CN101472894B - 苯基戊二烯衍生物及其作为par1拮抗剂的用途 - Google Patents
苯基戊二烯衍生物及其作为par1拮抗剂的用途 Download PDFInfo
- Publication number
- CN101472894B CN101472894B CN2007800223489A CN200780022348A CN101472894B CN 101472894 B CN101472894 B CN 101472894B CN 2007800223489 A CN2007800223489 A CN 2007800223489A CN 200780022348 A CN200780022348 A CN 200780022348A CN 101472894 B CN101472894 B CN 101472894B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- compound
- penta
- general formula
- piperazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 Phenylpentadienoyl Chemical class 0.000 title claims description 23
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 8
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 6
- 239000003146 anticoagulant agent Substances 0.000 claims description 5
- 210000001367 artery Anatomy 0.000 claims description 4
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 230000000702 anti-platelet effect Effects 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims description 2
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- 108010056764 Eptifibatide Proteins 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000019693 Lung disease Diseases 0.000 claims description 2
- 208000007718 Stable Angina Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 206010047249 Venous thrombosis Diseases 0.000 claims description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims description 2
- 229960003009 clopidogrel Drugs 0.000 claims description 2
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 claims description 2
- 229960004468 eptifibatide Drugs 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 230000002107 myocardial effect Effects 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229940107685 reopro Drugs 0.000 claims description 2
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 claims description 2
- 229960005001 ticlopidine Drugs 0.000 claims description 2
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 claims description 2
- 229960003425 tirofiban Drugs 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 206010048768 Dermatosis Diseases 0.000 claims 1
- 239000003560 cancer drug Substances 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 208000019423 liver disease Diseases 0.000 claims 1
- 238000007634 remodeling Methods 0.000 claims 1
- 208000017520 skin disease Diseases 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 11
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- KAVSMINTEBGDTI-UHFFFAOYSA-N pyridine;thiophene Chemical group C=1C=CSC=1.C1=CC=NC=C1 KAVSMINTEBGDTI-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 2
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 abstract 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract 1
- 125000000168 pyrrolyl group Chemical group 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 238000001819 mass spectrum Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000003513 alkali Substances 0.000 description 15
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000000370 acceptor Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 125000004494 ethyl ester group Chemical group 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 238000011010 flushing procedure Methods 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 238000007127 saponification reaction Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 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 5
- 230000000694 effects Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229940044551 receptor antagonist Drugs 0.000 description 5
- 239000002464 receptor antagonist Substances 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 102000032626 PAR-1 Receptor Human genes 0.000 description 4
- 108010070519 PAR-1 Receptor Proteins 0.000 description 4
- 230000001746 atrial effect Effects 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 235000014347 soups Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 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
- 241001597008 Nomeidae Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- PTPUOMXKXCCSEN-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-dichloro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(Cl)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(Cl)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O PTPUOMXKXCCSEN-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- CUXQLKLUPGTTKL-UHFFFAOYSA-M microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- BCRJHHFLBOQAMG-UHFFFAOYSA-N penta-1,3-dienylbenzene Chemical compound CC=CC=CC1=CC=CC=C1 BCRJHHFLBOQAMG-UHFFFAOYSA-N 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- PVMCQBPJKPMOKM-UHFFFAOYSA-N 1-cyclopentylpiperazine Chemical compound C1CCCC1N1CCNCC1 PVMCQBPJKPMOKM-UHFFFAOYSA-N 0.000 description 1
- 125000006183 2,4-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C(=C1[H])C([H])([H])*)C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- VMSMELHEXDVEDE-UHFFFAOYSA-N 3-(2-nitrophenyl)prop-2-enal Chemical compound [O-][N+](=O)C1=CC=CC=C1C=CC=O VMSMELHEXDVEDE-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 108010091478 C186 65 Proteins 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010016803 Fluid overload Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NINBMLXRTYLUQM-MHUSLGGSSA-O O=C(/C=C/C=C/c(cccc1)c1[NH+]=O)N(CC1)CCN1c1ccccc1 Chemical compound O=C(/C=C/C=C/c(cccc1)c1[NH+]=O)N(CC1)CCN1c1ccccc1 NINBMLXRTYLUQM-MHUSLGGSSA-O 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 102000003790 Thrombin receptors Human genes 0.000 description 1
- 108090000166 Thrombin receptors Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N but-2-enal Chemical compound CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- LXLODBXSCRTXFG-BQYQJAHWSA-N ethyl (e)-4-diethoxyphosphorylbut-2-enoate Chemical compound CCOC(=O)\C=C\CP(=O)(OCC)OCC LXLODBXSCRTXFG-BQYQJAHWSA-N 0.000 description 1
- SDGAEBKMHIPSAC-ONEGZZNKSA-N ethyl (e)-4-oxobut-2-enoate Chemical compound CCOC(=O)\C=C\C=O SDGAEBKMHIPSAC-ONEGZZNKSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 238000011554 guinea pig model Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003601 intercostal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 235000017103 tryptophane Nutrition 0.000 description 1
- 150000003654 tryptophanes Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- LQUPKVMEAATBSL-UHFFFAOYSA-L zinc;2,3,4-trichlorophenolate Chemical compound [Zn+2].[O-]C1=CC=C(Cl)C(Cl)=C1Cl.[O-]C1=CC=C(Cl)C(Cl)=C1Cl LQUPKVMEAATBSL-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyridine Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
本发明涉及通式(I)化合物或其治疗上可接受的盐或溶剂化物:其中R1和R2,相同或不同,代表:氢原子或卤素、CN或NO2,且R1和R2不同时代表氢,m代表1或2,n代表:0、1或2,R3代表未取代的或被一个或多个选自卤素、羟基或C1-C6烷基的基团取代的苯基;未取代的或被一个或多个选自卤素或羟基的基团取代的C2-C6烷基;环烷基;吡啶;噻吩;未取代的或被C1-C6烷基取代的吡咯;噻唑或呋喃。
Description
本发明涉及苯基戊二烯衍生物,它们的制备方法,包含它们的药物组合物及其作为用于治疗和/或预防动脉和静脉血栓形成、急性冠状动脉综合征、再狭窄、稳定型心绞痛、心率紊乱、心肌梗塞、高血压、心衰竭、中风、炎性疾病、肺部疾病、胃肠疾病、慢性肝病患者中的纤维化、癌症和皮肤病的药物的用途。本发明还涉及发明的化合物与其它心血管类药物的组合。
血栓形成被认为是血管堵塞的主要因素,它是许多病理生理并发症的起因。因为抗凝血治疗能降低心血管死亡率和冠心病事件的风险,因此非常重要。虽然几种类型的分子已经显示出有效的人类抗凝血活性,但是一些现有的化合物在出血时间上有负面影响或伴随其他不良的副作用(例如,阿司匹林的溃疡风险),因此仍然需要开发与这些现有的化合物相比提供优点的新分子。
最近克隆出蛋白酶激活受体-1(PAR-1)(Vu等人,Cell,1991,64:1057-1068)并且它的作用机制也被阐述(Coughlin等人,J.Clin.Invest.1992,89(2):351-355)。该受体不但大量存在于血小板的表面,而且存在于上皮细胞(O′Brien等人,J.Biol.Chem.2000,275:13502-13509)、平滑肌细胞(Hamilton等人,Br.J.Pharmacol.2000,130:181-188)和成纤维细胞(Hung等人,J.Cell.Biol.1992,116(3):827-832)的表面,该受体被凝血酶激活,因此也称为凝血酶受体。该蛋白质的N端在精氨酸41和色氨酸42间被凝血酶裂解以游离出新末端,经折叠活化位点后这些新末端充当受体拮抗剂(Vu等人,Nature,1991,353,674-677)。关于血小板,特定的PAR-1受体激活机制导致凝血酶调节的血小板凝集。
阻断激活,例如用PAR-1受体拮抗剂可以抑制凝血酶调节的血小板凝集(Ahn等人,Drug of the Future,2001,26:1065-1085)。因此阻断这些受体导致治疗或预防血栓形成(Derian等人,J.Pharmacol.Exp.Ther.,2003,855-861),急性冠状动脉综合征(Ossovskaya等人,Physiol.Rev.,2004,84:579-621)和再狭窄(Maryanoff等人,Curr.Med.Chem.Cardiovasc.Hematol.Agents.,2003,13-36),并且能在栓塞形成或再灌注期间降低心肌坏死(Steinberg等人,Mol.Pharmacol.2005,67:2-11)。在肺部位,PAR-1拮抗活性能预防某些炎性疾病(Moffatt等人,Curr.Op.Pharmacol.,2004,221-229)。在胃肠部位,PAR-l受体拮抗活性可以预防某些炎性疾病(Vergnolle等人,J.Clin.Invest.,2004,1444-1456)。PAR-1拮抗剂也可以用于治疗慢性肝病患者中的纤维化(Fiorucci等人,Hepatology,2004,39:365-375)。如果它们能控制细胞增殖和转移也可以用作抗癌剂(Evan-Ram等人,Nat.Med.,1998,909-914;Boire等人,Cell.,2005,120:303-313)。最后,PAR-1拮抗剂可以在皮肤学上用于治疗某些皮肤病(Schechter等人,J.Cell.Physiol.,1998,176:365-373;Algermissen等人,Arch.Dermatol.Res.,2000,292:488-495;Meyer-Hoffert等人,Exp.Dermatol.,2004,13:234-241)。
本发明涉及新类型的PAR-1拮抗剂,该PAR-1拮抗剂与现有技术区别在于它们不同的化学结构和它们显著的生物特性。
本发明化合物是通式(I)化合物或其治疗上可接受的盐或溶剂化物:
其中:
R1和R2,相同或不同,代表:
氢原子或卤素、CN或NO2,且R1和R2不同时代表氢,m代表:
1或2
n代表:
0、1或2
R3代表:
未取代的或被一个或多个选自卤素、羟基或C1-C6烷基的基团取代的苯基;未取代的或被一个或多个选自卤素或羟基的基团取代的C2-C6烷基;环烷基;吡啶;噻吩;未取代的或被C1-C6烷基取代的吡咯;噻唑或呋喃。
在前面的定义中:
所有取代基或变量的组合在它们能形成稳定化合物的可能范围。
术语“卤素”代表氟、氯、溴或碘。
术语“烷基”代表包含具体碳原子数目的直链或支链,饱和或不饱和的脂肪族烃链。
术语“环烷基”代表包含3-10个碳原子的环烃链。
本发明化合物治疗上可接受的盐包括本发明化合物的常规的无毒盐,例如由有机或无机酸形成的那些盐。下面的盐可以作为实例引用:无机酸盐,例如盐酸、氢溴酸、磷酸或硫酸,以及有机酸盐,例如乙酸、三氟乙酸、丙酸、琥珀酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、谷氨酸、苯甲酸、水杨酸、甲苯磺酸、甲磺酸、硬脂酸和乳酸。
这些盐可以根据常规化学方法从包含碱基部分的本发明化合物和相应酸反应合成。
本发明化合物的治疗上可接受的溶剂化物包括常规溶剂化物,例如在本发明化合物最后制备步骤期间由于溶剂的存在而形成的溶剂化物。由于水或乙醇的存在形成的溶剂化物可以作为实例引用。
在本发明的通式(I)化合物中,一个特别优选的化合物类别是通式(I)化合物,其中R1是硝基,R2是氢,m等于1,n等于0且R3是被一个或多个卤素或C1-C6烷基取代的苯基、环烷基或吡啶。
在本发明的通式(I)化合物中,第二个特别有利的化合物类别是通式(I)化合物,其中R1为氰基,R2是氢,m等于1,n等于0且R3是被一个或多个卤素或C1-C6烷基取代的苯基、环烷基或吡啶。
本发明还涉及通过下列合成方案图描述的常规方法制备通式(I)化合物,常规方法可以是文献中描述的任何标准技术,本领域技术人员公知,或者出现在实验部分。
方案图1
方案图1说明用于制备通式(I)化合物的第一种常规方法。在上面的通式中,R1、R2和R3如通式(I)在前面说明书中所定义。但是在上面的方案图1中,n仅代表1或2,P1代表保护基且X可以代表如氯或羟基的基团。通式(II)的原料化合物可以通过本领域技术人员已知的方法和技术制备。一个特别有利的方法包括将苄基卤与三苯基膦在如DMF或DMSO的极性溶剂中于20℃和100℃之间的温度反应形成磷盐。然后,例如在如DMF或THF溶剂中于-20℃和40℃之间的温度,使用如NaH的碱将磷盐去质子化,然后与具有酯的α,β-不饱和醛反应,例如(2E)-4-氧代-2-丁烯酸乙酯(ethyl(2E)-4-oxobut-2-enoate)。得到的酯(Z/E和E/E异构体的混合物)首先采用碘在如乙腈的极性溶剂中处理进行异构化从而仅得到E/E异构体,然后采用矿物碱如KOH、NaOH或LiOH在极性溶剂如水、乙醇或THF中于20℃和100℃之间的温度进行皂化,得到X是羟基的化合物(II)。第二个特别有利的方法包括将芳族醛与磷酸酯如4-(二乙氧基磷酰基)-2-丁烯酸乙酯(ethyl4-(diethoxyphosphoryl)but-2-enoate)在碱存在下,例如NaH、Cs2CO3或K2CO3在如THF、二氯甲烷或二氯乙烷溶剂中,于-20℃和100℃之间的温度反应。得到的酯(Z/E和E/E异构体的混合物)首先采用碘在如乙腈的极性溶剂中进行异构化,从而仅得到E/E异构体,然后采用采用矿物碱如KOH、NaOH或LiOH在极性溶剂如水、乙醇或THF中于20℃和100℃之间的温度进行皂化,得到X是羟基的化合物(II)。第三个特别有利的方法包括将芳族α,β-不饱和醛与(二乙氧基磷酰基)乙酸酯在碱存在下,例如的NaH、Cs2CO3或K2CO3在如THF、二氯甲烷或二氯乙烷溶剂中,于-20℃和100℃之间的温度反应。得到的酯采用矿物碱如KOH、NaOH或LiOH在溶剂如水、乙醇或THF中于20℃和100℃之间的温度进行皂化,得到X是羟基的化合物(II)。第四个特别有利的方法包括将含如溴或碘的卤素的芳烃与(E)-戊-2,4-二烯酰酯((E)-penta-2,4-dienoyl ester)如(E)-戊-2,4-二烯酸甲酯或乙酯,在如乙酸钯的钯催化剂,如三邻甲苯基膦或三苯基膦的膦存在下,在碱,例如Et3N或iPr2NEt存在下,在开放或密封的反应器中,无溶剂或在如DMF、DMSO或DMA的溶剂中,于20℃和120℃之间的温度反应。因此得到的酯(主要是E/E异构体)可以采用矿物碱如KOH、NaOH或LiOH在溶剂如水、乙醇或THF中于20℃和100℃之间的温度进行皂化,得到X是羟基的化合物(II)。在这种情况下,第一步反应是羧酸(II)和胺(III)的缩合反应。该反应可以通过本领域技术人员已知的方法和技术进行。一个特别有利的方法包括将这两个实体在1-(3-二甲基氨丙基)-3-乙基-碳化二亚胺(EDC)、3-羟基-1,2,3-苯并三氮杂苯-4(3H)-酮和如二异丙基乙胺的叔胺存在下在如二氯甲烷的极性非质子溶剂中,于-15℃和40℃之间的温度反应。该羧酸也可以与如亚硫酰氯的试剂在20℃和100℃之间的温度反应以转化成酰氯(X相应为氯)。在这种情况下,第一步由酰基氯和胺的反应组成。该反应可以通过本领域技术人员已知的方法和技术进行。一个特别有利的方法包括将这两个实体在有机或无机碱存在下,例如Et3N、iPr2NEt、吡啶、NaH、Cs2CO3或K2CO3在溶剂如THF、二氯甲烷、DMF或DMSO中于-20℃和100℃之间的温度反应。
通过本领域技术人员已知的方法和技术将中间体(IV)脱保护后(“Protective Groups in Organic Synthesis,”T.W.Greene,John Wiley &Sons,1981和“Protecting Groups,”P.J.Kocienski,Thieme Verlag,1994),得到的中间体可以与通式R3(CH2)nY的试剂反应,其中Y代表离去基团,例如Cl、Br、I、OSO2CH3、OSO2CF3或O-甲苯磺酰基。在这种情况下,反应在有机或无机碱存在下,例如Et3N、iPr2NEt、NaH,Cs2CO3或K2CO3,所述的碱在如PS-DIEA或MP-碳酸酯的树脂上得到支撑,在极性无水溶剂,如二氯甲烷、THF、DMF或DMSO中于-20°和100℃之间的温度进行。另一个制备方法由还原胺化反应组成,采用通式R3-(CH2)n-1-CHO的醛,其中R3和n如前面所定义,与脱保护的通式(IV)的胺和如NaBH4、NaBH3CN或NaBH(OAc)3的还原剂,所述还原剂得到如MP-BH3CN的树脂的支撑,在极性溶剂如1,2-二氯乙烷、二氯甲烷、THF、DMF或MeOH中,通过加入如乙酸的酸来调节pH,于-20℃和100℃之间的温度反应。
方案图2
方案图2说明用于制备通式(I)化合物的第二种常规方法。在上面的通式中,R1、R2、R3和n如通式(I)的定义。X可以代表如氯或羟基的基团。通式(II)的原料化合物可以通过本领域技术人员已知的方法和技术制备,特别是上面所述的那些方法和技术。在这种情况下X是氯,合成由酰基氯和胺的反应组成。该反应通过本领域技术人员已知的方法和技术进行。一个特别有利的方法包括将这两个实体在有机或无机碱存在下,例如Et3N、iPr2NEt、吡啶、NaH、Cs2CO3或K2CO3在溶剂如THF、二氯甲烷、DMF或DMSO中,于-20℃和100℃之间的温度反应。
在这种情况下X是羟基,合成由羧酸(II)和胺(V)的缩合组成。该反应通过本领域技术人员已知的方法和技术进行。一个特别有利的方法包括将通式(II)的羧酸与通式(III)的胺在1-(3-二甲基氨基丙基)-3-乙基-碳化二亚胺(EDC)、3-羟基-1,2,3-苯并三氮杂苯-4(3H)-酮和如二异丙基乙胺的叔胺存在下,在如二氯甲烷的极性非质子溶剂中,于-15℃和40℃之间的温度反应。
当期望通过加入酸分离含有至少一个碱功能基的盐态的通式(I)化合物,这一结果可以通过将通式(I)的游离碱(含有至少一个碱功能基)与合适的酸反应,优选当量反应。
下面的实施例用来说明本发明,而非以任何方式限制本发明的范围。
实施例1
2[5-氧代-5-(4-吡啶-2-基-哌嗪-1-基)-戊-1,3-二烯基]-苯甲腈
实施例1A:5-(2-氰基-苯基)-戊-2,4-二烯酸乙酯
2-溴甲基-苯甲腈(3克,15.3毫摩尔)的DMF(50毫升)溶液在80℃与三苯基膦(4.42克,16.83毫摩尔)反应。搅拌3小时后,将混合物降至室温,并加入氢化钠(在油中60%)(673毫克,16.83毫摩尔)和4-氧代-丁-2-烯酸乙酯(2.16克,16.83毫摩尔)。在室温下搅拌16小时后,将混合物蒸发至干燥,用乙酸乙酯吸收并用水冲洗。用Na2SO4干燥有机相,过滤并蒸发至干燥。得到的浆状物采用硅胶柱色谱纯化,并用9/1 EDP/AcOEt混合溶液洗脱。分离到的产品1A为E/E和Z/E异构体的黄色浆状物形式(2.73克,71%)。
质谱(ESI+):m/z 228(M+H+)
实施例1B:(2E,4E)-5(2-氰基-苯基)-戊-2,4-二烯酸乙酯
化合物1A(2.34克,10.3毫摩尔)的乙腈(14毫升)溶液在室温下与碘(15.0毫克,0.06毫摩尔)反应。搅拌3小时后,将混合物蒸发至干燥,用二氯甲烷吸收并用Na2SO3溶液(0.01M)冲洗。用Na2SO4干燥有机相,过滤并蒸发至干燥。分离到的产品1B为固体形式(2.26克,97%),并直接用于下一步。
1H NMR,DMSO-d6(ppm):1.25(t,3H);4.16(q,2H);6.21(d,1H);7.34(m,2H);7.50(m,2H);7.74(t,1H);7.87(d,1H);7.96(d,1H)。
实施例1C:5-(2-氰基-苯基)-戊-2,4-二烯酸
化合物1B(2.0克,8.82毫摩尔)的乙醇溶液(50毫升)与1N碳酸钾(13.2毫升,13.2毫摩尔)反应。回流搅拌1.5小时后,将混合物蒸发至干燥,用水吸收并用1N HCl调节至酸性pH。过滤形成的沉淀物,用水冲洗并在真空下干燥从而得到纯的产品1C(1.63克,93%)。
质谱(ESI-):m/z 198(M-H-)
实施例1:2-[5-氧代-5-(4-吡啶-2-基-哌嗪-1-基)-戊-1,3-二烯基]-苯甲腈
酸1C(700毫克,3.51毫摩尔)的二氯甲烷(10毫升)溶液在二异丙基乙胺(DIEA)(1.2毫升,7.02毫摩尔)存在下于室温与1-(3-二甲基氨丙基)-3-乙基碳化二亚胺(EDCI)盐酸盐(807毫克,4.21毫摩尔),3-羟基-1,2,3-苯并三氮杂苯-4(3H)-酮(HOOBT)(686毫克,4.21毫摩尔),然后和1-吡啶-2-基-哌嗪(642微升,4.21毫摩尔)反应。搅拌16小时后,用二氯甲烷稀释反应混合物,并用1N苏打和水冲洗。用MgSO4干燥有机相,过滤并蒸发至干燥。得到的浆状物采用硅胶柱色谱纯化,并用1/2石油醚/AcOEt混合溶液洗脱。分离到的产品1为黄色固体形式(910毫克,75%)。该产品用乙酸乙酯吸收,然后加入HCl的乙醚溶液成盐,从而得到相应的黄色固体形式的盐酸盐(1.04克)。
1H NMR,DMSO-d6(ppm):3.81(宽s,8H);6.94(m,2H);7.18(m,1H);7.38(m,3H);7.51(t,1H);7.74(t,1H);7.86(d,1H);7.91(d,1H);7.96(t,1H);8.06(d,1H)。
质谱(ESI+):m/z 345(M+H+)
实施例2-8
根据制备化合物1中描述的条件,由中间体1C和相应的胺合成化合物2-8。
实施例 | m | R1 | 化合物名称 | 质谱(M+H)+ |
2 | 1 | 环戊基 | 2-[5-(4-环戊基-哌嗪-1-基)-5-氧代-戊-1,3-二烯基]-苯甲腈 | 336 |
3 | 1 | 环己基 | 2-[5-(4-环己基-哌嗪-1-基)-5-氧代 | 350 |
-戊-1,3-二烯基]-苯甲腈 | ||||
4 | 1 | 3-Cl-丙基 | 2-{5-[4-(3-氯-丙基)-哌嗪-1-基]-5-氧代-戊-1,3-二烯基}-苯甲腈 | 344 |
5 | 1 | 3-Cl-苯基 | 2-{5-[4-(3-氯-苯基)-哌嗪-1-基]-5-氧代-戊-1,3-二烯基}-苯甲腈 | 378 |
6 | 1 | 2-OH-苯基 | 2-{5-[4-(2-羟基-苯基)-哌嗪-1-基]-5-氧代-戊-1,3-二烯基}-苯甲腈 | 360 |
7 | 2 | 2,4-二甲基-苄基 | 2-{5-[4-(2,4-二甲基-苄基)-[1,4]二氮杂庚烷-1-基]-5-氧代-戊-1,3-二烯基}-苯甲腈 | 400 |
8 | 2 | 2-甲基-苄基 | 2-{5-[4-(2-甲基-苄基)-[1,4]二氮杂庚烷-1-基]-5-氧代-戊-1,3-二烯基}-苯甲腈 | 386 |
实施例9
5-(2-氯-苯基)-1-(4-环戊基-哌嗪-1-基)-戊-2,4-二烯-1-酮
实施例9A:5-(2-氯-苯基)-戊-2,4-二烯酸乙酯
4-(二乙氧基-磷酰基)-丁-2-二烯酸乙酯(3.92克,15.65毫摩尔)的THF(70毫升)溶液在0℃与氢化钠(油中60%)(630毫克,15.7毫摩尔)反应。在0℃搅拌30分钟后,加入2-氯-苯甲醛(2.0克,14.22毫摩尔),将化合物从0℃至室温搅拌16小时。然后将化合物蒸发至干燥,用AcOEt吸收并用水冲洗。用MgSO4干燥有机相,过滤并蒸发至干燥。得到的浆状物采用硅胶柱色谱纯化并用2/1 EDP/CH2Cl2混合溶液洗脱。分离到的产品9A为黄色油状形式(1.1克,33%)。
实施例9B:5-(2-氯-苯基)-戊-2,4-二烯酸
化合物9A(2.1克,8.87毫摩尔)的THF(20毫升)溶液与1NLiOH溶液(35毫升,35.4毫摩尔)反应。在室温搅拌2小时且回流1时后,将化合物蒸发至干燥,用水吸收且用4N HCl调节至酸性pH。过滤形成的沉淀物,用水洗涤,然后在真空下干燥得到纯化合物9B(1.70克,92%)。
质谱(ESI-):m/z 207(M-H-)
实施例9:5-(2-氯-苯基)-1-(4-环戊基-哌嗪-1-基)-戊-2,4-二烯-1-酮
根据从1C制备化合物1中描述的条件,通过中间体9B(67.0毫克,0.32毫摩尔)和环戊基哌嗪(101.3毫克,0.45毫摩尔)合成化合物9。分离到的纯产品为盐酸盐的形式(99毫克,81%)。
质谱(ESI+):m/z 345(M+H+)
实施例10-15
根据从1C制备化合物1中描述的条件,由中间体9B和相应的胺合成化合物10-15。
实施例 | m | R1 | 化合物名称 | 质谱(M+H)+ |
10 | 1 | 环己基 | 5-(2-氯-苯基)-1-(4-环己基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 359 |
11 | 1 | 环庚基 | 5-(2-氯-苯基)-1-(4-环庚基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 373 |
12 | 1 | 3-Cl-丙基 | 5-(2-氯-苯基)-1-[4-(3-氯-丙基)-哌嗪-1-基]-戊-2,4-二烯-1-酮 | 353 |
13 | 1 | 2-吡啶 | 5-(2-氯-苯基)-1-(4-吡啶-2-基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 354 |
14 | 2 | 2-甲基-苄基 | 5-(2-氯-苯基)-1-[4-(2-甲基-苄基)-[1,4]二氮杂庚烷-1-基]-戊-2,4-二烯-1-酮 | 395 |
15 | 2 | 2F-苄基 | 5-(2-氯-苯基)-1-[4-(2-氟-苄基)-[1,4]二氮杂庚烷-1-基]-戊-2,4-二烯-1-酮 | 399 |
实施例16
5-(2-硝基-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮
实施例16A:5-(2-硝基-苯基)-戊-2,4-二烯酸乙酯
3-(2-硝基-苯基)-丙烯醛(4.0克,22.5毫摩尔)的甲苯(67毫升)溶液与(三苯基正磷基)-乙酸乙酯(8.25克,23.7毫摩尔)反应。回流搅拌2天后,将混合物蒸发至干燥,采用硅胶柱层析纯化并用2/1EDP/AcOEt混合溶液洗脱。分离到的产品16A为黄色固体形式(4.96克,90%)。
1H NMR,DMSO-d6(ppm):1.24(t,3H);4.16(q,2H);6.19(d,1H);7.17(dd,1H);7.35(d,1H);7.45(dd,1H);7.59(t,1H);7.77(t,1H);7.89(d,1H);8.00(d,1H)。
质谱(ESI+):m/z 248(M+H+)
实施例16B:5-(2-硝基-苯基)-戊-2,4-二烯酸
根据从1B制备化合物1C中描述的条件,将中间体16A(2.59克,10.5毫摩尔)进行皂化。分离到的纯产品为白色固体的形式(2.27克,99%)。
质谱(ESI-):m/z 218(M-H-)
实施例16:5-(2-硝基-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮
根据从1C制备化合物1中描述的条件,由中间体16B(404毫克,1.84毫摩尔)和苯基-哌嗪(415微升,2.20毫摩尔)合成化合物16。分离到的纯产品为盐酸盐的形式(621毫克,87%)。
1H NMR,DMSO-d6(ppm):3.29(宽s,4H);3.82(宽s,4H);6.94(d,1H);7.00(t,1H);7.20(m,4H);7.32(m,3H);7.57(t,1H);7.75(t,1H);7.87(d,1H);7.99(d,1H)。
质谱(ESI+):m/z 364(M+H+)
实施例17-26
根据从1C制备化合物1中描述的条件,由中间体16B和相应的胺合成化合物17-26。
实施例 | R1 | 化合物名称 | 质谱(M+H)+ |
17 | 环己基 | 1-(4-环己基-哌嗪-1-基)-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 370 |
18 | 环戊基 | 1-(4-环戊基-哌嗪-1-基)-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 356 |
19 | 4-F-苯基 | 1-[4-(4-氟-苯基)-哌嗪-1-基]-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 382 |
20 | 3-Cl-丙基 | 1-[4-(3-氯-丙基)-哌嗪-1-基]-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 364 |
21 | 2-吡啶 | 5-(2-硝基-苯基)-1-(4-吡啶-2-基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 365 |
22 | 环戊基-甲基 | 1-(4-环戊基甲基-哌嗪-1-基)-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 370 |
23 | 噻吩-3-甲基 | 5-(2-硝基-苯基)-1-(4-噻吩-3-基甲基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 384 |
24 | 4-F-苄基 | 1-[4-(4-氟-苄基)-哌嗪-1-基]-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 396 |
25 | 丁基 | 1-(4-丁基-哌嗪-1-基)-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 344 |
26 | 3-Cl-苯基 | 1-[4-(3-氯-苯基)-哌嗪-1-基]-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮 | 398 |
实施例27
5-(2,6-二氟-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮
实施例27A:5-(2,6-二氟-苯基)-戊-2,4-二烯酸乙酯
(二乙氧基-磷酰基)-乙酸乙酯(3.72毫升,18.7毫摩尔)的THF(114毫升)溶液与氢化钠(油中60%)(819毫克,20.4毫摩尔)在室温反应5分钟。然后滴加入3-(2,6-二氟-苯基)-丙烯醛(2.87克,17.0毫摩尔)的THF(29毫升)溶液。在室温搅拌3小时后,将混合物蒸发至干燥,用乙酸乙酯吸收并用水冲洗。用Na2SO4干燥有机相,过滤并蒸发至干燥。得到的黄色固体直接用于下一步反应。
实施例27B:5-(2,6-二氟-苯基)-戊-2,4-二烯酸
根据从1B制备化合物1C中描述的条件,将中间体27B(3.28克,13.76毫摩尔)进行皂化。分离到的纯产品为浅褐色固体的形式(2.56克,88%)。
质谱(ESI-):m/z 209(M-H-)
实施例27:5-(2,6-二氟-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮
根据从1C制备化合物1中描述的条件,由中间体27B(60毫克,0.285毫摩尔)和苯基-哌嗪(68.1微升,0.342毫摩尔)制备化合物27。分离到的纯产品为浅褐色粉末的形式(72毫克,79%)。
质谱(ESI+):m/z 355(M+H+)
实施例28-31
根据从1C制备化合物1中描述的条件,通过中间体27B和相应的胺合成化合物28-31。
实施例 | R1 | 化合物名称 | 质谱(M+H)+ |
28 | 环己基 | 1-(4-环己基-哌嗪-1-基)-5-(2,6-二氟-苯基)-戊-2,4-二烯-1-酮 | 361 |
29 | 3-Cl-丙基 | 1-[4-(3-氯-丙基)-哌嗪-1-基]-5-(2,6-二氟-苯基)-戊-2,4-二烯-1-酮 | 355 |
30 | 环戊基 | 1-(4-环戊基-哌嗪-1-基)-5-(2,6-二氟-苯基)-戊-2,4-二烯-1-酮 | 347 |
31 | 4-F-苄基 | 5-(2,6-二氟-苯基)-1-[4-(4-氟-苄基)-哌嗪-1-基]-戊-2,4-二烯-1-酮 | 387 |
实施例32
1-(4-环戊基-哌嗪-1-基)-5-(2-氟-苯基)-戊-2,4-二烯-1-酮
实施例32A:5-(2-氟-苯基)-戊-2,4-二烯酸乙酯
根据制备化合物27A中描述的条件,通过3-(2-二氟-苯基)-丙烯醛和(二乙氧基-磷酰基)-乙酸乙酯制备中间体32A。
质谱(ESI+):m/z 221(M+H+)
实施例32B:5-(2-氟-苯基)-戊-2,4-二烯酸
根据制备化合物27B中描述的条件,通过化合物32A制备中间体32B。
质谱(ESI-):m/z 191(M-H-)
实施例32:1-(4-环戊基-哌嗪-1-基)-5-(2-氟-苯基)-戊-2,4-二烯-1-酮
根据从1C制备化合物1中描述的条件,通过中间体32B(100.0毫克,0.52毫摩尔)和环戊基-哌嗪(165.3毫克,0.73毫摩尔)制备化合物32。分离到的纯产品为白色固体的形式(122毫克,64%)。
质谱(ESI+):m/z 329(M+H+)
实施例33-36
根据从1C制备化合物1中描述的条件,通过中间体32B和相应的胺合成化合物33-36。
实施例 | R1 | 化合物名称 | 质谱(M+H)+ |
33 | 环己基 | 1-(4-环己基-哌嗪-1-基)-5-(2-氟-苯基)-戊-2,4-二烯-1-酮 | 343 |
34 | 2-吡啶 | 5-(2-氟-苯基)-1-(4-吡啶-2-基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 338 |
35 | 苯基 | 5-(2-氟-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮 | 337 |
36 | 3-Cl-丙基 | 1-[4-(3-氯-丙基)-哌嗪-1-基]-5-(2-氟-苯基)-戊-2,4-二烯-1-酮 | 337 |
下面所述的模型表明本发明的衍生物是PAR-1受体拮抗剂:
在各种细胞类型中,通过SFLLR肽(选择性PAR-1拮抗剂)激活PAR-1受体触发细胞内信号通路导致通过内质网释放钙。中国仓鼠卵巢(CHO)细胞组成性表达PAR-1受体。在该细胞株中,使用钙选择性探针(Fluo-3AM)通过荧光技术(荧光成像阅读仪(fluorometricimaging plate reader)或FLIPR)测定通过SFLLR激活的对受体连续的钙释放。荧光的发射药理学上与PAR-1拮抗剂的功效和它的浓度成正比。已证明本发明所述的化合物能拮抗PAR-1受体,因此降低由激动剂诱导的钙释放。
原料:
培养基:补充有10%胎牛血清和抗菌素(Probenicid,2.5mM)的Ham′s F-12(Ham,R.G.,Proc.Nat.Acad.Sci.1965,53:288)。
荧光探针:Fluo-3AM(4μM;Teflabs,Austin,Texas,USA)
激动剂:SFLLR-NH2(丝氨酸、苯丙氨酸、亮氨酸、亮氨酸、精氨酸)。
方法:CHO细胞接种在含200μl培养基的96-孔板(每孔60,000个细胞)24小时。该细胞在37℃与钙荧光探针孵育1小时。在测定信号之前,冲洗细胞10分钟。然后注射入PAR-1拮抗剂(0.01μM至10μM)。将平板置于FLIPR(Molecular Devices,UK)中在两个波长测定钙荧光(488nm和540nm:Sullivan等人,Calcium SignalingProtocols 1999,125-136)。在加入拮抗剂前,进行5分钟的测量,加入后进行10分钟测量。在4个不同孔中测定最大荧光负基线荧光。测试一式两份进行。在这些条件下,本发明的衍生物被鉴定为PAR-1受体拮抗剂(在10μM钙信号拮抗作用>60%)。用SFLLR激动剂得到的剂量效应曲线(0.01μM至32μM)允许测定诱导50%最大效应的有效浓度(EC50)。使用Arunlakshana和Schild方法(Brit.J.Pharmacol.,1959,14:48-58),从三个浓度实测的EC50位移计算本发明所述的某些PAR-1拮抗剂的强度(pA2)。
结果:
下面几个选自本发明化合物的样品说明了这些化合物拮抗PAR-1受体的完全意料不到的能力。
样品 | pA2 |
1 | 6.5 |
2 | 6.63 |
9 | 6.64 |
16 | 7.23 |
18 | 7.16 |
21 | 7.11 |
PAR-1拮抗剂的体内抗血小板凝聚和抗凝血活性显示在动脉血栓形成的豚鼠模型中,其具有非常高的血液动力切应力(hemodynamicshear stress)。在血管床中,内皮损伤引起富血小板的血栓在血管内的形成,这将逐渐堵塞所有血管腔(lumen)。凝血酶经PAR-1受体强烈激活血小板凝聚过程。已证明本发明所述的化合物能拮抗PAR-1受体,因此延迟凝血酶的形成。
原料:
本研究使用豚鼠(PAR-1受体与人类相似)。在光敏剂存在下(静脉内给予玫瑰红)通过绿激光的照射破坏颈动脉的内皮。使用超声流量探针定量颈动脉的流量。测定完全堵塞颈动脉(流量为0)所需的时间。
方法:
将动物麻醉后(60毫克/千克戊巴比妥),切除5mm的颈动脉,在动脉上放置4mm激光。在上游放置流量探针测定堵塞时间。通过静脉内途径给予玫瑰红(20毫克/千克),并在514nm波长照射该血管(持续3分钟)。使用大丸剂通过静脉内途径迅速地给予PAR-1拮抗剂(超过2分钟,在给予玫瑰红前),接着进行15分钟的灌注,该灌注开始于激光打开时。
结果:
本发明所述的某些化合物与仅接受对照剂的动物相比,通过静脉内途径从0.16毫克/千克至2.5毫克/千克剂量给药后,能延迟血栓形成时间的10%至90%。
本发明的衍生物也可以用于治疗心房颤动。
在梗塞后的情况心腔(cardiac-cavity)容量过度负荷,右心房和左心房扩张,因此构成心房颤动形成的基底。在遭受心房颤动的患者的扩张的心房腔中的止血紊乱导致凝血酶的异常集中。发明人已证明凝血酶的积聚对PAR-1的增量调节负责,它触发成纤维细胞的增殖以及血小板性血栓的形成。
通过它们的作用机制,PAR-1拮抗剂可以预防心房扩张,成纤维细胞的增殖和遭受心房颤动的患者在心房中血栓的形成。
结果表明,PAR-1拮抗剂能有效预防和/或治疗心房颤动。已证明本发明所述的化合物能拮抗PAR-1受体和预防心房扩张。
原料:
本研究使用雄性大鼠。因为它们要尽力忍受外科手术,因此选择180-200克体重范围的大鼠用于实验。通过超声心电图对麻醉动物的各种心肌腔(myocardial cavities)进行测定。
方法:
使用含3.5%异氟烷的氧气混合物麻醉动物(易尔醚,BaxterLaboratories)。在左侧前肢面第四肋间空间水平上垂直胸骨切开约2厘米。在左冠状动脉起始1毫米处进行结扎(4-0丝(silk),CCl针,Ethicon)。在左冠状动脉周围打手术结,该手术结充分紧压以完全堵塞血管。连续记录的心电图能证明结扎令人满意的位置。该操作两个月后,再次麻醉动物,使用脉冲多普勒用于测量心腔的超声心动图和测量心肌内血流速度。最后,用过量戊巴比妥钠(160毫克/千克,IP)麻醉动物用于各种组织学测定。从梗塞形成24小时后直到动物被处死前,每日强行喂食动物PAR-1拮抗产品。
结果:
本发明所述的某些化合物与未处理的动物相比,通过口服途径以10-100毫克/千克/天的剂量给药60天后,能降低20%至90%的心房面(通过超声心动图测定)。
本发明还涉及包含通式(I)化合物或其药学上可接受的盐作为活性成分的药物组合物,该组合物与合适的赋形剂混合或组合。该组合物可以设定剂型,例如固体或液体组合物、乳剂、洗剂或乳膏剂。
作为口服给药的固体组合物,可以使用片剂、丸剂、粉剂(在胶囊或盒中)或颗粒。在该组合物中,本发明的活性成分与一种或多种惰性稀释剂,例如淀粉、纤维素、蔗糖、乳糖或硅胶在氩气流通中混合。该组合物也可以包括与稀释剂以外的物质,例如一种或多种如硬脂酸镁或滑石粉的润滑剂、着色剂、包衣(糖包衣丸剂)或涂剂。
作为口服给药的液体组合物,可以使用下列剂型:药学上可接受的溶液、混悬液、乳剂、糖浆剂和包含惰性稀释剂的酏剂,例如水、乙醇、甘油、植物油或液状石蜡。该组合物可以包括与稀释剂以外的物质,例如湿润剂、甜味剂、增稠剂、增香剂或稳定剂。
用于胃肠外给药的无菌组合物优选是水溶液或非水溶液、混悬液或乳液。作为溶剂或载体,可以使用下列物质:水、丙二醇、聚乙二醇、植物油、特别是橄榄油、可注射的有机酯,例如油酸乙酯或其它合适的有机溶剂。该组合物也可以包含添加剂,特别是湿润剂、等渗剂、乳化剂、分散剂和稳定剂。通过几种方式可以杀菌,例如通过杀菌过滤、通过在组合物中加入杀菌剂、通过照射或通过加热。该组合物也可以制备成无菌固体组合物,该组合物在使用前可以溶解于无菌水或其它可注射的无菌介质中。
用于直肠给药的组合物是栓剂或直肠用胶囊,除了活性产品,该栓剂或直肠用胶囊包含赋形剂,例如可可脂、半合成的甘油酯或聚乙二醇。
用于局部给药的组合物例如可以是乳膏剂、洗剂、滴眼剂、口腔洗剂、滴鼻剂或烟雾剂。
剂量取决于预期效应、治疗时间和给药途径,且通常在每天0.001克和1克之间(优选在0.005克和0.75克之间),优选对成人通过口服途径给药,单位剂量的范围为0.1毫克至500毫克的活性物质。
通常,医生会依据患者的年龄、体重和其它特定因素确定出合适的剂量。
依据具体实施方案,本发明还涉及包含通式(I)化合物和其它心血管类药物的产品,所述产品作为组合产品同时、分别或缓释用于心血管治疗,所述其它心血管类药物可以是抗血小板药物,例如阿司匹林、氯吡格雷、噻氯匹啶、阿昔单抗、替罗非班或依替巴肽。
Claims (17)
2.根据权利要求1所述的化合物,其中R1是硝基,R2是氢,m等于1,n等于0且R3是C3-C10环烷基、苯基或吡啶基。
3.根据权利要求1所述的化合物,其中R1为氰基,R2是氢,m等于1,n等于0且R3是C3-C10环烷基。
4.根据权利要求1所述的化合物,该化合物选自:
2-[5-氧代-5-(4-吡啶-2-基-哌嗪-1-基)-戊-1,3-二烯基]-苯甲腈;
2-[5-(4-环戊基-哌嗪-1-基)-5-氧代-戊-1,3-二烯基]-苯甲腈;
5-(2-氯-苯基)-1-(4-吡啶-2-基-哌嗪-1-基)-戊-2,4-二烯-1-酮;
5-(2-硝基-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮;
1-(4-环戊基-哌嗪-1-基)-5-(2-硝基-苯基)-戊-2,4-二烯-1-酮;
5-(2-硝基-苯基)-1-(4-吡啶-2-基-哌嗪-1-基)-戊-2,4-二烯-1-酮;
5-(2,6-二氟-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮;
1-(4-环戊基-哌嗪-1-基)-5-(2,6-二氟-苯基)-戊-2,4-二烯-1-酮;
1-(4-环己基-哌嗪-1-基)-5-(2-氟-苯基)-戊-2,4-二烯-1-酮;
5-(2-氟-苯基)-1-(4-吡啶-2-基-哌嗪-1-基)-戊-2,4-二烯-1-酮;
5-(2-氟-苯基)-1-(4-苯基-哌嗪-1-基)-戊-2,4-二烯-1-酮;
或其治疗上可接受的盐。
7.一种药物组合物,其包含:
作为活性产品的至少一种权利要求1-4中任一项所述的化合物,和
药学上可接受的载体。
8.根据权利要求1-4中任一项所述的化合物在制备抗血小板凝集药物中的用途。
9.根据权利要求1-4中任一项所述的化合物在制备治疗和/或预防动脉或静脉血栓形成的药物中的用途。
10.根据权利要求1-4中任一项所述的化合物在制备治疗和/或预防稳定型心绞痛、心率紊乱、脑血管意外、心衰竭、高血压或心肌梗塞的药物中的用途。
11.根据权利要求1-4中任一项所述的化合物在制备治疗和/或预防急性冠状动脉综合征的药物中的用途。
12.根据权利要求1-4中任一项所述的化合物在制备治疗再狭窄药物中的用途。
13.根据权利要求1-4中任一项所述的化合物在制备治疗和/或预防心房颤动和心肌重塑药物中的用途。
14.根据权利要求1-4中任一项所述的化合物在制备治疗和/或预防炎性疾病、肺部疾病、胃肠疾病、慢性肝疾病患者中的纤维化或皮肤病药物中的用途。
15.根据权利要求1-4中任一项所述的化合物在制备治疗和/或预防癌症药物中的用途。
16.包含至少一种根据权利要求1-4中任一项所述的化合物和另一种心血管类药物的产品,所述产品作为组合产品同时、分别或缓释用于心血管治疗。
17.根据权利要求的16所述的产品,其中所述的另一种心血管类药物是选自阿司匹林、氯吡格雷、噻氯匹啶、阿昔单抗、替罗非班或依替巴肽的抗血小板凝集药物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0605418 | 2006-06-19 | ||
FR0605418A FR2902427B1 (fr) | 2006-06-19 | 2006-06-19 | Derives de phenylpentadienoyle |
PCT/EP2007/056078 WO2007147822A1 (en) | 2006-06-19 | 2007-06-19 | Phenylpentadienoyl derivatives and their use as par 1 antagonists |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101472894A CN101472894A (zh) | 2009-07-01 |
CN101472894B true CN101472894B (zh) | 2012-09-05 |
Family
ID=37622010
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2007800223489A Expired - Fee Related CN101472894B (zh) | 2006-06-19 | 2007-06-19 | 苯基戊二烯衍生物及其作为par1拮抗剂的用途 |
Country Status (24)
Country | Link |
---|---|
US (1) | US8022064B2 (zh) |
EP (1) | EP2046748B1 (zh) |
JP (1) | JP5268897B2 (zh) |
KR (1) | KR20090031735A (zh) |
CN (1) | CN101472894B (zh) |
AR (1) | AR061519A1 (zh) |
AT (1) | ATE500223T1 (zh) |
AU (1) | AU2007263049B2 (zh) |
BR (1) | BRPI0713582A2 (zh) |
CA (1) | CA2655728A1 (zh) |
DE (1) | DE602007012888D1 (zh) |
ES (1) | ES2361061T3 (zh) |
FR (1) | FR2902427B1 (zh) |
IL (1) | IL195869A0 (zh) |
MA (1) | MA31131B1 (zh) |
MX (1) | MX2008016446A (zh) |
NO (1) | NO20090269L (zh) |
NZ (1) | NZ573591A (zh) |
RU (1) | RU2440985C2 (zh) |
TN (1) | TNSN08521A1 (zh) |
TW (1) | TW200815371A (zh) |
UA (1) | UA97370C2 (zh) |
WO (1) | WO2007147822A1 (zh) |
ZA (1) | ZA200810629B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104496879A (zh) * | 2015-01-13 | 2015-04-08 | 佛山市赛维斯医药科技有限公司 | 一种含腈基苯和二烯氟代金刚烷结构的化合物和用途 |
KR20190113623A (ko) * | 2018-03-27 | 2019-10-08 | 주식회사 바이오웨이 | (2e,4e)-5-페닐-펜타-2,4-다이엔-1-온 유도체 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61106564A (ja) * | 1984-10-30 | 1986-05-24 | Terumo Corp | 不飽和脂肪酸アミド誘導体およびこれを含有する血小板凝集抑制剤 |
JPS61137866A (ja) * | 1984-12-07 | 1986-06-25 | Terumo Corp | イミダゾ−ル誘導体およびこれを含有する血小板凝集抑制剤 |
US4792553A (en) * | 1986-02-04 | 1988-12-20 | Terumo Kabushiki Kaisha | Diene derivatives and vasodilators containing the same |
FR2917622B1 (fr) * | 2007-06-19 | 2009-10-23 | Pierre Fabre Medicament Sa | Utilisation d'un antagoniste par1 dans le traitement de la fibrillation atriale. |
-
2006
- 2006-06-19 FR FR0605418A patent/FR2902427B1/fr not_active Expired - Fee Related
-
2007
- 2007-06-19 AU AU2007263049A patent/AU2007263049B2/en not_active Ceased
- 2007-06-19 NZ NZ573591A patent/NZ573591A/en not_active IP Right Cessation
- 2007-06-19 CN CN2007800223489A patent/CN101472894B/zh not_active Expired - Fee Related
- 2007-06-19 EP EP07765492A patent/EP2046748B1/en active Active
- 2007-06-19 AT AT07765492T patent/ATE500223T1/de not_active IP Right Cessation
- 2007-06-19 DE DE602007012888T patent/DE602007012888D1/de active Active
- 2007-06-19 US US12/305,447 patent/US8022064B2/en not_active Expired - Fee Related
- 2007-06-19 UA UAA200900375A patent/UA97370C2/ru unknown
- 2007-06-19 JP JP2009515858A patent/JP5268897B2/ja not_active Expired - Fee Related
- 2007-06-19 ES ES07765492T patent/ES2361061T3/es active Active
- 2007-06-19 WO PCT/EP2007/056078 patent/WO2007147822A1/en active Application Filing
- 2007-06-19 BR BRPI0713582-3A patent/BRPI0713582A2/pt not_active Application Discontinuation
- 2007-06-19 MX MX2008016446A patent/MX2008016446A/es active IP Right Grant
- 2007-06-19 AR ARP070102684A patent/AR061519A1/es not_active Application Discontinuation
- 2007-06-19 CA CA002655728A patent/CA2655728A1/en not_active Abandoned
- 2007-06-19 RU RU2008149917/04A patent/RU2440985C2/ru not_active IP Right Cessation
- 2007-06-19 KR KR1020097000945A patent/KR20090031735A/ko not_active Application Discontinuation
- 2007-06-20 TW TW096122075A patent/TW200815371A/zh unknown
-
2008
- 2008-12-11 IL IL195869A patent/IL195869A0/en unknown
- 2008-12-16 TN TNP2008000521A patent/TNSN08521A1/en unknown
- 2008-12-17 ZA ZA2008/10629A patent/ZA200810629B/en unknown
- 2008-12-18 MA MA31483A patent/MA31131B1/fr unknown
-
2009
- 2009-01-16 NO NO20090269A patent/NO20090269L/no not_active Application Discontinuation
Non-Patent Citations (3)
Title |
---|
JP昭61-106564A 1986.05.24 |
JP昭61-137866A 1986.06.25 |
Samuel Chackalamannil, et.al..Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents.《Expert Opinion on Therapeutic Patents》.2006,第16卷(第4期),第493-505页. * |
Also Published As
Publication number | Publication date |
---|---|
AR061519A1 (es) | 2008-09-03 |
JP5268897B2 (ja) | 2013-08-21 |
EP2046748A1 (en) | 2009-04-15 |
AU2007263049A1 (en) | 2007-12-27 |
EP2046748B1 (en) | 2011-03-02 |
JP2009541258A (ja) | 2009-11-26 |
US20100003260A1 (en) | 2010-01-07 |
AU2007263049B2 (en) | 2011-10-27 |
BRPI0713582A2 (pt) | 2012-10-23 |
UA97370C2 (ru) | 2012-02-10 |
MA31131B1 (fr) | 2010-02-01 |
US8022064B2 (en) | 2011-09-20 |
WO2007147822A1 (en) | 2007-12-27 |
RU2008149917A (ru) | 2010-07-27 |
TNSN08521A1 (en) | 2010-04-14 |
CN101472894A (zh) | 2009-07-01 |
ES2361061T3 (es) | 2011-06-13 |
IL195869A0 (en) | 2009-09-01 |
ATE500223T1 (de) | 2011-03-15 |
MX2008016446A (es) | 2009-01-22 |
CA2655728A1 (en) | 2007-12-27 |
ZA200810629B (en) | 2010-02-24 |
FR2902427A1 (fr) | 2007-12-21 |
NO20090269L (no) | 2009-02-27 |
FR2902427B1 (fr) | 2008-08-22 |
TW200815371A (en) | 2008-04-01 |
DE602007012888D1 (de) | 2011-04-14 |
NZ573591A (en) | 2010-10-29 |
RU2440985C2 (ru) | 2012-01-27 |
KR20090031735A (ko) | 2009-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101472907B (zh) | 肉桂酰基-哌嗪衍生物及其作为par-1拮抗剂的用途 | |
EP1201239A1 (en) | Cyclic amine ccr3 antagonists | |
CN101472894B (zh) | 苯基戊二烯衍生物及其作为par1拮抗剂的用途 | |
PL127056B2 (en) | Method of obtaining new derivatives of 2-ketoimidazo-/4,5-b/-pyridine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1129385 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1129385 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120905 Termination date: 20190619 |
|
CF01 | Termination of patent right due to non-payment of annual fee |