, observe the survival of a mice, observes altogether 7 days, and statistics survival has there was no significant difference.
Alternate model is caecum puncture and ligation (CLP).After mouse anesthesia, cut off the osculum of 1.5-2 centimetre at its abdominal part, caecum is taken out.Feces is extruded into caecum bottom, be 5 millimeters away from caecum top locate ligation, then wear an aperture with No. 22 syringe needles, extrude some feces.Caecum is put back to abdominal cavity, with linear slit well and wound closure.After one and a half hours, inject certain density medicine, within every 12 hours, observe the survival of a mice, observe altogether 7 days, statistics survival has there was no significant difference.
Result shows, in the test of above two kinds of models, Compound C o.1, Co.4, Co.9, Co.13, Co.18, Co.21, Co.28, Co.29, Co.33 be respectively to inject once a day (0.4mg/kg i.p.) successive administration after 3 days, in the time that within 7 day, the observation period finishes, show that these compounds all can significantly improve the survival rate of mice (P < 0.05, with the matched group comparison of not giving medicine).
list of references:
1.Bone，R.C.Sir?Isaac?Newton，sepsis，SIRS，and?CARS.Crit.Care?Med.24，1125-1128(1996).
2.Braun，J.S.et?al.Neuroprotection?by?a?caspase?inhibitor?in?acute?bacterial?meningitis.Nat.Med.5，298-302(1999).
3.Hotchkiss，R.S.et?al.Caspase?inhibitors?improve?survival?in?sepsis：a?critical?role?of?the?lymphocyte.Nat.Immunol.1，496-501(2000).
4.Chung，C.S.et?al.Inhibition?of?Fas?signaling?prevents?hepatic?injury?and?improves?organ?blood?flow?during?sepsis.Surgery?130，339-345(2001).
5.Weaver，J.G.，Rouse，M.S.，Steckelberg，J.M.&?Badley，A.D.Improved?survival?in?experimental?sepsis?with?an?orally?administered?inhibitor?of?apoptosis.FASEBJ.18，1185-1191(2004).
6.Wesche-Soldato，D.E.et?al.In?vivo?delivery?of?caspase?8?or?Fas?siRNA?improves?the?survival?of?septic?mice.Blood?106，2295-2301(2005).
7.White，K.et?al.Genetic?control?of?programmed?cell?death?in?Drosophila.Science?264，677-683(1994).
8.White，K.，Tahaoglu，E.&?Steller，H.Cell?killing?by?the?Drosophila?gene?reaper.Science?271，805-807(1996).
9.Ayala，A，Xin?Xu，Y.，Ayala，C.A.，Sonefeld，D.E.，Karr，S.M.，Evans，T.A.&Chaudry，I.H.Increased?mucosal?B-lymphocyte?apoptosis?during?polymicrobial?sepsis?is?a?Fas?ligand?but?not?an?endotoxin-mediated?process.Blood?91，1362-1372(1998).
10.Parker，S.J.&?Watkins，P.E.Experimental?models?of?gram-negative?sepsis.Br.J.Surg.88，22-30(2001).
11.Wichterman，K.A.，Baue，A.E.&?Chaudry，I.H.Sepsis?and?septic?shock-a?review?of?laboratory?models?and?a?proposal.J.Surg.Res.29，189-201(1980).
12.Kyncl，J.J.et?al.Terazosin，a?new?quinazoline?antihypertensive?agent.I.General?phannacology?In：Focus?on?Alpha?Blockade?and?Terazosin，edited?by?J.Rosenthal，Zuckschwerdt?Verlag?Munich(1985).
13.Cavero，I.，Lefevre，F.&?Roach，A.G.Differential?effects?of?prazosin?on?the?pre-and?postsynaptic?a-adrenoceptors?in?the?rat?and?dog.Br.J.Pharmac.61，469P(1977).
14.McCall，K.&?Steller，H.Facing?death?in?the?fly：genetic?analysis?of?apoptosis?in?Drosophila.Trends?Genet.13，222-226(1997).
15.Mazzoni?et?al.，PGK1，the?gene?encoding?the?glycolitic?enzyme?phosphoglycerate?kinase，acts?as?a?mutilcopy?suppressor?of?apoptotic?phenotypes?in?S.cerevisiae.Yeast?26：31-37(2009).
16.Lamb，J.et?al.The?Connectivity?Map：using?gene-expression?signatures?to?connect?small?molecules，genes，and?disease.Science?313，1929-1935(2006).
Claims (12)
1. formula I compound or the acceptable salt of its pharmacy treat and/or prevent the purposes in septicemic cemia medicine in preparation,
Wherein
R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkyl acyl-, C
5-6cycloalkyl, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 6-ring, wherein said alkyl is optionally selected from following substituent group by 1-3 and replaces: hydroxyl, halogen;
R
2and R
3be selected from independently of one another halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
1-6alkoxyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, C
1-6alkanoylamino-, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit heterocycle;
R
4and R
5be selected from independently of one another H, halogen, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, halo C
1-6alkyl-, C
1-6alkoxyl-, C
1-6alkanoylamino-.
2. according to the purposes of claim 1, wherein
R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-4alkoxy-C
1-4alkyl-, C
2-4thiazolinyl-, C
2-4alkynyl-, C
1-4alkyl acyl-, C
5-6cycloalkyl, wherein said alkyl is optionally selected from following substituent group by 1-3 and replaces: hydroxyl, halogen;
R
2and R
3be selected from independently of one another halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
1-6alkoxyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, C
1-6alkanoylamino-;
R
4and R
5be selected from independently of one another H, halogen, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl-, C
1-6alkanoyl oxygen base-, halo C
1-6alkyl-, C
1-6alkoxyl-, C
1-6alkanoylamino-.
3. according to the purposes of claim 1, wherein R
1aand R
1bbe selected from independently of one another H ,-NH
2,-OH.
4. according to the purposes of claim 1, wherein R
4and R
5be selected from independently of one another H.
5. according to the purposes described in claim 1-4 any one, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.
6. according to the purposes described in claim 1-4 any one, in wherein said medicine, also comprise at least one antimicrobial agents.
7. according to the purposes described in claim 1-4 any one, in wherein said medicine, also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.
8. be selected from the following Co.1 to Co.33 of being numbered the definition of each substituent group treat and/or prevent the purposes in septicemic cemia medicine with following formula I compound or the acceptable salt of its pharmacy in preparation:
9. purposes according to claim 8, the compound of the wherein said Co.33 of being numbered is hydrochlorate or its hydrate of terazosin.
10. purposes according to claim 8 or claim 9, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.
11. purposes according to claim 8 or claim 9, also comprise at least one antimicrobial agents in wherein said medicine.
12. purposes according to claim 8 or claim 9, in wherein said medicine, also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110412182.XA CN102552272B (en) | 2010-12-22 | 2011-12-12 | Method for treating sepsis |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010600075.5 | 2010-12-22 | ||
| CN201010600075 | 2010-12-22 | ||
| CN201110124255.5 | 2011-05-16 | ||
| CN201110124255 | 2011-05-16 | ||
| CN201110173409.X | 2011-06-27 | ||
| CN201110173409 | 2011-06-27 | ||
| CN201110412182.XA CN102552272B (en) | 2010-12-22 | 2011-12-12 | Method for treating sepsis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102552272A CN102552272A (en) | 2012-07-11 |
| CN102552272B true CN102552272B (en) | 2014-11-12 |
Family
ID=46334883
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104139310A Active CN102526057B (en) | 2010-12-22 | 2011-12-12 | Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator |
| CN201110412182.XA Active CN102552272B (en) | 2010-12-22 | 2011-12-12 | Method for treating sepsis |
| CN201110410902.9A Active CN102532110B (en) | 2010-12-22 | 2011-12-12 | Quinazoline derivative and application of serving as cell apoptosis inhibitor |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104139310A Active CN102526057B (en) | 2010-12-22 | 2011-12-12 | Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110410902.9A Active CN102532110B (en) | 2010-12-22 | 2011-12-12 | Quinazoline derivative and application of serving as cell apoptosis inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN102526057B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11201501212QA (en) * | 2012-03-23 | 2015-05-28 | Linx Pharmaceutical Co Ltd | Quinazoline derivatives and uses thereof as apoptosis inhibitor |
| CN102908352A (en) * | 2012-09-12 | 2013-02-06 | 北京英科博雅科技有限公司 | Application of terazosin or its salt in preparing drug for treating septicemia/stroke |
| CN103739596A (en) * | 2013-12-10 | 2014-04-23 | 刘磊 | Quinazoline derivative used for cardio cerebrovascular diseases |
| CN104887682A (en) * | 2015-06-18 | 2015-09-09 | 刘磊 | Application of terazosin type medicines |
| CN113403387B (en) * | 2021-07-16 | 2022-09-30 | 兰州大学 | Pgk1 application of target in preparing or screening medicine for treating gastrointestinal tract diseases |
| CN117430614B (en) * | 2023-12-20 | 2024-03-08 | 首都医科大学 | Isoquinoline derivative and synthetic method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134023A (en) * | 2006-08-31 | 2008-03-05 | 海南海灵制药厂有限公司 | Hydrochloric acid terazosin oral cavity disintegrating lyophilized tablets and method for preparing the same |
| CN1927166A (en) * | 2006-09-29 | 2007-03-14 | 何岩 | Terazosin slowly releasing preparation |
| CN101444512A (en) * | 2008-12-29 | 2009-06-03 | 孙少芳 | Application of terazosin for preparing medicines for treating postpartum urinary retention |
-
2011
- 2011-12-12 CN CN2011104139310A patent/CN102526057B/en active Active
- 2011-12-12 CN CN201110412182.XA patent/CN102552272B/en active Active
- 2011-12-12 CN CN201110410902.9A patent/CN102532110B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN102526057A (en) | 2012-07-04 |
| CN102532110B (en) | 2014-12-03 |
| CN102552272A (en) | 2012-07-11 |
| CN102532110A (en) | 2012-07-04 |
| CN102526057B (en) | 2013-11-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102552272B (en) | Method for treating sepsis | |
| Wei et al. | Salidroside inhibits inflammation through PI3K/Akt/HIF signaling after focal cerebral ischemia in rats | |
| Huang et al. | Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy | |
| Mester et al. | When overgrowth bumps into cancer: The PTEN‐Opathies | |
| Shen et al. | Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice | |
| Zhao et al. | Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice | |
| Lee et al. | Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor | |
| Yuan et al. | Nuclear translocation of histone deacetylase 4 induces neuronal death in stroke | |
| CN102834098A (en) | Use of benzo-heterocycle derivatives for preventing and treating cancer or for inhibiting cancer metastasis | |
| Fu et al. | Oridonin inhibits myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by regulating transforming growth factor β (TGFβ)/Smad pathway | |
| Zhang et al. | lncRNA Ttc3-209 promotes the apoptosis of retinal ganglion cells in retinal ischemia reperfusion injury by targeting the miR-484/Wnt8a axis | |
| CN110831595A (en) | Novel spirocyclic and cyclic bis-benzylidene proteasome inhibitors for the treatment of cancer, diabetes and neurological disorders | |
| Hao et al. | MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling | |
| Saunders et al. | Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma | |
| Deng et al. | CSF-1R inhibition attenuates ischemia-induced renal injury and fibrosis by reducing Ly6C+ M2-like macrophage infiltration | |
| Geng et al. | Hedgehog signaling in the murine melanoma microenvironment | |
| Zhan et al. | Cangrelor alleviates pulmonary fibrosis by inhibiting GPR17-mediated inflammation in mice | |
| EP2924037A1 (en) | Quinazoline derivate and use thereof as apoptosis inhibitor | |
| Chen et al. | Zanubrutinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-β1 signaling pathway | |
| Liu et al. | Chemotherapy‐induced phlebitis via the GBP5/NLRP3 inflammasome axis and the therapeutic effect of aescin | |
| US20090264533A1 (en) | Methods and Compositions for Modulating RHO-Mediated Gene Transcription | |
| CN113230249A (en) | Application of pseudolaric acid B in serving as or preparing Hedgehog signal path inhibitor | |
| Fort et al. | mTORC1 regulates high levels of protein synthesis in retinal ganglion cells of adult mice | |
| US20090041751A1 (en) | Sepsis Prevention Through Adenosine Receptor Modulation | |
| Luo | Augmentation of transforming growth factor-β signaling for the treatment of neurological disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Free format text: FORMER OWNER: XU XIAOCHUN LI XIAOYU Effective date: 20150331 |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20150331 Address after: 214092, Meiliang Road, Binhu District, Jiangsu, Wuxi, 88 Patentee after: Liu Lei Address before: 214092, Meiliang Road, Binhu District, Jiangsu, Wuxi, 88 Patentee before: Liu Lei Patentee before: Xu Xiaochun Patentee before: Li Xiaoyu |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20200428 Address after: Room 116, Jinan biomedical industrial park, 1268 Gongye 4th Road, Bucun street, Zhangqiu District, Jinan City, Shandong Province Patentee after: Jinan anlianuo Enterprise Management Co.,Ltd. Address before: 214092, Meiliang Road, Binhu District, Jiangsu, Wuxi, 88 Patentee before: Liu Lei |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200529 Address after: Room 116, Jinan biomedical industrial park, 1268 Gongye 4th Road, Bucun street, Zhangqiu District, Jinan City, Shandong Province Patentee after: Shandong bangentei Biomedical Technology Group Co.,Ltd. Address before: Room 116, Jinan biomedical industrial park, 1268 Gongye 4th Road, Bucun street, Zhangqiu District, Jinan City, Shandong Province Patentee before: Jinan anlianuo Enterprise Management Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Room 116, Jinan biomedical industrial park, 1268 Gongye 4th Road, Bucun street, Zhangqiu District, Jinan City, Shandong Province, 250219 Patentee after: Bonentai (Shandong) Biomedical Technology Group Co.,Ltd. Address before: Room 116, Jinan biomedical industrial park, 1268 Gongye 4th Road, Bucun street, Zhangqiu District, Jinan City, Shandong Province, 250219 Patentee before: Shandong bangentei Biomedical Technology Group Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220419 Address after: 250109 room 1-610, Lushang Phoenix Plaza, 4567 Tangye Middle Road, Jinan area, China (Shandong) pilot Free Trade Zone, Jinan City, Shandong Province Patentee after: Jinan anlianuo Enterprise Management Co.,Ltd. Address before: Room 116, Jinan biomedical industrial park, 1268 Gongye 4th Road, Bucun street, Zhangqiu District, Jinan City, Shandong Province, 250219 Patentee before: Bonentai (Shandong) Biomedical Technology Group Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220706 Address after: 100080 staff dormitory, No.5, Yiheyuan Road, Haidian District, Beijing Patentee after: Liu Lei Address before: 250109 room 1-610, Lushang Phoenix Plaza, 4567 Tangye Middle Road, Jinan area, China (Shandong) pilot Free Trade Zone, Jinan City, Shandong Province Patentee before: Jinan anlianuo Enterprise Management Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220729 Address after: 102445 room 904, floor 9, building 12, yard 2, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Daxing District, Beijing (Yizhuang group, high-end industrial area of Beijing Pilot Free Trade Zone) Patentee after: Beijing Ansai Biotechnology Co.,Ltd. Address before: 100080 staff dormitory, No.5, Yiheyuan Road, Haidian District, Beijing Patentee before: Liu Lei |
|
| TR01 | Transfer of patent right |