CN1332939C - 抑制因子Xa活性的新化合物 - Google Patents
抑制因子Xa活性的新化合物 Download PDFInfo
- Publication number
- CN1332939C CN1332939C CNB018145353A CN01814535A CN1332939C CN 1332939 C CN1332939 C CN 1332939C CN B018145353 A CNB018145353 A CN B018145353A CN 01814535 A CN01814535 A CN 01814535A CN 1332939 C CN1332939 C CN 1332939C
- Authority
- CN
- China
- Prior art keywords
- phenyl
- compound
- alkyl
- tof
- esi
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 79
- 108010074860 Factor Xa Proteins 0.000 title claims abstract description 11
- 230000002401 inhibitory effect Effects 0.000 title abstract description 3
- 230000000694 effects Effects 0.000 title description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- -1 4-picolyl Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 208000005189 Embolism Diseases 0.000 claims description 8
- 208000001435 Thromboembolism Diseases 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000003051 glycosyloxy group Chemical group 0.000 claims description 5
- 229910004013 NO 2 Inorganic materials 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000004122 cyclic group Chemical class 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 206010051113 Arterial restenosis Diseases 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 206010040047 Sepsis Diseases 0.000 claims description 2
- 208000038016 acute inflammation Diseases 0.000 claims description 2
- 230000006022 acute inflammation Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 208000013223 septicemia Diseases 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 238000007631 vascular surgery Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 14
- 230000009424 thromboembolic effect Effects 0.000 abstract description 4
- 238000009472 formulation Methods 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 238000001425 electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 53
- 239000002994 raw material Substances 0.000 description 51
- 239000002585 base Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 25
- 229910052760 oxygen Inorganic materials 0.000 description 25
- 239000001301 oxygen Substances 0.000 description 25
- 238000000034 method Methods 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 20
- 125000003710 aryl alkyl group Chemical group 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000023555 blood coagulation Effects 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 7
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 7
- 230000002785 anti-thrombosis Effects 0.000 description 7
- 229960004676 antithrombotic agent Drugs 0.000 description 7
- 125000004475 heteroaralkyl group Chemical group 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000004423 acyloxy group Chemical group 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 125000001207 fluorophenyl group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 230000000452 restraining effect Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 206010047249 Venous thrombosis Diseases 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000003698 antivitamin K Substances 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 229940019333 vitamin k antagonists Drugs 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000002527 isonitriles Chemical class 0.000 description 3
- 239000003055 low molecular weight heparin Substances 0.000 description 3
- 229940127215 low-molecular weight heparin Drugs 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108010074864 Factor XI Proteins 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010022562 Intermittent claudication Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-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
- 208000006193 Pulmonary infarction Diseases 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- 108010064129 Thrombogen Proteins 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 108060005989 Tryptase Proteins 0.000 description 2
- 102000001400 Tryptase Human genes 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- 125000003968 arylidene group Chemical group [H]C(c)=* 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 108010073651 fibrinmonomer Proteins 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000021156 intermittent vascular claudication Diseases 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000007575 pulmonary infarction Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012056 semi-solid material Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 1
- UXTFKIJKRJJXNV-UHFFFAOYSA-N 1-$l^{1}-oxidanylethanone Chemical compound CC([O])=O UXTFKIJKRJJXNV-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WTLNOANVTIKPEE-UHFFFAOYSA-N 2-acetyloxypropanoic acid Chemical compound OC(=O)C(C)OC(C)=O WTLNOANVTIKPEE-UHFFFAOYSA-N 0.000 description 1
- BWNBLGQCCSCCHF-UHFFFAOYSA-N 2-ethyl-1h-indole Chemical compound C1=CC=C2NC(CC)=CC2=C1 BWNBLGQCCSCCHF-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GOVXKUCVZUROAN-UHFFFAOYSA-N 3-ethyl-1h-indole Chemical compound C1=CC=C2C(CC)=CNC2=C1 GOVXKUCVZUROAN-UHFFFAOYSA-N 0.000 description 1
- HGZJJKZPPMFIBU-UHFFFAOYSA-N 3-formylbenzonitrile Chemical compound O=CC1=CC=CC(C#N)=C1 HGZJJKZPPMFIBU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 108010001779 Ancrod Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102100030563 Coagulation factor XI Human genes 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010074105 Factor Va Proteins 0.000 description 1
- 101710145505 Fiber protein Proteins 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 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
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010061599 Lower limb fracture Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- FKFMMMVFFYPIEE-UHFFFAOYSA-N [(3-aminophenyl)-azaniumylidenemethyl]azanium;dichloride Chemical compound Cl.Cl.NC(=N)C1=CC=CC(N)=C1 FKFMMMVFFYPIEE-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000003024 amidolytic effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 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
- 230000037396 body weight Effects 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N boron trifluoride etherate Substances FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 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 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BGOFCVIGEYGEOF-UJPOAAIJSA-N helicin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1C=O BGOFCVIGEYGEOF-UJPOAAIJSA-N 0.000 description 1
- 229940068628 helicin Drugs 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 239000002607 heparin antagonist Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 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
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 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
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- BGOFCVIGEYGEOF-UHFFFAOYSA-N salicylaldehyde beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=CC=C1C=O BGOFCVIGEYGEOF-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 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
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 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
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P9/10—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
- C07D295/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Diabetes (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明涉及以下通式(I)的化合物:或其药物学上可接受的盐、溶剂化物、水合物或药物学上可接受的制剂。这些化合物可用于抑制因子Xa以及预防和/或治疗血栓栓塞病症。
Description
技术领域
本发明涉及具有抗凝血作用的新化合物(所谓的抗凝剂)及其药物可接受的盐、溶剂化物和水合物,包含所述化合物作为活性成分的药物组合物,制备该化合物、盐及组合物的方法,以及在预防和/或治疗血栓栓塞病症中的应用。本发明的化合物、盐以及组合物是非常有效的因子Xa抑制剂。本发明还涉及所述化合物和盐的前药、旋光体、外消旋体和非对映异构体。
背景技术
血栓栓塞病症是人体中血液凝块倾向增加导致的,其风险因素例如是相对较大的手术、长时间不动、下肢折断、肥胖、血脂代谢紊乱、格兰氏阴性菌感染、癌症以及年龄老化。
静脉血栓形成有可能导致形成浮肿或者受损血管引流组织的炎症。深部静脉的血栓形成(所谓的深静脉血栓形成)有可能导致严重的并发症,例如肺栓塞。动脉血栓形成有可能导致依靠受损动脉供氧组织的缺血性坏死,例如冠状动脉受损时可导致心肌梗塞。其他血栓栓塞病症例如是动脉硬化、中风、心绞痛、间歇性跛行。
在正常生理条件下,自然的血液凝块可防止受损血管中产生更多的血液流失。在血液凝块期间,液态血液转化为血块,其是一种凝胶状物质,在受损血管处形成塞子并密封该血管。在此过程中,血浆中存在的可溶性纤维蛋白原在多级过程(所谓的凝血级联反应)中转化为纤维凝胶状的凝块物质一一纤维蛋白。
在两种不同的激活血液凝块的过程之间存在明显的差异。当血液接触非生理表面时,将启动内源性血液凝块过程。外源性血液凝块过程是在血管受损时开始启动。这两种血液凝块过程具有一个共同的过程,其中血液凝块因子X(一种丝氨酸蛋白酶)转化为其活性形式(因子Xa)。在所谓的凝血酶原酶复合物中,因子Xa与因子Va和Ca2+一起使凝血酶原转化为凝血酶,后者通过除去肽而由纤维蛋白原中释放纤维蛋白单体,该纤维蛋白单体能够凝集形成纤维蛋白纤维。最后,因子XIII产生交联并由此稳定纤维蛋白的纤维。
抗凝剂可用于预防和治疗血栓栓塞病症。对于狭义的抗凝剂,肝素(立即有效并直接抑制某些血液凝块因子)与维生素K拮抗剂(例如香豆素衍生物)有显著的差别。后者在肝脏中依赖于维生素K的存在抑制某些凝血因子的产生,并开始缓慢地发生作用。其他抗凝剂是纤维蛋白溶解剂和血小板聚集抑制剂(例如乙酰水杨酸),前者直接或者间接地激活纤维蛋白溶解系统。更不太常用的方法是用酶ancrod降低血液中的纤维蛋白原浓度。使用抗凝剂的目的是防止可阻塞血管的血块的发展或者是在血块形成时立即将其溶解。
上述狭义的抗凝剂(如肝素和维生素K拮抗剂)具有许多缺陷。对于肝素,有完整的肝素(UFH)和低分子量肝素(LMWH)之分。UFH的缺陷是通常需要静脉给药,抗凝作用经常变化,并因此必须时常监测患者以及剂量的适合性。虽然LMWH可以恒定且无需监测的剂量通过皮下给药,但由于其链较短,与UFH相比其作用大大降低。
维生素K拮抗剂如华法林在不同的患者之间具有不同的活性程度,这有可能是由于遗传因素。除上述的开始作用缓慢外,维生素K拮抗剂还具有以下缺陷:需要监测患者,而且个体所需剂量需要调节。
其他已知的抗凝剂属于凝血酶抑制剂类。该领域相关研究活动的当前概要可参考例如:Jules A.Shafer,Current Opinion in Chemical Biology,1988,2:458-485;Joseph P.Vacca,Current Opinion in Chemical Biology,200,4:394-400;以及Fahad Al-Obeidi和James A.Ostrem,DDT,第3卷5号,1998年5月:223-231。
凝血酶抑制剂的主要缺陷在于,为得到所希望的作用,必须非常大程度地抑制凝血酶体内活性,使得有可能增加出血的倾向,这也使剂量给药发生困难。
相反,因子Xa抑制剂可抑制由疑血酶原形成新的凝血酶,但不会损害已存在的且对于主要止血所必须的凝血酶的活性。
除上述综述文章外,例如还可参考以下文献:DE 197 43 435、DE 19755 268、DE 198 19 548、DE 198 39 499和WO 0031068。
这些因子Xa抑制剂的作用范围以及副作用的范围在某些情况下还没有完全调查清楚。
发明内容
本发明的目的是提供具有有用的性质、特别是具有抗疑作用的新化合物。
更具体而言,本发明的目的是提供具有更高活性、更少副作用和/或选择性增加的新型因子Xa抑制剂。另外,还提供合适的药物组合物。本发明的化合物及组合物可通过口服给药。
本发明的再一个目的是提供制备上述新化合物的方法。
这些新的化合物还适合用于预防和/或治疗血栓栓塞病症。
本发明所述的新抗凝化合物、其药物学上可接受的盐和溶剂化物和水合物以及药物制剂具有高活性和选择性,并可通过口服给药。本发明还涉及上述化合物及盐的前药、旋光体、外消旋体和非对映异构体。所述化合物及盐本身也可以是前药,仅通过代谢作用被活化。本发明还涉及包含上述化合物或其盐作为活性成分的药物组合物。还描述了多个直接且简单地合成本发明化合物、前药、盐及组合物的方法以及可用于这些方法中的中间体。本发明还描述了这些活性成分在预防和/或治疗血栓栓塞病症中的应用。
本发明涉及通式(I)的化合物:
其中:
X是Cl、Br或R1-N=CH(-NH2)-,其中R1是H、-OH、-C(=O)OR2、烷基、芳烷基、芳烷基氧基或者杂烷基例如烷氧基、酰基或酰氧基,而R2是烷基,如甲基、乙基或叔丁基,杂烷基、碳环基、杂环烷基、芳基、杂芳基、杂芳基烷基或芳烷基如苄基;
Ar是亚芳基、亚杂芳基、杂芳基亚烷基或亚芳烷基,其中X直接键连在芳香环上;
R3是H、烷基如C1-4烷基、杂烷基或芳烷基;
R4相互独立地是可被一个或者多个-OH或-NH2取代的烷基,或者是杂烷基,碳环基,杂环烷基,芳基,杂芳基或芳烷基,这些基团可被一个或者多个以下未经取代的基团取代:烷基、杂烷基如烷氧基、酰基或酰基氧基、碳环基、杂环烷基、芳基、杂芳基和芳烷基,或者是羟基或糖氧基,
n是0-5的整数,优选为0、1或2(根据优选实施方案n=0),R5是H、烷基、杂烷基、碳环基、杂环烷基、芳基、杂芳基、杂芳烷基或芳烷基,
R6和R7相互独立地是H、烷基、杂烷基、碳环基、杂环烷基如芳基-杂环烷基、芳基、杂芳基、芳烷基或杂芳烷基,这些基团可被一个或者多个优选未取代的以下基团取代:烷基、杂烷基如烷氧基、酰基或酰基氧基、碳环基、杂环烷基、芳基、杂芳基、杂芳烷基、芳烷基、-OH和-NH2,
或者R6和R7一起形成杂环烷基环、特别是芳基杂环烷基环的一部分,例如芳基-或杂芳基-哌嗪基,或者是杂芳香环的一部分,这些环系可被-个或者多个优选未取代的以下基团取代:烷基、杂烷基如烷氧基、酰基或酰基氧基、碳环基、杂环烷基、芳基、杂芳基、杂芳烷基、芳烷基、-OH和-NH2,以及
R8是H、烷基、杂烷基、碳环基、杂环烷基、芳基、杂芳基、杂芳烷基、或芳烷基,或者与R5一起形成杂环烷基环的一部分;
或其药物学上可接受的盐、溶剂化物、水合物或药物学上可接受的制剂。
由于其取代方式,式(I)化合物可包含一个或者多个手性中心。因此,本发明还包括所有纯的对映异构体以及所有纯的非对映异构体以及它们以任何混合比的混合物。
具体实施方式
术语“烷基”是指饱和或者至少部分不饱和的、直链或支链烃基,例如具有1-12个碳原子,优选具有1-6个碳原子,例如是甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基、2,2-二甲基丁基、正辛基、烯丙基、异戊二烯基或者己-2-烯基。
术语“杂烷基”是指其中一个或者多个碳原子被至少一个氧、氮、磷或硫原子置换的烷基,其中优选氧和氮原子,例如烷氧基如甲氧基或乙氧基、或甲氧基甲基、氰基或2,3-二氧基乙基。术语“杂烷基”还指羧酸或者衍生于羧酸的基团,如酰基、酰基氧基、羧基烷基、羧基烷基酯如羧基烷基甲基酯、羧基烷基酰胺、烷氧基羰基、或者烷氧基羰基氧基。
术语“碳环基”是指饱和或者部分不饱和的环状基团,其具有一个或者多个成环结构,每个环包含例如3-14个碳原子、优选5或6-10个碳原子,例如环丙基、环己基、1,2,3,4-四氢化萘或环己-2-烯基。杂环烷基可进一步被未取代的烷基、杂烷基、杂芳基或芳基取代。
术语“杂环烷基”是指其中一个或者多个碳原子相互独立地被氧、氮、磷或硫原子置换的碳环基。杂环烷基可进一步被未取代的烷基、杂烷基、杂芳基或芳基取代,并例如是哌啶、吗啉、N-甲基哌嗪或N-苯基哌嗪基。
术语“芳基”是指具有一个或者多个环并由以下结构形成的芳香环基团,所述结构包含例如5-14个碳原子、优选5或6-10个碳原子。另外,芳基可被未取代的烷基或杂烷基、OH、CN、NO2或NH2取代,并例如是苯基、萘基、2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基、2-乙氧基苯基、3-乙氧基苯基或4-乙氧基苯基、4-羧基苯基烷基或4-羟基苯基。
术语“杂芳基”是指其中一个或者多个碳原子相互独立地被氧、氮、磷或硫原子置换的芳基。优选仅1或2个碳原子被置换。此等基团的例子是4-吡啶基、2-咪唑基、3-吡唑基和异喹啉基。
术语“芳烷基”是指包括如上定义的芳基和烷基和/或碳环基的基团,例如苄基或四氢萘基。术语“杂芳基烷基”是指其中一个或者多碳原子相互独立地被氧、氮、磷或硫原子置换的芳烷基,例如四氢异喹啉基、2-或3-乙基吲哚基或者4-甲基吡啶基。
术语烷基、杂烷基、碳环基、杂环烷基、芳基、杂芳基、杂芳烷基、和芳烷基还指其中一个或者多个氢原子被氟、氯、溴或碘原子或者被-OH、NH2或SH基团取代的基团。这些术语还包括被未取代的烷基、杂烷基、芳烷基或芳烷氧基取代的相应基团。
术语亚芳基、亚杂芳基、亚杂芳基烷基和亚芳烷基是指二取代的芳基、杂芳基、杂芳烷基和芳烷基,例如携带至少两个除H之外的取代基的基团。
在本发明中,术语“糖氧基”是指通过α-或β-O-糖基键连接的糖,特别是单糖,优选葡萄糖或果糖。
通式(I)或(II)的化合物优选为其中X=R1-N=C(-NH2)-。
通式(I)或(II)的化合物还优选为其中R1=H、OH或C1-4烷氧基,如甲氧基或乙氧基。
另外,通式(I)的化合物还优选为其中Ar是取代或未取代的间-亚苯基。
通式(I)的化合物特别优选为其中Ar是在X的对位被OH、NH2、C1-4烷氧基(如甲氧基)、C1-4烷基氨基或C2-6二烷基氨基或卤原子(如氯或氟)取代的间-亚苯基。
通式(I)的化合物还优选为其中R3=H。
通式(I)的化合物还优选为其中R4基团相互独立地是OH、-OCH2COOH、-COOH、C1-4烷氧基或糖氧基或卤原子如F或Cl。特别优选的是,R4为-OCH2COOH、-COOH或β-D-糖氧基。
通式(I)的化合物优选为其中R5是H、C1-6烷基、C1-6杂烷基或者天然氨基酸的侧链。特别优选地,R5是H或甲基。
通式(I)的化合物还优选为其中R6和R7一起形成芳基-或杂芳基-哌嗪环(特别优选4-芳基-或4-杂芳基-哌嗪环)的一部分。
通式(I)的化合物还优选为其中R8=H或C1-6烷基,如甲基。
通式(I)的化合物还优选具有以下结构(II):
其中:
R1是H、OH或C1-4烷氧基,如甲氧基或乙氧基,
R4相互独立地是OH、-OCH2COOH、-COOH、C1-4烷氧基或糖氧基(特别是β-D-糖氧基)或卤原子如F或Cl,是0、1或2,优选是0或1,
R5是H或C1-4烷基,如甲基,
R9是H、OH、F或C1-4烷氧基(特别优选甲氧基),
R10是H、卤原子(特别优选F)、CN、NO2或C1-4烷氧基(特别优选甲氧基),
Y是N或CR11,而R11是H、卤原子(特别优选F)、CN、NO2或C1-4烷氧基(特别优选甲氧基)。
式(I)或(II)化合物之药物学上可接受的盐例如是生理学上可接受的矿物酸的盐,如盐酸、硫酸和磷酸,或者是有机酸的盐,如甲磺酸、对甲苯磺酸、乳酸、乙酸、三氟乙酸、柠檬酸、琥珀酸、富马酸、马来酸和水杨酸。式(I)或(II)化合物可被溶剂化、特别是水合化。水合作用可例如在制备过程中发生,或者是由于式(I)或(II)之起始无水化合物的吸湿特性。
根据本发明的药物组合物包括至少一种式(I)或(II)的化合物作为活性成分以及任选的赋形剂和/或辅剂。
本发明涉及的前药由式(I)或(II)的化合物以及至少一个药物学上可接受的保护基组成,该保护基可在生理条件下脱除,例如是烷氧基、芳烷基氧基、酰基或酰基氧基,如乙氧基、苄基氧基、乙酰基或乙酰基氧基。
其中X是氰基的式(I)或(II)化合物可作为合成生理活性化合物的起始物。这些化合物可用本领域中形成酰胺键的已知方法来合成。例如,式(III)的酸化合物和式(IV)的胺化合物
在溶剂如二甲基甲酰胺中通过偶联剂偶联在一起,所述偶联剂例如是羰基二咪唑或二环己基二酰亚胺、以及1-羟基苯并三唑。
其中X是氰基的式(III)化合物可如下合成:使其中X为氰基的式(V)的胺与式(VI)的α-酮基酸
在溶剂如乙醇或甲醇中反应,例如使用氰基硼氢化钠和催化量的乙酸。
或者,式(III)的化合物还可如下合成:使α-溴酸与碱如氢氧化钠反应,蒸发溶剂,然后添加过量的式(V)胺,接着在80-120℃的优选温度下加热所得的混合物数小时。
式(III)的化合物还可如下合成:使醛如3-氰基苯甲醛与氨基酸在碱的水溶液如氢氧化钠水溶液中反应,然后优选在低于5℃的温度下添加例如氰基硼氢化钠。
在立体选择性地合成式(I)或(II)化合物的优选方法中,式(III)的化合物是如下合成的:使芳基溴化物如3-溴苄腈与苯基甘氨酸衍生物如(S)-苯基甘氨酸反应。该合成可例如类似于在以下文献中描述的方法来实施:D.Ma等人,J.Amer.Chem.Soc.1998,120:12459-12467。对于以此方式立体选择性地制备的化合物,发现在苯基甘氨酸单元处具有(R)构型的式(I)或(II)化合物以及具有(S)构型的相应化合物都是非常有效的因子Xa抑制剂,在具有相同的取代基时,具有(S)构型的化合物具有略微更高的抑制性质。对于通式(I)或(II)化合物的第二个氨基酸单元,具有(S)构型的化合物类似地为略微更好的因子Xa抑制剂,而具有(R)构型的相应化合物也是非常有效的因子Xa抑制剂。根据本发明,优选具有S,S-构型的式(I)或(II)化合物,同时具有R,S-、S,R-和R,R-构型的化合物也表现出非常良好的抑制性质并构成本发明的一部分。
式(IV)的化合物是如下合成的:使用标准的偶联方法,用偶联剂和1-羟基苯并三唑,所述偶联基例如是羰基二咪唑或二环己基碳二亚胺,使N-Boc保护的氨基酸与式(XI)的胺反应。式(IV)的化合物也可通过使用混合酸酐或者N-Boc保护的相应氨基酸的4-硝基苯基酯来合成。在水或者二氯甲烷中用酸如盐酸、三氟乙酸或甲酸处理,脱除氨基处的保护基,形成最终的式(IV)化合物。
其中X是-CN或-C(=NH)NH2而R8是H的式(I)化合物也可根据本发明通过使式(VII)的胺、式(VIII)的醛和式(IX)的异腈例如在溶剂(如甲醇、异丙醇、乙醇、氯仿、乙腈、二氯甲烷)或者溶剂混合物(如甲醇/水、异丙醇/水、乙腈/水或氯仿/水)中一起反应而一步合成。
上述反应可通过添加Broensted酸,如对甲苯磺酸或2,4-二硝基苯磺酸,或者Lewis酸,如二氯化锌、三氯化铁、三氟化硼乙醚合物或者三氟磺酸镱,进行催化。
式(IX)的化合物可如下合成:使式(X)的异腈与式(XI)的胺在溶剂(如甲醇、二氯甲烷或二甲基甲酰胺)中,或者也可不用溶剂,例如在室温或者高至80℃的温度下反应(参见:K.Matsumoto等人,Synthesis,1997,249-250)。
上述起始化合物,特别是式(VII)、(VIII)、(XI)、(V)和(VI)的化合物,可市售得到或者可根据文献中已知的方法制备。式(X)的化合物可用根据I.Ugi(I.Ugi编辑,有机化学中的异腈化学(IsonitrileChemistry in Organic Chemistry),第20卷,Academic Press,1971,NewYork and London)的已知方法来合成。
在将-CN转化为-C(=NH)NH2时,起始腈可溶解在溶剂(如乙醇或甲醇)或者溶剂混合物(如氯仿和甲醇或者氯仿和乙醇)中,然后将该溶液与无水氯化氢气流在低于10℃的温度下接触。数小时-数天的反应时间后,用醚沉淀出中间体然后过滤。用碱如碳酸钠或氢氧化钠中和后,将该中间体溶解在水中并用溶剂如二氯甲烷、氯仿或乙酸乙酯萃取。所得物质接着与无水氨或者铵盐如氯化铵在溶剂如甲醇或乙醇中优选于高至80℃的温度下反应。或者,过滤得到的中间体可立即在溶剂如甲醇或乙醇中与无水氨或铵盐如氯化铵反应。
在将-CN转化为-C(=N-OH)NH2时,起始腈可溶解在溶剂如二甲基甲酰胺或乙醇中,然后将该溶液优选在低于5℃的温度下添加至碱如钠、氢化钠或三乙胺与羟胺或羟胺盐如盐酸羟胺在溶剂如二甲基甲酰胺或乙醇中的溶液混合物中。在将-CN转化为-C(=N-R1)NH2(其中R1是烷氧基)时,使用相应的烷基羟胺替代羟胺。
在将-CN转化为-C(=NH)NH2时,该转化可首先根据上述方法进行转变为其中X是-C(=N-OH)NH2的式(I)化合物。在第二步中,将上述式(I)化合物溶解在溶剂如乙醇或乙酸中,然后用催化剂如钯或钯/炭或者铂或者Raney镍在氢气氛中进行氢化。
其中X是-C(=O)OR2的式(I)化合物可如下合成:使其中R1是H的式(I)化合物在溶剂如二甲基甲酰胺或二氯甲烷中与式ClC(=O)OR2的氯甲酸酯反应。
根据上述方法之一制得的式(I)化合物可通过HPLC法分离为单独的立体异构体。
合成后,其中X是-C(=N-R1)NH2的式(I)化合物可任选地转化为生理相容盐、溶剂化物或水合物。
本发明的化合物或者药物组合物可用于抑制因子Xa活性,预防和/或治疗血栓栓塞性病症、动脉再狭窄、败血病、癌症、急性炎症或者因子Xa介导的其他病症,并特别是例如静脉血栓形成、浮肿或炎症、深静脉血栓形成、肺栓塞,较大的手术、长时间不动、下肢折断等导致的血栓栓塞并发症,动脉硬化、中风、心绞痛、间歇性跛行。
通常情况下,如开始时所述,根据本发明的活性成分对因子Xa具有尽可能高的抑制作用,同时又具有尽可能高的选择性。在本发明中,选择性是通过比较对因子Xa、类胰蛋白酶和凝血酶(两种其他的丝氨酸蛋白酶)的抑制作用来评估的。
如上所述,式(I)或(II)化合物及其药物学上可接受的盐、溶剂化物和水合物以及制剂和药物组合物都是在本发明的范围内。
本发明还涉及这些活性成分在制备用于预防和/或治疗血栓栓塞性病症的药物中的应用。通常情况下,式(I)或(II)的化合物可单独或者与其他所希望的治疗剂组合使用已知并可接受的方式给药。所述治疗有用的药物可按照以下途径之-给药:口服,例如为锭剂、包衣片剂、丸剂、半固体物质、软或硬胶囊、溶液、乳液剂或混悬剂的剂型;非胃肠道途径,例如为注射液;直肠途径,例如为栓剂;吸入途径,例如粉末剂或喷雾剂;透皮或者鼻腔内途径。在制备片剂、丸剂、半固体物质、包衣片、锭剂和硬明胶胶囊时,治疗有用的产物可与药理学上惰性的无机或有机赋形剂混合,例如乳糖、蔗糖、葡萄糖、明胶、麦芽、硅胶、淀粉或其衍生物、滑石、硬脂酸或其盐、脱脂乳粉等。在制备软胶囊时,可使用诸如植物油、矿物、动物或者合成油、蜡、脂和多元醇的赋形剂。在制备液态溶液和糖浆剂时,可使用诸如水、醇、盐水溶液、葡萄糖水溶液、多元醇、甘油、植物油、矿物和动物或者合成油脂。对于栓剂,可使用诸如植物油、矿物、动物或者合成油、蜡、脂和多元醇。对于喷雾剂,可使用合适的压缩气体,如氧气、氮气和二氧化碳。药物制剂还可包括以下添加剂:防腐剂、稳定剂、乳化剂、甜味剂、调味剂、用于改变渗透压的盐、缓冲剂、包封添加剂和抗氧剂。
与其他治疗剂的组合可包括通常用于预防和/或治疗血栓栓塞病症的其他活性成分,如华法林等。
在预防和/或治疗如上所述的病症时,本发明生理活性化合物的剂量可在较宽的范围内变化,并可针对个体的需要进行调节。通常情况下,每日0.1μg-10mg/kg体重的剂量是合适的,优选的剂量为每日0.5-4mg/kg。在合适的情况下,剂量也可低于或者高于以上数值。
以下实施例用于说明本发明。3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基的立体化学相应于β-D-葡萄糖的立体化学。
实施例
实施例1
0.05M的2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯甲醛在甲醇中的溶液(helicin)、0.05M的3-氨基苄脒二盐酸盐在甲醇中的溶液和0.05M的2-异氰基-1-[4-(2-甲氧基-苯基)-哌嗪-1-基]-乙烷酮在甲醇中的溶液在封闭容器中于室温下反应24小时。蒸发溶剂后,产物进行液相色谱和质谱分析,以确定最终产物的结构。通过液相色谱使用水/乙腈梯度作为洗脱剂在反相色谱柱上可纯制产物2-(3-脒基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C34H42N6O9(678.7486)
ESI-TOF-MS:679[M+H]+
实施例2
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(4-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C34H42N6O9(678.7486)
ESI-TOF-MS:679[M+H]+
实施例3
类似于实施例1,并使用相应合适的起始原料,得到2-联苯基-4-基2-(3-脒基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-乙酰胺。
C34H36N6O3(576.7044)
ESI-TOF-MS:577[M+H]+
实施例4
类似于实施例1,并使用相应合适的起始原料,得到2-联苯基-4-基2-(3-脒基-苯基氨基)-N-{2-[4-(4-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-乙酰胺。
C34H36N6O3(576.7044)
ESI-TOF-MS:577[M+H]+
实施例5
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-2-(3,4-二甲氧基-苯基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-乙酰胺。
C30H36N6O5(560.6586)
ESI-TOF-MS:561[M+H]+
实施例6
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-2-(3,4-二甲氧基-苯基)-N-{2-[4-(4-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-乙酰胺。
C30H36N6O5(560.6586)
ESI-TOF-MS:561[M+H]+
实施例7
类似于实施例1,并使用相应合适的起始原料,得到2-[(3-氰基-苯基氨基]-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)苯基]-乙酰胺。
C34H39N5O9(661.72)
ESI-TOF-MS:662[M+H]+
实施例8
将0.8mmol实施例7的产物添加至包含等摩尔量之盐酸羟胺及合适碱如三乙胺或甲醇钠的甲醇溶液中,在室温下搅拌24小时。蒸发掉所有挥发性物质后,通过类似于实施例1的液相色谱法纯制化合物。得到淡黄色粉末形式的2-[3-(N-羟基脒基)-苯基氨基]-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺
C34H42N6O10(694.7480)
ESI-TOF-MS:695[M+H]+
实施例9
类似于实施例1,并使用相应合适的起始原料,得到2-(5-脒基-2-羟基-苯基氨基)-N-{2-[4-(2,4-二氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C33H38F2N6O9(700.7024)
ESI-TOF-MS:701[M+H]+
实施例10
类似于实施例1,并使用相应合适的起始原料,得到[3-((3-脒基-苯基氨基)-{2-[4-(2,4-二氟-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C29H30F2N6O5(580.5965)
ESI-TOF-MS:581[M+H]+
实施例11
类似于实施例1,并使用相应合适的起始原料,得到2-(5-脒基-2-羟基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C34H42N6O10(694.7480)
ESI-TOF-MS:695[M+H]+
实施例12
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2-氰基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C34H39N7O8(673.7320)
ESI-TOF-MS:674[M+H]+
实施例13
类似于实施例1,并使用相应合适的起始原料,得到2-(5-脒基-吡啶-2-基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C33H41N7O9(679.7362)
ESI-TOF-MS:680[M+H]+
实施例14
类似于实施例1,并使用相应合适的起始原料,得到{2-[{2-[4-(4-溴-苯基)-4-羟基-哌啶-1-基]-2-氧代-乙基氨甲酰基}-(3-脒基-苯基氨基)-甲基]-苯氧基}-乙酸。
C30H32BrN5O6(638.5234)
ESI-TOF-MS:639[M+H]+
实施例15
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{1-[4-(2-甲氧基-苯基)-哌嗪-1-羰基]-2-甲基-丙基}-2-苯基-乙酰胺。
C31H38N6O3(542.6869)
ESI-TOF-MS:543[M+H]+
实施例16
类似于实施例1,并使用相应合适的起始原料,得到[3-((3-脒基-苯基氨基)-{2-[4-(2-硝基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C29H31N7O7(589.6131)
ESI-TOF-MS:590[M+H]+
实施例17
类似于实施例1,并使用相应合适的起始原料,得到[5-((3-脒基-苯基氨基)-{2-[4-(2,4-二氟-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-2-甲氧基-苯氧基]-乙酸。
C30H32F2N6O6(610.6229)
ESI-TOF-MS:611[M+H]+
实施例18
类似于实施例1,并使用相应合适的起始原料,得到[3-((3-脒基-苯基氨基)-{2-[4-(2,4-二甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C31H36F2N6O7(604.6686)
ESI-TOF-MS:605[M+H]+
实施例19
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-[2-氧代-2-(4-吡啶-4-基甲基-哌嗪-1-基)-乙基]-2-苯基-乙酰胺。
C27H31N7O2(485.5938)
ESI-TOF-MS:486[M+H]+
实施例20
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2-硝基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-苯基-乙酰胺。
C27H29N7O4(515.5767)
ESI-TOF-MS:516[M+H]+
实施例21
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2,4-二氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-苯基-乙酰胺。
C27H28F2N6O2(506.5600)
ESI-TOF-MS:507[M+H]+
实施例22
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2,4-二氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C33H38F2N6O8(684.7030)
ESI-TOF-MS:685[M+H]+
实施例23
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-[2-氧代-2-(4-吡啶-4-基哌嗪-1-基)-乙基]-2-苯基-乙酰胺。
C26H29N7O2(471.5667)
ESI-TOF-MS:472[M+H]+
实施例24
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2,4-二甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C35H44N6O10(708.7751)
ESI-TOF-MS:709[M+H]+
实施例25
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-[2-氧代-2-(4-吡啶-4-基哌嗪-1-基)-乙基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C32H39N7O8(649.7097)
ESI-TOF-MS:650[M+H]+
实施例26
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2-硝基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C33H39N7O10(693.7197)
ESI-TOF-MS:694[M+H]+
实施例27
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2,4-二甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-苯基-乙酰胺。
C29H34N6O4(530.6321)
ESI-TOF-MS:531[M+H]+
实施例28
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-苯基-乙酰胺。
C28H32N6O3(500.6056)
ESI-TOF-MS:501[M+H]+
实施例29
类似于实施例1,并使用相应合适的起始原料,得到[2-((3-脒基-苯基氨基)-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C30H34N6O6(574.6421)
ESI-TOF-MS:575[M+H]+
实施例29a
类似于实施例1,并使用相应合适的起始原料,得到[3-((3-脒基-苯基氨基)-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C30H34N6O6(574.6421)
ESI-TOF-MS:575[M+H]+
实施例30
类似于实施例1,并使用相应合适的起始原料,得到[2-((3-脒基-苯基氨基)-{2-[4-(2-羟基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C29H32N6O6(560.6150)
ESI-TOF-MS:561[M+H]+
实施例31
类似于实施例1,并使用相应合适的起始原料,得到[2-((3-脒基-苯基氨基)-{2-[4-(3-氰基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C30H31N7O5(569.6255)
ESI-TOF-MS:570[M+H]+
实施例32
类似于实施例1,并使用相应合适的起始原料,得到4-((3-脒基-苯基氨基)-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯甲酸。
C29H32N6O5(544.6156)
ESI-TOF-MS:545[M+H]+
实施例33
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-[2-(4-羟基-4-苯基-哌啶-1-基)-2-氧代-乙基]-2-苯基-乙酰胺。
C28H31N5O3(485.5910)
ESI-TOF-MS:486[M+H]+
实施例34
类似于实施例1,并使用相应合适的起始原料,得到[4-((3-脒基-苯基氨基)-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C30H34N6O6(574.6421)
ESI-TOF-MS:5 75[M+H]+
实施例35
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(4-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-苯基-乙酰胺。
C28H32N6O3(500.6056)
ESI-TOF-MS:501[M+H]+
实施例36
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-2-(2-羟基-苯基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-乙酰胺。
C28H32N6O4(516.6050)
ESI-TOF-MS:517[M+H]+
实施例37
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{[(吡啶-3-基甲基)-氨甲酰基]-甲基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C29H34N6O8(594.6297)
ESI-TOF-MS:595[M+H]+
实施例38
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[3-(3-三氟甲基-苯氧基)苯基]-乙酰胺。
C35H35F3N6O4(660.7022)
ESI-TOF-MS:661[M+H]+
实施例39
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-2-(3,4-二甲氧基-苯基)-N-{2-[4-(4-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-乙酰胺。
C30H36N6O5(560.6586)
ESI-TOF-MS:561[M+H]+
实施例40
类似于实施例1,并使用相应合适的起始原料,得到[2-苄氧基-5-((3-脒基-苯基氨基)-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C37H40N6O7(680.7674)
ESI-TOF-MS:681[M+H]+
实施例41
40mmol的3-溴苄腈、40mmol的(S)-苯基甘氨酸、60mmol的碳酸钾和4mmol的碘化亚铜(I)在50ml的二甲基甲酰胺中于100℃、惰性气体氛围(N2)下搅拌24小时。除去溶剂后,用液相色谱纯制部分I。
在110ml的二甲基甲酰胺(DMF)中于室温(RT)下搅拌分别为20mmol的Boc-肌氨酸、HOBt、二异丙基碳二亚胺(DIC)、哌嗪和三乙胺过夜。真空除去溶剂后,所得的粗产物通过柱色谱纯制。所得的产物在20ml三氟乙酸和20ml二氯甲烷的混合物中于室温下搅拌5小时。除去溶剂后,通过液相色谱纯制部分II。
在14ml的DMF中于室温下过夜搅拌分别为2mmol的部分I、部分II、DIC、HOBt和三乙胺。除去溶剂后,粗产物通过液相色谱纯制。为将氰化物转化为脒,将1mmol的氰化物溶解在10ml氯仿中,向其中添加氯化氢在无水甲醇中的饱和溶液5ml,然后使反应混合物在4℃下放置2天。真空除去溶剂后,向其中添加氨在甲醇中的无水溶液20ml,并在室温下搅拌4小时。通过HPLC纯制所希望的产物,2-(3-脒基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-N-甲基-2-苯基-乙酰胺。
C29H34N6O3(514.6327)
ESI-TOF-MS:515[M+H]+
实施例42
类似于实施例1,并使用相应合适的起始原料,得到2-(3-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-1-甲基-2-氧代-乙基}-2-苯基-乙酰胺。
类似于实施例41,并使用相应合适的起始原料,选择性地合成了四种非对映异构体。
C29H34N6O3(514.6327)
ESI-TOF-MS:515[M+H]+
实施例43
类似于实施例1,并使用相应合适的起始原料,得到[2-苄氧基-5-((3-脒基-苯基氨基)-{2-[4-(2-羟基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸。
C36H38N6O7(666.7403)
ESI-TOF-MS:667[M+H]+
实施例44
类似于实施例1,并使用相应合适的起始原料,得到4-((3-脒基-苯基氨基)-{2-[4-(2-硝基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯甲酸。
C28H29N706(559.5866)
ESI-TOF-MS:560[M+H]+
实施例45
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-{[(吡啶-3-基甲基)-氨甲酰基]-甲基}-2-喹啉-4-基-乙酰胺。
C26H25N7O2(467.5349)
ESI-TOF-MS:468[M+H]+
实施例46
类似于实施例1,并使用相应合适的起始原料,得到2-(3-脒基-苯基氨基)-N-[2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C34H41N5O10(679.7334)
ESI-TOF-MS:680[M+H]+
实施例47
类似于实施例1,并使用相应合适的起始原料,得到N-[2-(4-乙酰基-4-苯基-哌啶-1-基)-2-氧代-乙基]-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C36H43N5O9(689.7722)
ESI-TOF-MS:690[M+H]+
实施例48
类似于实施例1,并使用相应合适的起始原料,得到(3-{(3-脒基-苯基氨基)-[2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基-氨甲酰基]-甲基}-苯氧基)-乙酸。
C30H33N5O7(575.6268)
ESI-TOF-MS:576[M+H]+
实施例49
类似于实施例1,并使用相应合适的起始原料,得到{3-[[2-(4-乙酰基-4-苯基哌啶-1-基)-2-氧代-乙基氨甲酰基]-(3-脒基-苯基氨基)-甲基]-苯氧基}-乙酸。
C32H35N5O6(585.6657)
ESI-TOF-MS:586[M+H]+
实施例50
类似于实施例1,并使用相应合适的起始原料,得到[3-((3-脒基-苯基氨基)-{2-[4-(2,4-二氟-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-苯氧基]-乙酸叔丁基酯。
C33H38F2N6O5(636.7048)
ESI-TOF-MS:637[M+H]+
实施例51
类似于实施例1,并使用相应合适的起始原料,得到2-(5-脒基-2-甲氧基-苯基氨基)-N-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺。
C35H44N6O10(708.7751)
ESI-TOF-MS:709[M+H]+
实施例52
类似于实施例1,并使用相应合适的起始原料,得到4-[4-((3-脒基-苯基氨基)-{2-[4-(2-甲氧基-苯基)-哌嗪-1-基]-2-氧代-乙基氨甲酰基}-甲基)-3-甲氧基-苯氧基]-丁酸。
C33H40N6O7(632.7228)
ESI-TOF-MS:633[M+H]+
为证明对因子Xa的抑制作用,使用显色肽底物。如下验证上述化合物对因子Xa的amidolytic活性的抑制作用。测量是在室温下于微滴定板中进行的。将化合物溶解在二甲基亚砜中,然后将5μl的该溶液添加至1nM的人重组因子Xa(Enzyme Research Laboratories,South Bend,IN,USA)于缓冲液(pH:8.0,并使用50mMTris-HCl、100mM氯化钠、0.1%的PEG 6000和0.005%的Tween 80)中的溶液内。最后,添加在缓冲液中的N-甲氧基羰基-D-正亮氨酰基-甘氨酰基-L-精氨酸-4-苯基重氮酸乙酸盐(Roche Diagnostics,Mannheim,Germany),然后用Spectra Flour Plus分光光度计(Tecan,Crailsheim,Germany)监测底物的水解共20分钟。通过Erithacus Software Ltd.(Staines,Middlesex,UK)制造的“GraFit 4”程序计算IC50值。假设动力学包括竞争性抑制作用,则可通过Cheng-Prusoff等式:Ki=IC50/(1+[S]Km))测定Ki值(Cheng和Prusoff,Biochemical Pharmacology 1973,22:3099-3108)。使用相同的方法,但在Hepes缓冲液(pH 7.8)中使用甲苯磺酰基-甘氨酰基-脯氨酰基-赖氨酸-4-苯基重氮酸乙酸盐作为底物,测定所述化合物对重组人类胰蛋白酶(Promega,Madison,WI,USA)之蛋白水解活性的抑制作用。
上述实施例的IC50值在1nM至1μM的范围内。
Claims (8)
1、通式(I)的化合物:
其中:
X是R1-N=C(-NH2)-,其中R1是H或-OH;
Ar是未取代或者在X的对位被OH或C1-4烷氧基取代的间亚苯基,或Ar是亚吡啶基;
R3是H;
R4相互独立地是羟基、-OCH2COOH、-COOH、C1-4烷氧基或糖氧基,n是0、1或2,
R5是H或C1-6烷基,
R6和R7一起形成包含6个环原子的杂环烷基环的一部分,该环系可被一个或者多个以下基团取代:C1-6烷基、C1-6杂烷基、4-吡啶基、4-甲基吡啶基、任选被氟、氯、溴或碘原子、NO2、CN、OH或甲氧基中的一个取代的苯基、以及-OH,
R8是H或C1-6烷基;
或其药物学上可接受的盐、溶剂化物、水合物或药物学上可接受的制剂。
2、如权利要求1所述的化合物,其中,R4相互独立地是-OH、-OCH2COOH、-COOH、或β-D-糖氧基。
3、如权利要求1所述的化合物,其中,R6和R7-起形成哌啶环的一部分或者如权利要求1所述被取代的哌嗪环的一部分。
4、如权利要求1-3之一所述的化合物,其中,R5是H、甲基或异丙基。
5、药物组合物,其包含如权利要求1-4之一所述的化合物作为活性成分以及任选的赋形剂和/或辅剂。
6、如权利要求1-5之一所述的化合物或药物组合物在制备用于抑制因子Xa的药物中的应用。
7、如权利要求1-5之一所述的化合物或药物组合物在制备用于治疗和/或预防血栓栓塞病症、动脉再狭窄、败血病、癌症、急性炎症或者因子Xa介导的其他病症的药物中的应用。
8、如权利要求1-5之一所述的化合物或药物组合物在制备用于血管手术的药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10041402.8 | 2000-08-23 | ||
DE10041402A DE10041402A1 (de) | 2000-08-23 | 2000-08-23 | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1460101A CN1460101A (zh) | 2003-12-03 |
CN1332939C true CN1332939C (zh) | 2007-08-22 |
Family
ID=7653525
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018145353A Expired - Fee Related CN1332939C (zh) | 2000-08-23 | 2001-08-23 | 抑制因子Xa活性的新化合物 |
Country Status (17)
Country | Link |
---|---|
US (1) | US6794507B2 (zh) |
EP (1) | EP1311473A2 (zh) |
JP (1) | JP2004534717A (zh) |
KR (1) | KR20040007388A (zh) |
CN (1) | CN1332939C (zh) |
AU (2) | AU9550701A (zh) |
BR (1) | BR0113389A (zh) |
CA (1) | CA2418283A1 (zh) |
CZ (1) | CZ2003453A3 (zh) |
DE (1) | DE10041402A1 (zh) |
HK (1) | HK1052170A1 (zh) |
HU (1) | HUP0301670A2 (zh) |
IL (1) | IL154319A0 (zh) |
NZ (1) | NZ524262A (zh) |
PL (1) | PL365925A1 (zh) |
WO (1) | WO2002016312A2 (zh) |
ZA (1) | ZA200300998B (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19939910A1 (de) * | 1999-08-23 | 2001-03-01 | Morphochem Ag | Neue Verbindungen, die Tryptase-Aktivität hemmen |
CA2437114A1 (en) * | 2001-02-23 | 2002-09-06 | Morphochem Aktiengesellschaft Fuer Kombinatorische Chemie | Diamides which inhibit tryptase and factor xa activity |
ATE384713T1 (de) | 2001-07-26 | 2008-02-15 | Lilly Co Eli | 1-glycinyl-4-(1-methylpiperidin-4-yl)piperazine und -piperidine als faktor-xa-antagonisten |
KR20040096541A (ko) * | 2002-01-31 | 2004-11-16 | 모르포켐 악티엥게셀샤프트 퓌르 콤비나토리셰 케미 | 인자 Xa 활성을 저해하는 화합물 |
DE10300049A1 (de) * | 2003-01-03 | 2004-07-15 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | Neue Verbindungen, die Faktor VIIa inhibieren |
DE10204072A1 (de) * | 2002-01-31 | 2003-08-14 | Morphochem Ag Komb Chemie | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
ES2538469T3 (es) | 2003-06-05 | 2015-06-22 | Genentech, Inc. | Terapia de combinación para trastornos de células B |
AU2006318539B2 (en) | 2005-11-23 | 2012-09-13 | Genentech, Inc. | Methods and compositions related to B cell assays |
US7615556B2 (en) * | 2006-01-27 | 2009-11-10 | Bristol-Myers Squibb Company | Piperazinyl derivatives as modulators of chemokine receptor activity |
US7601844B2 (en) * | 2006-01-27 | 2009-10-13 | Bristol-Myers Squibb Company | Piperidinyl derivatives as modulators of chemokine receptor activity |
EP2200631A1 (en) | 2007-10-16 | 2010-06-30 | Zymogenetics, Inc. | Combination of blys inhibition and anti-cd 20 agents for treatment of autoimmune disease |
EP2283355A2 (en) | 2008-04-25 | 2011-02-16 | Zymogenetics, Inc. | Levels of bcma protein expression on b cells and use in diagnostic methods |
US8003335B2 (en) | 2008-04-30 | 2011-08-23 | Universite Paris-SUD11 | Levels of APRIL in serum and use in diagnostic methods |
CA2720651C (en) | 2008-05-01 | 2020-03-10 | Zymogenetics, Inc. | Levels of blys/april heterotrimers in serum and use in diagnostic methods |
TWI433838B (zh) | 2008-06-25 | 2014-04-11 | 必治妥美雅史谷比公司 | 作為趨化因子受體活性調節劑之六氫吡啶衍生物 |
WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
CN107385034B (zh) | 2009-09-03 | 2021-08-17 | 弗·哈夫曼-拉罗切有限公司 | 用于治疗、诊断和监控类风湿性关节炎的方法 |
US8642622B2 (en) | 2010-06-16 | 2014-02-04 | Bristol-Myers Squibb Company | Piperidinyl compound as a modulator of chemokine receptor activity |
WO2013110354A1 (en) | 2012-01-25 | 2013-08-01 | Université Catholique de Louvain | Compositions and methods for cell transplantation |
EP2680884B1 (en) | 2011-02-28 | 2018-01-17 | F. Hoffmann-La Roche AG | Biological markers and methods for predicting response to b-cell antagonists |
EP3078378B1 (en) | 2015-04-08 | 2020-06-24 | Vaiomer | Use of factor xa inhibitors for regulating glycemia |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0921116A1 (de) * | 1997-12-04 | 1999-06-09 | F. Hoffmann-La Roche Ag | N-(4-carbamimido-phenyl)-glycinamidderivate |
EP1020434A1 (en) * | 1997-08-27 | 2000-07-19 | Kissei Pharmaceutical Co., Ltd. | 3-amidinoaniline derivatives, activated blood coagulation factor x inhibitors, and intermediates for producing both |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19653036A1 (de) * | 1996-12-19 | 1998-06-25 | Merck Patent Gmbh | Cyclopeptidderivate |
DE19939910A1 (de) | 1999-08-23 | 2001-03-01 | Morphochem Ag | Neue Verbindungen, die Tryptase-Aktivität hemmen |
-
2000
- 2000-08-23 DE DE10041402A patent/DE10041402A1/de not_active Withdrawn
-
2001
- 2001-08-23 EP EP01976140A patent/EP1311473A2/de not_active Withdrawn
- 2001-08-23 WO PCT/EP2001/009753 patent/WO2002016312A2/de not_active Application Discontinuation
- 2001-08-23 AU AU9550701A patent/AU9550701A/xx active Pending
- 2001-08-23 KR KR10-2003-7002513A patent/KR20040007388A/ko not_active Application Discontinuation
- 2001-08-23 PL PL01365925A patent/PL365925A1/xx not_active Application Discontinuation
- 2001-08-23 JP JP2002521188A patent/JP2004534717A/ja not_active Withdrawn
- 2001-08-23 NZ NZ524262A patent/NZ524262A/en unknown
- 2001-08-23 CN CNB018145353A patent/CN1332939C/zh not_active Expired - Fee Related
- 2001-08-23 AU AU2001295507A patent/AU2001295507B2/en not_active Expired - Fee Related
- 2001-08-23 US US10/362,149 patent/US6794507B2/en not_active Expired - Fee Related
- 2001-08-23 IL IL15431901A patent/IL154319A0/xx unknown
- 2001-08-23 CZ CZ2003453A patent/CZ2003453A3/cs unknown
- 2001-08-23 BR BR0113389-6A patent/BR0113389A/pt not_active IP Right Cessation
- 2001-08-23 HU HU0301670A patent/HUP0301670A2/hu unknown
- 2001-08-23 CA CA002418283A patent/CA2418283A1/en not_active Abandoned
-
2003
- 2003-02-05 ZA ZA200300998A patent/ZA200300998B/en unknown
- 2003-06-19 HK HK03104407.6A patent/HK1052170A1/zh unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1020434A1 (en) * | 1997-08-27 | 2000-07-19 | Kissei Pharmaceutical Co., Ltd. | 3-amidinoaniline derivatives, activated blood coagulation factor x inhibitors, and intermediates for producing both |
EP0921116A1 (de) * | 1997-12-04 | 1999-06-09 | F. Hoffmann-La Roche Ag | N-(4-carbamimido-phenyl)-glycinamidderivate |
Also Published As
Publication number | Publication date |
---|---|
ZA200300998B (en) | 2004-05-05 |
BR0113389A (pt) | 2003-07-29 |
US6794507B2 (en) | 2004-09-21 |
KR20040007388A (ko) | 2004-01-24 |
IL154319A0 (en) | 2003-09-17 |
US20030153510A1 (en) | 2003-08-14 |
AU2001295507B2 (en) | 2007-07-19 |
WO2002016312A2 (de) | 2002-02-28 |
CZ2003453A3 (cs) | 2003-05-14 |
CA2418283A1 (en) | 2003-02-03 |
EP1311473A2 (de) | 2003-05-21 |
JP2004534717A (ja) | 2004-11-18 |
HUP0301670A2 (hu) | 2003-09-29 |
PL365925A1 (en) | 2005-01-10 |
HK1052170A1 (zh) | 2003-09-05 |
NZ524262A (en) | 2004-08-27 |
CN1460101A (zh) | 2003-12-03 |
WO2002016312A3 (de) | 2002-06-20 |
DE10041402A1 (de) | 2002-03-14 |
AU9550701A (en) | 2002-03-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1332939C (zh) | 抑制因子Xa活性的新化合物 | |
US5629324A (en) | Thrombin inhibitors | |
US6262069B1 (en) | 1-amino-7-isoquinoline derivatives as serine protease inhibitors | |
EP1948608B1 (en) | Pharmaceutical salts and polymorphs of n-(5-chloro-2-pyridinyl)-2-[[4-[(dimethylamino)iminomethyl]benzoyl]amino]-5-methoxy-benzamide , a factor xa inhibitor | |
EP2077995B1 (en) | Methods of synthesizing pharmaceutical salts of a factor xa inhibitor | |
RU2286337C2 (ru) | ПРОИЗВОДНЫЕ (ТИО)МОЧЕВИНЫ, ИНГИБИРУЮЩИЕ ФАКТОР VIIa, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ | |
US7772251B2 (en) | N-sulphonylated amino acid derivatives, method for the production and use thereof | |
US4873253A (en) | Phenylalanine derivative and proteinase inhibitor | |
JP4274522B2 (ja) | Xa因子阻害剤としてのグアニジンおよびアミジン誘導体 | |
AU776797B2 (en) | N-guanidinoalkylamides, their preparation, their use, and pharmaceutical preparations comprising them | |
US20080051388A1 (en) | Novel Compounds That Inhibit Factor Xa Activity | |
CN1322001C (zh) | 抑制因子Xa活性的新化合物 | |
JP2004502759A (ja) | アミノイソキノリン基を有するトロンビン阻害剤 | |
AU758007B2 (en) | Benzamide derivatives as thrombin inhibitors | |
US20060058389A1 (en) | Novel compounds that inhibit factor xa activity | |
EP0486702A1 (en) | Phenyl 4-guanidinobenzoate derivative, process for producing the same, and protease inhibitor containing the same | |
DE69717147T2 (de) | Thrombin inhibitoren | |
CZ2003452A3 (en) | Data processing system, with an Internet connection facility has a structured program loaded in memory for use in assigning predetermined data from a multiplicity of data to hierarchical memory addresses |
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 | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |