WO1995009859A1 - Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring - Google Patents
Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring Download PDFInfo
- Publication number
- WO1995009859A1 WO1995009859A1 PCT/US1994/011049 US9411049W WO9509859A1 WO 1995009859 A1 WO1995009859 A1 WO 1995009859A1 US 9411049 W US9411049 W US 9411049W WO 9509859 A1 WO9509859 A1 WO 9509859A1
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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- methyl
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- Prior art date
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- 108090000190 Thrombin Proteins 0.000 title abstract description 22
- 229960004072 thrombin Drugs 0.000 title abstract description 22
- 239000003112 inhibitor Substances 0.000 title abstract description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 229940002612 prodrug Drugs 0.000 claims abstract description 12
- 239000000651 prodrug Substances 0.000 claims abstract description 12
- -1 cyclic boron ester Chemical class 0.000 claims description 169
- 150000001875 compounds Chemical class 0.000 claims description 145
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 41
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 40
- 239000001301 oxygen Substances 0.000 claims description 39
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 229910052796 boron Inorganic materials 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 108010022999 Serine Proteases Proteins 0.000 claims description 8
- 102000012479 Serine Proteases Human genes 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 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 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims description 2
- PHRABVHYUHIYGY-UHFFFAOYSA-N 1-methylnaphthalene Chemical group C1=CC=C2C([CH2])=CC=CC2=C1 PHRABVHYUHIYGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006345 2,2,2-trifluoroethoxymethyl group Chemical group [H]C([H])(*)OC([H])([H])C(F)(F)F 0.000 claims description 2
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 2
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 2
- 229930194542 Keto Natural products 0.000 claims description 2
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 2
- 229910006095 SO2F Inorganic materials 0.000 claims description 2
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 2
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 125000004001 thioalkyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 7
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 abstract description 4
- 235000008206 alpha-amino acids Nutrition 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000002585 base Substances 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229940122388 Thrombin inhibitor Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000003868 thrombin inhibitor Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 235000013930 proline Nutrition 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 150000001540 azides Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 0 *N1Cc2ccccc2C1 Chemical compound *N1Cc2ccccc2C1 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 5
- 238000005345 coagulation Methods 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
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- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
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- 102000004190 Enzymes Human genes 0.000 description 3
- 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 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
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- 238000005917 acylation reaction Methods 0.000 description 3
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- 125000000539 amino acid group Chemical group 0.000 description 3
- 230000002965 anti-thrombogenic effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 3
- 229940077388 benzenesulfonate Drugs 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 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
- 230000035602 clotting Effects 0.000 description 3
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- 230000020764 fibrinolysis Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
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- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000006623 intrinsic pathway Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- KIHQEVXNQJYINH-WHFBIAKZSA-N methyl (2s,4s)-4-chloropyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1C[C@H](Cl)CN1 KIHQEVXNQJYINH-WHFBIAKZSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- XXTWZTPVNIYSJZ-DEOSSOPVSA-N n-[(2s)-3-(4-carbamimidoylphenyl)-1-oxo-1-piperidin-1-ylpropan-2-yl]-2-(naphthalen-2-ylsulfonylamino)acetamide Chemical compound C1=CC(C(=N)N)=CC=C1C[C@@H](C(=O)N1CCCCC1)NC(=O)CNS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 XXTWZTPVNIYSJZ-DEOSSOPVSA-N 0.000 description 1
- IJTLXOBSKIIETJ-UHFFFAOYSA-N n-[3-(2-amino-1,4,5,6-tetrahydropyrimidin-5-yl)-1-(4-methylpiperidin-1-yl)-1-oxopropan-2-yl]-5-(dimethylamino)naphthalene-1-sulfonamide;dihydrochloride Chemical compound Cl.Cl.C1CC(C)CCN1C(=O)C(NS(=O)(=O)C=1C2=CC=CC(=C2C=CC=1)N(C)C)CC1CNC(=N)NC1 IJTLXOBSKIIETJ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 108010068110 nazumamide A Proteins 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to the discovery of novel and useful ⁇ -amino acid analogs, and the
- These compounds contain a disubstituted- pyrrolidine ring conjugated to an ⁇ -amino acid functionalized with an electrophilic group such as boronic acids and their esters, ⁇ -perhaloketones and aldehydes.
- Thrombin plays several critical roles in
- hemostasis the normal physiological process by which bleeding from an injured blood vessel is arrested.
- Thrombin cleaves soluble fibrinogen to form insoluble fibrin in the. last proteolytic step of both the
- Fibrin may be further insolubilized through crosslinking by the thrombin-activated enzyme, factor Xllla.
- thrombin-induced activation of platelets leads to their aggregation and the secretion of additional factors that further accelerate creation of a hemostatic plug.
- Thrombin also potentiates its own production by the activation of factors V and VIII.
- thrombosis Treatment of thrombosis.
- Specific thrombin inhibitors are anticipated to exhibit few of the adverse side effects, such as bleeding and interpatient variability, caused by anticoagulants currently in clinical use (B. Furie and B. C. Furie, The New England Journal of
- thrombin inhibitors A number of naturally occurring thrombin inhibitors have been isolated. These include the marine sponge natural products Theonella sp . occidentalamide A, a linear tetrapeptide reported by Fusetani et al., Tetrahedron Let t . 32, 7073-4 (1991); Theonel la sp . cyclotheonamides A and B reported by Fusenati et al., J. Am . Chem . Soc .
- Peptide analogs of thrombin substrates and reaction intermediates also inhibit thrombin.
- examples of these include the tripeptide aldehyde (D)-Phe-Pro-Arg-H, disclosed by Bajusz et al., Int . J. Peptide Protein Res . 12, 217-221 (1978); a chloromethyl ketone analog (Ac- (D)-Phe-Pro-ArgCH 2 Cl, disclosed by Kettner and Shaw, Thromb . Res .
- thrombin Representative examples of these compounds include t-butyloxycarbonyl-(D)-trimethylsilylalanine-Pro-boroArg-pinanediol, disclosed in Metternich, European Patent Application EP 471 651 A2; Ac-(D)- ⁇ -napthylalanine-Pro-boroArg pinanediol ester, disclosed in Kakkar et al., PCT Application WO 92/07869; N- (t-butyloxycarbonyl)-(D)-phenylglycyl-(L)-prolyl-(L)-arginine aldehyde, disclosed in Gesellchen and Shuman, European Patent Application EP 0 479 489 A2 and J. Med .
- thrombin inhibitors many of which incorporate an arginine or arginine mimic, have also been disclosed.
- arylsulfonylarginine amides such as ( 2R,4R-1-[N 2 -(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-(L)-arginyl]-4-methyl-2-piperidinecarboxylate, disclosed by Okamoto et al., U.S. Patent No. 4,258,192; Okamoto et al., Biochem . Biophys . Res . Commun . 101, 440-446 (1981); Kikumoto et al.,
- amidinophenylalanine derivatives such as (2-naphthylsulfonylglycyl)-4-amidino-phenylalanyl piperidine disclosed in Stuber and Dickneite, European Patent Application EP 508 220; amino phenylalanine derivatives, disclosed in Okamoto et al., U.S. Patent No.
- thrombin inhibitors contain a 5-membered pyrrolidine ring. In most cases, the pyrrolidine ring is incorporated into the inhibitor as an integral component of the amino acid proline, a 2-substituted pyrrolidine, which in turn is bonded to the remaining atoms of the inhibitor via amide linkages. None of the cited references describe or suggest the new thrombin-inhibiting compounds of the present invention.
- novel compounds described in the present invention are substituted at the 4-position of the pyrrolidine ring.
- Winter et al. in European Patent Application WO 91/04247, have disclosed that 4-substituted-(L)-proline can mimic a dipeptide within a larger peptide or protein, and variably substituted prolines have been incorporated into compounds including bradykinin antagonists disclosed by Kyle et al., J.
- X is a) halogen
- R 3 and R 10 are independently selected at each occurrence from the group consisting of:
- R 4 and R 5 are independently selected at each occurrence from the group consisting of:
- R 6 , R 7 , R 8 and R 9 are independently selected at each
- R 6 or R 7 can alternatively be taken together with R 6 or R 7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or k) R 8 or R 9 can alternatively be taken
- R 11 and V when taken together, can also be:
- Y 1 and Y 2 are a) -OH
- a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
- a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
- a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
- W can be independently selected at each occurence from the group consisting of:
- V is selected from the group consisting of: a) -(CH 2 ) x -,
- Z is selected from the group consisiting of a) -(CH 2 ) x -,
- Preferred compounds of formula (I) are those compounds wherein: R 1 is (C 3 -C 4 alkyl);
- X is selected from the group consisting of:
- More prefe rred compounds of f ormu la ( I ) are compounds of formula ( Ia ) :
- R 1 is (C 3 -C 4 alkyl
- X is selected from the group consisting of:
- R 2 is hydrogen or C 1 -C 4 alkyl
- R 3 and R 10 are independently selected at each occ urrence from the group consisting of:
- R 4 and R 5 are independently selected at each occurrence from the group consisting of:
- R 6 , R 7 , R 8 , R 9 are independently selected at each
- a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
- a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
- a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
- W can be independently selected at each occurrence from the group consisting of:
- V is selected from the group consisting of:
- Z is selected from the group consisiting of:
- w can be independently selected at each occurrence from
- x can be independently selected at each occurrence from 0 to 3; with the following provisos: (a) when V is (CH 2 ) x , x cannot be 0 when R 3 is
- R 1 is (C 3 -C4 a lkyl);
- X is from the group consisting of
- R 2 is hydrogen or C 1 -C 4 alkyl
- R 3 is independently selected from the group consisting of:
- R 10 is independently selected from the group consisting of:
- R 11 is hydrogen
- a cyclic boron ester where said chain or ring contains from 2 to 20 carbcn atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
- a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
- a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
- V is independently selected from the group consisting of:
- phenethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 3- phenylprop-1-yl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 1,1- dimethyl-2-phenylethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 2,2- dimethyl-2-phenylethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is diphenylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenoxymethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylsulfonylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is (m- fluorophenyl)ethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is (3- pyridyle ⁇ hyl) and R 10 is methyl
- (D) indicates the amino acid is in the (D)-configuration.
- “D,L” indicates the amino acid is present as a mixture of the (D)- and the (L)-configuration.
- the prefix "bore” indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if R 1 is isopropyl and Y 1 and Y 2 are OH, the C-terminal residue is abbreviated "boroVal-OH" or
- boroValine where "-OH” indicates the boronic acid is in the form of the free acid.
- the pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated “-C 10 H 16 " and “-C 6 H 12 ", respectively.
- Examples of other useful diols for esterification with the boronic acids are 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, and 1,2-dicyclohexylethanediol.
- Some common abbreviations used herein are: CBZ or Z, benzyloxycarbonyl; BSA,
- LRMS and HRMS are low and high resolutior. mass spectrometry, respectively, using ammonia (NH 3 -CI) or methane (CH 4 -CI) as an ion source.
- the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties.
- the present invention comprises all of the stereoisomers or mixtures thereof. If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard
- R 3 is - (CR 6 R 7 ) t -W-(CR 8 R 9 ) u -aryl, and u is 0 it is the same as :
- R 6 and R 7 are taken to for a double bond, and R 8 and R 9 taken to be a triple bond would be:
- amine-blocking group or "amineprotecting group” as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substituents on these groups may include either alkyl, aryl and alkaryl which may contain the heteroatoms, O, S, and N as a substituent or as an inchain component. A number of amine-blocking groups are recognized by those skilled in the art of organic synthesis.
- suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl (also referred to as t-butyloxycarbonyl) or adamantyloxycarbonyl.
- aromatic urethane protecting groups such as benzyloxycarbonyl
- aliphatic urethane protecting groups such as t-butoxycarbonyl (also referred to as t-butyloxycarbonyl) or adamantyloxycarbonyl.
- amino acid residues refers to natural or unnatural amino acid of either (D)- or (L)-configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys,
- amino acid residue also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art.
- the Peptides Vol 3, 3-88 (1981) describes numerous suitable protecting groups and is incorporated herein by reference for that purpose.
- alkyl is intended to include both branched and straight-chain saturated aliphatic
- hydrocarbon groups having the specified number of carbon atoms "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl” is intended to include saturated ring groups, including mono-,bi- and polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth. "Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo.
- aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three
- heteroaryl is meant to include 5-, 6- or 10-rnernbered mono- or bicyclic aromatic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents.
- heteroaryl include the following: 2-, or 5-, or 4-pyridyl; 2-or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ; 2-or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4-or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5- isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or
- heterocycle is meant to include 5-, 6-or 10-membered mono- or bicyclic rings which can
- heterocycle optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents.
- group heterocycle but not limited to, 2- or 3-pyrrolidinyl, a 2-, 3-, or 4-piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4-tetrahydroquinolinyl, 2- or 3-tetrahydrofuranyl, 2- or
- 3-tetrahydrothiophene 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino. Particularly preferred are 1-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl.
- the substituents that may be attached to the aryl, heteroaryl or heterocycle ring(s) may be independently selected at each occurrence from the group consisting of:
- stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
- pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I).
- Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids and the like.
- compositions of the invention can be prepared by reacting the free acid or base forms of these compounds with a
- Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vi vo when such prodrug is administered to a mammalian subject.
- Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
- Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
- Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I).
- (L)-4-hydroxyproline benzyl ester hydrochloride which is commercially available, or any other suitably protected hydroxyproline, can be treated with a trialkylamine base, typically 4-methylmorpholine, and an acid chloride (R 10 COCl) to afford acylation product (II) selectively.
- the hydroxyl group can be converted to a corresponding ester by treatment with a second acid chloride (R 3 COCl) in the presence of a trialkylamine or heterocyclic amine base, such as pyridine, and a suitable catalyst, such as but not limited to DMAP to generate (III).
- the carboxylic acid of the proline moiety can be liberated by hydrogenation using conditions reported by Hartney and Simonoff, Org . React . VII, 263 (1953) wherein an alcohol solution of the compound (III) may be affected under an atmosphere of hydrogen gas using a suitable catalyst, preferably platinum or palladium on carbon catalyst, to provide (IV).
- the DCC/DMAP esterification procedure reported by Hassner, and Alexanian, Tetrahedron Let t . 19, 4475 (1978) has proved useful for performing the second acylation reaction.
- an ester other than benzyl which might be removed hydrolytically or
- photilytically such as photlytic deprotection.
- a methyl ester of (II) treatment of an alcoholic solution of the compound with a solution of sodium hydroxide so as to deliver 1 equivalent amount of NaOH followed by acidification should provide the carboxylic acid.
- N-acyl-4-(alkoxy)proline intermediates can prepared as shown in Scheme 2.
- the hydroxyl function of an N-protected 4-hydroxyproline (V) can be alkylated according to the method of Smith et al., JV Med . Chem . 31, 875 (1988), by treatment with an alkali metal hydride, such as but not limited to sodium hydride and an alkyl halide (R 3 X) to give (VI).
- an alkali metal hydride such as but not limited to sodium hydride and an alkyl halide (R 3 X) to give (VI).
- the t-butyl carbamate can be cleaved upon treating with acid under anhydrous conditions; for example, trifluoroacetic acid in dichloromethane solution removes the t-butyl urethane of derivatives of (IV) at ambient temperature as reported by Bryan et. al., J. Am . Chem . Soc . 99, 2353 (1977); alternatively anhydrous hydrogen chloride in dioxane may be used to prepare the HCI salt.
- Other methods for protection of the amine are delineated in Greene and Wuts (1991).
- the use of benzyl urethane is also viable where hydrogenation over palladium catalyst deliveres the free amine (VII). Acydlation by one of the methods discussed previously can provide (VIII).
- thrombin inhibitors of the present invention requires the coupling of either of the aforementioned intermediates, (IV), (VIII), or (XII) with a boron-containing fragment followed by
- XVII begins with the coupling of amine hydrochloride (XIII), disclosed by Kettner and Shenvi U.S. Patent No. 5.187.147, to provide amide (XIV).
- XIII amine hydrochloride
- One method calls for the combination of (XIII) and the acid chloride derived from (IV), (VIII) or (XII) in the presence of an amine base, such as but not limited to pyridine.
- DCC/HOBT method may be used to access amines XIV and/or XII
- Conversion of the bromide to the X group in R 1 of formula (I) can be accomplished by first reaction of bromide (X) with an inorganic azide, such as sodium or potassium azide, in an anhydrous polar aprotic solvent, such as acetone, N, ⁇ -dimethylformamide or methyl
- the amine (XVI) can be isolated as the free base or a salt, typically, but not exclusively hydrochloride or benzenesulfonate; other salts which impart improved physical properties may be preferred.
- the preferred method for preparation of the free boronic acid (XVII) involves transesterification in the presence of excess phenylboric acid.
- the amidine-type analogs, where the X group in R 1 of formula (I) is modified, can be prepared as shown in
- guanidinium analogs can be prepared in a similar manner starting from amine hydrochloride (XVIII) .
- Amide bond formation using one of the methods previously described provides (XIX), which can be converted to the azide (XX) by nucleophilic displacement of the bromide. Reduction of the azide using conditions already described can provide the amine (XXI) .
- Preparation of formamidine (XXII) can be accomplished by reaction of amine (XXI) with ethyl formimidate hydrochloride in the presence of DMAP according to the method of Ohme and Schmitz, Angew, Chem mt. Ed 6,566 (1967) .
- isothiouronium can be prepared as shown in Scheme 6.
- Part B To a solution of the product from Part A (370 mg, 1.41 mmol) and pyridine (0.17 mL, 2.10 mmol) in CH 2 Cl 2 (14 mL) at 0 °C was added 3-phenylpropionyl chloride (0.23 mL, 1.55 mmol). The reaction mixture was warmed to room temperature over 3 hours and added to EtOAc (ca. 75 mL). The organic layer was washed with sat. aq. NaHCO 3 (1 ⁇ 25 mL), half-saturated aqueous copper (II) sulfate (1 ⁇ 25 mL), sat. aq. NaCl (1 ⁇ 25 mL), dried (Na 2 SO 4 ) and was concentrated under reduced pressure. The residue was purified by flash
- Part C A solution of the product from Part E (340 mg, 0.86 mmol) together with palladium on charcoal (50 mg) in methanol (MeOH, 9 mL) was stirred under hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give (4R)- ⁇ -acetyl-4-(3-phenylpropionyl)oxy-(L)-proline (245 mg) as a foam in 93% yield.
- Part D To a solution of the product from Part C (240 mg, 0.79 mmol) and 4-methylmorpholine (0.26 mL, 2.36 mmol) in tetrahydrofuran (THF, 6 mL) at -20 °C was added i-butyl chloroformate (0.11 mL, 0.87 mmol) after which the reaction mixture was stirred for 2 minutes.
- Part E A mixture of the product from Part D (470 mg, 0.75 mmol) and sodium azide (NaN 3 , 97 mg, 1.50 mmol) in DMF (8 mL) was heated at 65-70 °C for 4 hours. The mixture was poured into EtOAc (ca. 75 mL). and washed with H 2 O (3 ⁇ 20 mL), sat. aq.
- Example 303 To a mixture of Example 303 (1.95 g, 2.52 mmol) in H 2 O (10 mL), Et 2 O (15 mL), and sufficient MeOH (ca. 1.5 mL) to maintain a clear, biphasic system was added phenylboric acid (1.54 g, 12.6 mmol). The mixture was stirred for 14 hours, the layers were separated and the aqueous phase was extracted with Et 2 O (5 ⁇ 20 mL). The aqueous layer was concentrated under reduced pressure to give the title compound (1.20 g) as an amorphous powder in 75% yield. LRMS 482 (M+H), 464 (base); HRMS Calcd for C 28 H 39 BN 3 O 5 (ethylene gycol ester): 508.2983. Found:
- Part B A solution of the product from Part A (17.03 g, 64.5 mmol) in trifluoroacetic acid (20 mL) and CH 2 Cl 2 (20 mL) was stirred 18 hours. The reaction mixture was concentrated under reduced pressure to give (4S)-4-chloro-(L)-proline methyl ester (18.05 g) as an oil in quanitative yield.
- 1 H NMR 300 MHz, CDCI 3 ) ⁇ 4.75 (comp,
- Part C A solution of the product from Part B (30.28 g, 109 mmol) in CH 2 Cl 2 (50 mL) was cooled to 0 °C and Et 3 N (45.6 mL, 327 mmol) followed by hydrocinnamoyl chloride (17.8 mL, 120 mmol) were added slowly in order to maintain an internal temperature less than 10 °C .
- Part D EtOH (50 mL) was cooled to 0 °C and sodium (0.78 g, 33.8 mmol) was added. After the hydrogen evolution ceased, thiophenol (3.72 g, 33.8 mmol) was added and the reaction mixture stirred for 15 minutes at 0 °C, and the product from Part C (5 g, 16.9 mmol) was added. The stirring was continued for an additional 16 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and acidified with 1N HCI to pH 4. The aqueous solution was extracted with EtOAc (3 ⁇ 30 mL), the organics dried with Na 2 SO 4 and concentrated under reduced pressure.
- Part E Using the method described above for the preparation of Example 78, Part D, ( 1R)-5-bromo-[(4R) -N-(3-phenylpropionyl)-4-(phenyl)thio-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (2.43 g) as an oil in 85% yield. LRMS 681.2 683.2 (M+H, base).
- Part F Using the method described above for Example 78, Part E, the intermediate ( 1R)-5-azido-[(4R)- ⁇ -(3-phenylpropionyl)-4-(phenyl)thio-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (2.42 g) as an oil in quantitative yield.
- Part G A solution of the product from Part F (2.42 g, 3.76 mmol) in 1,3-propanedithiol (1.62 g, 15 mmol), triethylamine (1.52 g, 15 mmol) and methanol (20 mL) was stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduce pressure and purified by flash chromatography through florosil, eluting with 1:9 MeOH-CH 2 Cl 2 . The concentrated residue was dissolved in diethyl ether (10 mL), acidified with 1 equivalent of IN HCI in Et 2 O and concentrated to give the title compound
- Part A A solution of the commercially available starting material, (4R)- ⁇ -BOC-4-(benzyl)oxy-(L)-proline, previously reported by Smith et al., J. Med . Chem . 31, 875 (1988); (2.11 g, 6.57 mmol), in CH 2 Cl 2 (27 mL) was treated with anhydrous hydrogen chloride in dioxanes (4 M, 6.60 mL). The reaction mixture was stirred for 18 hours, during which time a white precipitate formed. The reaction was diluted with diethyl ether (Et 2 O, ca.
- Part B A suspension of the product from Part A (1.50 g, 5.83 mmol) in CH 2 Cl 2 (58 mL) at 0 °C was treated with
- HCI aqueous hydrochloric acid
- EtOAc aqueous hydrochloric acid
- the organic layer was washed with H 2 O (3 ⁇ 50 mL), sat. aq. NaCl (1 ⁇ 50 mL), dried (MgSO 4 ) and concentrated under reduced pressure.
- the resulting solid was
- Part C Using the method described above for the preparation of Example 78, Part D, (1R)-5-bromo-[(4R)-N-(3-phenylpropionyl)-4-(benzyl)oxy-(L)-prolyl]aminopentane-1-boronic acid (+)-pinanediol ester was isolated (2.80 g) as an oil in 90% yield. LRMS 679, 681 (M+H, base).
- Part E A solution of product from Part D (2.24 g, 3.50 mmol) in MeOH (35 mL) together with palladium on charcoal (225 mg) was stirred under hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 30 mL) and the filtrate was concentrated under reduced pressure to give a foam which contained a small amount of unreacted azide. This material was resubjected to the
- Example 303 A solution of Example 303 (2.00 g, 3.25 mmol) in methanol (25 mL) was treated with a solution of
- Part A A mixture of the product from Example 302, Part C (3.00g, 10.1 mmol) and NaN 3 (3.30 g, 50.7 mmol) in DMF (15 mL) was heated to 75 °C for 18 hours. Tne reaction mixture was dissolved in H 2 O (25 mL). The aqueous solution was extracted with Et 2 O (3 ⁇ 25 mL), dried with MgSO 4 and concentrated to give (4R)- ⁇ -(3-phenylpropionyl)-4-azido-(L)-proline methyl ester (2.13 g) as an oil in 83% yield. 1 H NMR (300 MHz, CDCl 3 ) ⁇
- Part B Using the method described above for the preparation of Example 78, Part F, ( 4R) -N- ( 3-phenylpropionyl)-4-amino-(L)-proline methyl ester was isolated (2.43 g) as an oil in 85% yield.
- 1 H ⁇ MR 300 MHz, CDCI 3 ) ⁇ 7.24 (comp, 5H), 4.58 (m, 1H), 3.74
- Part C A mixture of the product from Part B (1.51 g, 5.46 mmol), benzaldehyde (0.58 g, 5.46 mmol), potassium acetate (0.54 g, 5.46 mmol) and 5% palladium on charcoal (0.21 g) was stirred in MeOH (25 mL) under hydrogen (3 atm) for 5 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate concentrated under reduced pressure to give (4R)- ⁇ -(3-phenylpropionyl)-4-(benzyl)amino-(L)-proline methyl ester (2.00 g) as an oil in quantitative yield. 1 H ⁇ MR (300 MHz, CDCI3) ⁇ 7.27 (comp, 10H), 4.58
- Part D A solution of the product from Part C (2.00 g, 5.46 mmol) methanol (15 mL) and IN sodium hydroxide (9 mL) was stirred for 24 hours. The pH of the solution was adjusted to 6 with 1N HCI and a white precipitate formed. The solid material was collected by suction filtration to give (4R)- ⁇ -(3-phenylpropionyl)-4- (benzyl)amino-(L)-proline (1.31 g) as a white powder in 68% yield. LRMS 353.2 (M+H, base).
- Part E Using the method described above for the preparation of Example 78, Part D, ( 1R)-5-bromo-[(4R)- ⁇ - (3-phenylpropionyl)-4-(benzyl)amino-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (0.71 g) as an oil in 49% yield. LRMS 678.3 680.3 (M+H, base).
- Part F Using the method described above for Example 78, Part E, the intermediate (1R)-5-azido-[(4R)-N-(3-phenylpropionyl)-4-(benzyl)amino-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (0.45 g) as an oil in 67% yield.
- Part G A solution of the product from Part F (0.45 g, 0.70 mmol) in MeOH (5 mL) together with 20% palladium hydroxide on charcoal (0.04 g) was stirred under
- Part B A mixture of the product from Part A (365 mg, 0.55 mmol) and thiourea (83 mg, 1.10 mmol) in ethanol (EtOH, 10 mL) was heated at reflux for 16 hours and cooled to room temperature. The reaction was poured into Et 2 O (ca. 120 mL) and concentrated under reduced pressure. The residue was triturated with Et 2 O (ca. 50 mL), which was decanted. Purification of the residue by size exclusion chromatography on Sephadex LH-20, elution with MeOH, gave a glass which was dissolved in THF (1.5 mL) and treated with Et 2 O (ca. 20 mL) to give a solid. The solid was washed with Et 2 O (ca.
- inhibitors of serine proteases notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes.
- Inhibition constants were determined by the method described by Kettner et al. in J. Bi ol . Chem . 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis cf the chromogenic substrate S2238 (Helena Laboratories,
- Plasma 0.2 mL
- buffer 0.05 mL, 0.10 M
- Tris [hydroxymethyl] -aminomethane hydrochloride, pH 7.4, 0.9% (w/v) sodium chloride, and 2.5 mg/mL bovine serum albumin) containing inhibitor were incubated 3 min at 37 °C in a fibrameter. Reactions were initiated by adding thrombin (0.05 mL) to achieve a final concentration of 4 NIH units/mL. The effectiveness of compounds as
- anticoagulants is reported as the level of inhibitor required to prolong clotting to that observed for 2 NIH units/mL of thrombin in the absence of inhibitor. In this assay then, better inhibitors require lower
- the compounds of formula (I) have anti-thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for the control of the coagulation of the fibrinolysis system in mammals or they may be added to blood for the
- these compounds may be administered orally, parenterally or intravenously to a host to obtain an anti-thrombogenic effect.
- the dosage of the active compound depends on the mammalian species, body weight, age, and mode of administration as determined by one skilled in the art. In the case of large mammals such as humans, the compounds may be
- pharmaceutical carriers or diluents at a dose of from 0.02 to 15 mg/kg to obtain the anti-thrombogenic effect, and may be given as a single dose or in
- compositions or as a sustained release formulation.
- Pharmaceutical carriers or diluents are well known and include sugars, starches and water, which may be used tc make tablets, capsules, injectable solutions or the like which can serve as suitable dosage forms for
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Abstract
This invention relates to the discovery of novel and useful α-amino acid analogs, and the pharmaceutically acceptable salts and prodrugs thereof, containing a disubstituted pyrrolidine ring conjugated to an α-amino acid, useful as inhibitors of thrombin.
Description
Title
Boropeptide Inhibitors of Thrombin which Contain a
Substituted Pyrrolidine Ring
Field of the Invention
This invention relates to the discovery of novel and useful α-amino acid analogs, and the
pharmaceutically acceptable salts or prodrugs thereof, as inhibitors of thrombin. These compounds contain a disubstituted- pyrrolidine ring conjugated to an α-amino acid functionalized with an electrophilic group such as boronic acids and their esters, α-perhaloketones and aldehydes.
Background of the Invention
Thrombin plays several critical roles in
hemostasis, the normal physiological process by which bleeding from an injured blood vessel is arrested.
Thrombin cleaves soluble fibrinogen to form insoluble fibrin in the. last proteolytic step of both the
extrinsic and intrinsic pathways of the coagulation cascade. Fibrin may be further insolubilized through crosslinking by the thrombin-activated enzyme, factor Xllla. In addition, thrombin-induced activation of platelets leads to their aggregation and the secretion of additional factors that further accelerate creation of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII.
Recent reviews of the roles of thrombin in coagulation have been reported by Fenton in Ann . N. Y. Acad . Sci . 485, 5-15 (1986); and Fenton et al. in Blood Coagulati on and Fibrinolysis 2, 69-75 (1991).
Owing to its multiple roles in clot formation, inhibition of thrombin offers a therapeutic opportunity for development of anticoagulants useful in the
treatment of thrombosis. Specific thrombin inhibitors are anticipated to exhibit few of the adverse side effects, such as bleeding and interpatient variability, caused by anticoagulants currently in clinical use (B. Furie and B. C. Furie, The New England Journal of
Medicine 326, 800-806 (1992)).
A number of naturally occurring thrombin inhibitors have been isolated. These include the marine sponge natural products Theonella sp . nazumamide A, a linear tetrapeptide reported by Fusetani et al., Tetrahedron Let t . 32, 7073-4 (1991); Theonel la sp . cyclotheonamides A and B reported by Fusenati et al., J. Am . Chem . Soc .
112, 7053-4 (1990); and Toxadocia cylindrica toxadocial A, a sulfated C47 aldehyde reported by Nakao et al., Tetrahedron Let t . 34, 1511-4 (1993). Hirudin, a 65 amino acid polypeptide, is responsible for the
anticoagulant activity of the medicinal leech, Hirudo medi cinalis . Recombinant versions of hirudin disclosed by Brauer et al. in AU-A-45977/85 and compounds
incorporating- hirudin fragments that have been disclosed by Maraganore et al. in PCT application WO91/02750;
DiMaio et al., J. Med . Chem . 35, 3331-3341 (1992);
DiMaio and Konishi, PCT application W091/19734; Witting et al., Biochem . J. 283, 737-743 (1992); Krstenansky in European Patent Application EP 372 503 A2; may be clinically useful anticoagulants as suggested by Fareed et al., Blood Coagulation and Fibrinolysis 2, 135-147 (1991).
Peptide analogs of thrombin substrates and reaction intermediates also inhibit thrombin. Examples of these include the tripeptide aldehyde (D)-Phe-Pro-Arg-H, disclosed by Bajusz et al., Int . J. Peptide Protein Res . 12, 217-221 (1978); a chloromethyl ketone analog (Ac-
(D)-Phe-Pro-ArgCH2Cl, disclosed by Kettner and Shaw, Thromb . Res . 14, 969-73 (1979); polyfluorinated analogs such as (D)-Phe-Pro-Arg-CF2-CF3 disclosed by Kolb et al., AU-B-52881/86; Neises and Ganzhorn, European Patent Application EP 503 203 A1;
Neises et al., European Patent Application EP 504 064 A1); and boronic acid analogs (Ac-(D)-Phe-Pro-boroArg, Kettner and Shenvi, European Patent Application EP 0 293 881 A2; Kettner et al., J. Biol . Chem. 265, 18289-97 (1990). Borolysine, boroornithine and boroarginine inhibitors that contain various amino acid replacements have also been synthesized and shown to inhibit
thrombin. Representative examples of these compounds include t-butyloxycarbonyl-(D)-trimethylsilylalanine-Pro-boroArg-pinanediol, disclosed in Metternich, European Patent Application EP 471 651 A2; Ac-(D)-β-napthylalanine-Pro-boroArg pinanediol ester, disclosed in Kakkar et al., PCT Application WO 92/07869; N- (t-butyloxycarbonyl)-(D)-phenylglycyl-(L)-prolyl-(L)-arginine aldehyde, disclosed in Gesellchen and Shuman, European Patent Application EP 0 479 489 A2 and J. Med . Chem . 36, 314-319 (1993); and (HOOC-CH2)2-(L) -β-cyclohexylalanine-Pro-Arg-CH2-O-CH2-CF3, disclosed by Atrash et al., European Patent Application EP 530 167 Al.
Numerous synthetic thrombin inhibitors, many of which incorporate an arginine or arginine mimic, have also been disclosed. These include arylsulfonylarginine amides such as ( 2R,4R-1-[N2-(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-(L)-arginyl]-4-methyl-2-piperidinecarboxylate, disclosed by Okamoto et al., U.S. Patent No. 4,258,192; Okamoto et al., Biochem . Biophys . Res . Commun . 101, 440-446 (1981); Kikumoto et al.,
Biochemistry 23, 85-90 (1984); amidinophenylalanine derivatives such as (2-naphthylsulfonylglycyl)-4-amidino-phenylalanyl piperidine disclosed in Stuber and
Dickneite, European Patent Application EP 508 220; amino phenylalanine derivatives, disclosed in Okamoto et al., U.S. Patent No. 4,895,842; 1-[2-[5-(dimethylamino)naphth-1-ylsulfonamido]-3-(2-iminohexahydropyrimidin-5-yl)propanoyl]-4-methylpiperidine dihydrochloride, disclosed in Ishikawa et al., JP 88/227572 and JP 88/227573); and (R)-Ν-[(RS)-1-amidino-3-piperidinylmethyl]-α-(o-nitro¬benzenesulfonamido)indole-3-propionamide, disclosed in Ackermann et al., European Patent Application EP 468 231). Isoquinolinyl guanidino benzoate derivatives, disclosed by Takeshita et al., European Patent
Application EP 435 235 A1; and 2-[3-(4-amidinophenyl)]propionic acid derivatives, disclosed by Mack et al., PCT Application WO 93/01208 also act as thrombin inhibitors.
Many natural and synthetic thrombin inhibitors contain a 5-membered pyrrolidine ring. In most cases, the pyrrolidine ring is incorporated into the inhibitor as an integral component of the amino acid proline, a 2-substituted pyrrolidine, which in turn is bonded to the remaining atoms of the inhibitor via amide linkages. None of the cited references describe or suggest the new thrombin-inhibiting compounds of the present invention.
The novel compounds described in the present invention are substituted at the 4-position of the pyrrolidine ring. Although Winter et al., in European Patent Application WO 91/04247, have disclosed that 4-substituted-(L)-proline can mimic a dipeptide within a larger peptide or protein, and variably substituted prolines have been incorporated into compounds including bradykinin antagonists disclosed by Kyle et al., J.
Med . Chem . 34, 2649-2653 (1991); as well as vasopressin analogs Buku et al., J. Med . Chem . 30, 1509-1512 (1987), no thrombin inhibitors containing a 5-membered
pyrrolidine ring substituted in the manner described here have been disclosed.
Despite considerable research in the area, more efficacious and specific thrombin inhibitors are needed as potentially valuable therapeutic agents for the treatment of thrombosis.
Summary of the Invention
[1] The present invention provides novel compounds of formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 is
a) -(C1-C12 alkyl)-X, or
b) -(C2-C12 alkenyl)-X, or
X is
a) halogen,
b) -CN,
c) -NO2,
d) -CF3,
e) -S(O)pR2,
f) -NHR2,
g) -NHS(O)pR2,
h) -NHC(=NH)H,
i) -NHC(=NH) NHOH,
j) -NHC(=NH)NHCN,
k) -NHC(=NH)NHR2,
l) -NHC(=NH)NHC(=O) R2,
m) -C(=NH)H,
n) -C(=NH)NHR2,
o) -C(=NH)NHC(=O)R2,
p) -C(=O)NHR2,
q) -C(=O)NHC(=O)R2,
r) -C(=O)OR2,
s) -OR2,
t) -OC(=O)R2,
u) -OC(=O)OR2,
v) -OC(=O)NHR2,
w) -OC(=O)NHC(=O)R2,
x) -SC(=NH)NHR2;
R2 is
a) hydrogen,
b) -CF3
c) C1-C4 alkyl,
d) -(CH2)q-aryl;
R3 and R10 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) halogen,'
c) -(CR6R7)tW(CR8R9)u-R9,
d) (CR6R7)tW(CR8R9)u-aryl,
e) (CR6R7)tW(CR8R9)u-heteroaryl, f) (CR6R7)tW(CR8R9)u-heterocycle, g) (CR6R7)tW(CR8R9)u-adamantyl, h) (CR6R7)tW(CR8R9)u(C5-C7)cycloalkyl, i)
j )
l )
, m)
n)
R3 and R10 when taken together form a ring such as :
a) -(CR6R7)t(CR8R9)u-W-(CR8R9)u(CR6R7)t;
b) -(CR6R7)tW(CR8R9)u-aryl-(CR8R9)uW(CR6R7)t-;
c) -(CR6R7)tW(CR8R9)u-heteroaryl-(CR8R9)uW(CR6R7)t-; d) -(CR6R7)tW(CR8R9)u-heterocycle-(CR8R9)uW(CR6R7)t-; e) -(CR6R7)tw(CR8R9)u-W-(CR8R9)u-w-(CR6R7)t-;
R4 and R5 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) C1-C4 alkyl,
c) C1-C4 alkoxy,
d) C5-C7 cycloalkyl,
e) phenyl,
f) benzyl;
R6, R7, R8 and R9 are independently selected at each
occurrence from the group consisting of:
a) hydrogen,
b) C1-C6 alkyl,
c) C1-C6 alkoxy,
d) C3-C8 cycloalkyl,
e) aryl,
f) heterocycle,
g) heteroaryl,
h) -W-aryl,
i) -(CH2)wC(=O)OR4,
j) R6 or R7 can alternatively be taken together with R6 or R7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or k) R8 or R9 can alternatively be taken
together with R8 or R9 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons;
R11 is
a) hydrogen,
b) C1-C4 alkyl,
c) C1-C4 thioalkyl,
d) -(CR6R7)tW(CR8R9)u-aryl,
e) -(CR6R7)tW(CR8R9)u-heteroaryl,
f ) -(CR6R7)tW(CR8R9)u-heterocycle;
g) -(CR6R7)tW(CR8R9)u-R9; R11 and V, when taken together, can also be:
a) keto,
b) =NR10,
c) =C[(CR6R7)tW(CR8R2)uR9]2;
d) -(CR6R7)tW(CR8R9)uW-(CR6R7)tW(CR8R9)u-A is
a) -BY1Y2,
b) -C(=O)CF3,
c) -C(=O)CF2CF3,
d) -PO3H2
d) -C(=O)H,
e) -C(=O)-1-piperdinyl,
f) -C(=O)CH2OCH2CF3,
g) CH2Cl
h) SO2F;
Y1 and Y2 are
a) -OH,
b) -F,
C) -NR4R5 -,
d) -C1-C8 alkoxy, or;
when taken together Y1 and Y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
W can be independently selected at each occurence from the group consisting of:
a) -(CH2)x-,
b) -C(=O)-,
c) -C(=O)O-,
d) -C(=O)NR4-,
e) -O-,
f) -OC(=O)-,
g) -OC(=O)O-,
h) -OC(=O)NR4-,
i) -NR4-,
j) -NR4C(=O)-,
k) -NR4C(=O)O-,
1) -NR4C(=O)NR5-,
m) -NR4S(O)p- n) -S(O)p-,
o) -S(O)pO-,
p) -S(O)PN1R4-,
q) -S(O)pNR4C ( =O ) - ,
r ) - S (O ) pNR4C ( =O ) NR5- ;
V is selected from the group consisting of: a) -(CH2)x-,
b) -(CH2)xC(=O)-,
c) -(CH2)xC(=O)O-,
d) -C(=O) (CH2)x-,
e) -O-(CH2)x-,
f) -O(CH2)xC(=O)-,
g) -O(CH2)xC(=O)O-,
h) -O(CH2)xC(=O)NR4-,
i) -O(CH2)xS(O)p-,
j) -(CH2)xS(O)p-,
k) -(CH2)xS(O)pO-,
1) -(CH2)xS(O)pNR4-,
m) -(CH2)xS(O)pNR4C(=O)-,
n) -(CH2)xS(O)pNR4C(=O)NR5-,
o) -(CH2)xNR4-,
p) -(CH2)xNR4C(=O)-,
q) -(CH2)xNR4C(=O)O-,
r) -(CK2)xNR4C(=O)NR5-,
S) -(CK2)xNR4S(O)p-; Z is selected from the group consisiting of a) -(CH2)x-,
b) -(CH2)xC(=O)-,
c) -C(=O) (CH2)x-,
d) -(CH2)xC(=O)O-,
e) -(CH2)xC(=O)NR4-,
f) -(CH2)xNR4-,
g) -(CH2)xNR4C(=O)-,
h) -(CH2)xNR4C(=O)O-,
i) -(CH2)xNR4C(=O)NR5-,
j) -(CH2)xNR4S(O)p-,
k) -(CH2)xS(O)p-,
1) -(CH2)xS(O)pNR4-, m can be 0 to 4; n can be 0 to 4; p can be 0 to 2 q can be 0 to 4; r, s, t, u, and v are independently selected at each
occurrence from 0 to 6, w and x are independently selected at each occurence
from 0 to 4; with the following provisos: (a) when V is (CH2)x, x cannot be 0 when R3 is
hydrogen;
(b) when Z is - (CH2)xC(=O)- and -C(=O) (CH2)x and x is 0, R10 cannot be halogen.
[2] Preferred compounds of formula (I) are those compounds wherein: R1 is (C3-C4 alkyl);
X is selected from the group consisting of:
-NHC(=NH)H, -NHC(=NH)NHR2, -NH2 or -SC(=NH)NHR2 ; R2 is hydrogen or C1-C4 alkyl.
[ 3 ] More prefe rred compounds of f ormu la ( I ) are compounds of formula ( Ia ) :
R1 is (C3-C4 alkyl);
X is selected from the group consisting of:
-NHC(=NH)H, -NHC(=NH)NHR2, -NH2 or -SC(=NH)NHR2;
R2 is hydrogen or C1-C4 alkyl;
R3 and R10 are independently selected at each occ urrence from the group consisting of:
a) hydrogen,
b) halogen,
c) -(CR6R7)tW(CR8R9)u-R9
d) -(CR6R7)tW(CR8R9)u-aryl
e) -(CR6R7)tW(CR8R9)u-heteroaryl;
R4 and R5 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) C1-C4 alkyl,
c) C1-C4 alkoxy,
d) phenyl,
e) benzyl; R6, R7, R8, R9 are independently selected at each
occurrence from the group consisting of:
a) hydrogen
b) C1-C6 alkyl,
c) aryl,
d) -(CH2)wC(=O)OR4, or;
Y1 and Y2 are
a) -OH,
b) -F,
c) -NR4R5-,
d) -C1-C8 alkoxy, or;
when taken together Y1 and Y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
W can be independently selected at each occurrence from the group consisting of:
a) -(CH2)x-,
b) -O-,
c) -S(O)p-,
d) -NR4-,
e) -NR4C(=O)-,
f ) -NR4C (=O) O- ,
V is selected from the group consisting of:
a) -(CH2)x-,
b) -O(CH2)x-,
c) -O(CH2)x(C=O)-,
d) -(CH2)xS(O)p-,
e) -(CH2)xNR4- f) -(CH2)xNR4C(=O)-,
g) -(CH2)xNR4C(=O)O-;
Z is selected from the group consisiting of:
a) -(CH2)xC(=O)-,
b) -C(=O) (CH2)x-,
c) -(CH2)xC(=O)O-, p can be 0 or 2; r can be independently selected at each occurrence from 0 to 3; s can be independently selected at each occurrence from 0 to 3; t can be independently selected at each occurrence from 0 to 2; u can be independently selected at each occurrence from
0 to 2; w can be independently selected at each occurrence from
0 to 2; x can be independently selected at each occurrence from 0 to 3; with the following provisos:
(a) when V is (CH2)x, x cannot be 0 when R3 is
hydrogen;
(b) when Z is -(CH2)xC(=O)- and -C(=O) (CH2)x and x is 0, R10 cannot be halogen.
[4] Most preferred compounds of formula (I) are those compounds of formula (Ia)
or a pharmaceutically acceptable salt or prodrug
thereof, wherein:
R1 is (C3-C4 alkyl);
X is from the group consisting of
-NHC(=NH)K, -NHC (=NH)NHR2, -NH2 or -SC(=NH)NHR2 ;
R2 is hydrogen or C1-C4 alkyl;
R3 is independently selected from the group consisting of:
benzyl, phenyl, phenethyl, (3-phenyl)prop-1-yl, (2- methyl-1-phenyl)prop-2-yl, (2-methyl-2-phenyl)prop- 1-yl, 1,1-diphenylmethyl, phenoxymethyl,
phenylsulfonylmethyl, 2-(m-fluorophenyl) ethyl, 2- (3-pyridyl)ethyl, (m-aminophenyl)methyl, (m-
methylphenyl) methyl, (p-methylphenyl)methyl, 1- naphthylmethyl; R10 is independently selected from the group consisting of:
methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl -N-t- butoxycarbonylaminomethyl, N-methylaminomethyl, (m- methyl) phenethyl, (m-fluoro) phenoxymethyl, (m- methyl) phenoxymethyl, (3-pyridyl) ethyl
R11 is hydrogen;
Y1 and Y2 are
a) -OH,
b) -F,
c) -ΝR4R5 -,
d) -C1-C8 alkoxy, or;
when taken together Y1 and Y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbcn atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
V is independently selected from the group consisting of:
O, -OC(=O)-, S, -NH-;
Z is -C(=O)-.
[5] Specifically preferred compounds of formula (I) are those compounds of formula (lb):
phenylmethyl and R10 is methyl; the compound of formula (lb) wherein R3 is
phenethyl and R10 is methyl; the compound of formula (lb) wherein R3 is 3- phenylprop-1-yl and R10 is methyl; the compound of formula (lb) wherein R3 is 1,1- dimethyl-2-phenylethyl and R10 is methyl; the compound of formula (lb) wherein R3 is 2,2- dimethyl-2-phenylethyl and R10 is methyl;
the compound of formula (lb) wherein R3 is diphenylmethyl and R10 is methyl; the compound of formula (lb) wherein R3 is phenoxymethyl and R10 is methyl; the compound of formula (lb) wherein R3 is phenylsulfonylmethyl and R10 is methyl; the compound of formula (lb) wherein R3 is (m- fluorophenyl)ethyl and R10 is methyl; the compound of formula (lb) wherein R3 is (3- pyridyleτhyl) and R10 is methyl; the compound of formula (lb) wherein R3 is phenylethyl and R10 is phenethyl.
[6] Also specifically preferred compounds of formula (I) are those compounds of formula (Ic):
[7] Also specifically preferred compounds cf formula (I) are those compounds of formula (Id):
selected from the list consisting of: the compound of formula (Id) wherein V is oxygen, R3 is phenylmethyl and R10 is phenethyl;
the compound of formula (Id) wherein V is oxygen, R3 is (m-fluorophenyl)methyl and R10 is phenethyl. the compound of formula (Id) wherein V is oxygen, R3 is phenylmethyl and R10 (m-methyl)phenethyl;
Detailed Description of the Invention
The "(D)" prefix for the foregoing abbreviations indicates the amino acid is in the (D)-configuration. "D,L" indicates the amino acid is present as a mixture of the (D)- and the (L)-configuration. The prefix "bore" indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if R1 is isopropyl and Y1 and Y2 are OH, the C-terminal residue is abbreviated "boroVal-OH" or
"boroValine" where "-OH" indicates the boronic acid is in the form of the free acid. The pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "-C10H16" and "-C6H12", respectively.
Examples of other useful diols for esterification with the boronic acids are 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, and 1,2-dicyclohexylethanediol. Some common abbreviations used herein are: CBZ or Z, benzyloxycarbonyl; BSA,
benzenesulfonic acid; THF, tetrahydrofuran; Boc-, t-butoxycarbonyl-; Ac-, acetyl; pNA, p-nitroaniline; DMAP, 4-dimethylaminopyridine; HOBT, 1-hydroxybenzotriazole and hydrate thereof; DCC, 1,3-dicyclohexylcarbodimide; Tris, Tris(hydrqxymethyl)aminomethane; MS, mass
spectrometry; FAB/MS, fast atom bombardment mass
spectrometry. LRMS and HRMS are low and high resolutior.
mass spectrometry, respectively, using ammonia (NH3-CI) or methane (CH4-CI) as an ion source.
It is understood that many of the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties. The present invention comprises all of the stereoisomers or mixtures thereof. If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard
techniques, including chiral chromatography and
recrystallization of diastereomeric salts.
When any variable (for example, R 1 through R10, m, n, W, Z, etc.) occurs more than one time in any
constituent or in formula (I), or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence.
In the instance that a subscript of a group is 0, it is intended to mean that the previous group is bonded directly with the next group in the sequence. For example, when:
R3 is - (CR6R7)t-W-(CR8R9)u-aryl, and u is 0 it is the same as :
-(CR6R7)t-W-aryl.
As described broadly above for R6 and R7, in the case "where R6 (R8) or R' (R9) can alternatively be taken together with R6 (R8) or R7 (R9) on an adjacent carbon atom to form a direct bond", this can only occur when t (u) is greater than 1. The structure that would result from:
R3 is -(CR6R7)t-W-(CR8R9)u-aryl, t = 2, u=2,
R6 and R7 are taken to for a double bond, and R8 and R9 taken to be a triple bond would be:
-CR6=CR7-W-C=C-aryl.
The term "amine-blocking group" or "amineprotecting group" as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substituents on these groups may include either alkyl, aryl and alkaryl which may contain the heteroatoms, O, S, and N as a substituent or as an inchain component. A number of amine-blocking groups are recognized by those skilled in the art of organic synthesis. Examples of suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl (also referred to as t-butyloxycarbonyl) or adamantyloxycarbonyl. Gross and Meienhofer, eds., The Peptides, Vol 3; 3-88 (1981), Academic Press, New York, and Greene and Wuts Protecti ve Groups in Organi c Synthesis, 315-405 (1991), J. Wiley and Sons, Inc., New York describe numerous suitable amine protecting groups and they are incorporated herein by reference for that purpose.
"Amino acid residues" as used herein, refers to natural or unnatural amino acid of either (D)- or (L)-configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys,
Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, describe numerous suitable unnatural amino acids for use in this application and is
incorporated herein by reference for that purpose.
"Amino acid residue" also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art. "The Peptides", Vol 3, 3-88 (1981) describes numerous suitable protecting groups and is incorporated herein by reference for that purpose.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- and polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo.
The term "aryl" is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three
substituents.
The term "heteroaryl" is meant to include 5-, 6- or 10-rnernbered mono- or bicyclic aromatic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heteroaryl, but not limited to, are the following: 2-, or 5-, or 4-pyridyl; 2-or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ; 2-or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4-or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5- isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-
cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring. Particularly preferred are 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or
4-isoquinolinyl.
The term "heterocycle" is meant to include 5-, 6-or 10-membered mono- or bicyclic rings which can
optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heterocycle, but not limited to, 2- or 3-pyrrolidinyl, a 2-, 3-, or 4-piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4-tetrahydroquinolinyl, 2- or 3-tetrahydrofuranyl, 2- or
3-tetrahydrothiophene, 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino. Particularly preferred are 1-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl.
The substituents that may be attached to the aryl, heteroaryl or heterocycle ring(s) may be independently selected at each occurrence from the group consisting of:
halogen, -CF3, C1-C4 alkyl, nitro, phenyl, cyano, - (CH2)rR4, -(CH2)rC(=O) (CH2)sR4,
-(CH2)rC(=O)O(CH2)sR4,
-(CH2)rC(=O)N[ (CH2)sR4] [ (CH2)sR5], methyienedioxy, C1-C4 alkoxy, -CH2)rO(CH2)sR4, -(CH2)rOC(=O) (CH2)sR4, -(CH2)rOC(=O)O(CH2)sR4,
-(CH2)rOC(=O)N[ (CH2)sR4] [ (CH2)sR5],
-(CH2)rOC(=O)N[ (CH2)sR4] [C(=O) (CH2)sR5],
-(CH2)rS(O)p(CH2)sR4, - (CH2)rS(O)p(CH2)sC(=O)R4, -(CH2)rS(O)p(CH2)sC(=O)OR4,
-(CH2)rS(O)pN[ (CH2)sR4] [ (CH2)sR5],
-(CH2)rS(O)pN[ (CH2)sR4] [C(=O) (CH2)sR5] ,
-(CH2)rN[ (CH2)sR4] [ (CK2)sR5],
-(CH2)rN[(CH2)SR4][C(=O) (CH2)SR5],
-(CH2)rN[(CH2)SR4][C(=O)0(CH2)sR5],
-(CH2)rN[(CH2)sR4]CON[(CH2)SR4][(CH2)sR5],
-(CH2)rN[(CH2)sR4]C(=O)-N[(CH2)sR4][C(=O) (CH2)sR5], -(CH2)rN[(CH2)SR4][S(O)p(CH2)sR5].
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I).
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, methanol, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vi vo when such prodrug is administered to a mammalian subject. Prodrugs of the
compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I).
Synthesis Discussion
Compounds of formula (I) can be prepared using the synthetic sequences that follow. The solvents employed are compatible with the reagents selected and the transformations being performed. It will be understood by those skilled in the art of organic synthesis that the order of the transformations proposed will be consistent with functionality present in the molecules and may require judgements during the selection of a procedure for preparation of a compound of the
invention.
The general synthesis of N-acyl-4-(acyloxy)proline intermediates can be prepared by sequential acylations of the amine and hydroxyl functionalities and is shown in Scheme 1. Scheme 1
Thus, as an example, (L)-4-hydroxyproline benzyl ester hydrochloride, which is commercially available, or any other suitably protected hydroxyproline, can be treated with a trialkylamine base, typically 4-methylmorpholine, and an acid chloride (R10COCl) to afford acylation product (II) selectively. The hydroxyl group can be converted to a corresponding ester by treatment with a second acid chloride (R3COCl) in the presence of a trialkylamine or heterocyclic amine base, such as pyridine, and a suitable catalyst, such as but not limited to DMAP to generate (III). The carboxylic acid of the proline moiety can be liberated by hydrogenation using conditions reported by Hartney and Simonoff, Org . React . VII, 263 (1953) wherein an alcohol solution of the compound (III) may be affected under an atmosphere of hydrogen gas using a suitable catalyst, preferably platinum or palladium on carbon catalyst, to provide (IV).
One may vary the transformations indicated above depending upon the nature of the groups to be appended. One may employ alternative methods such as a mixed anhydride coupling, as reported by Anderson, et al. J. Am. Chem . Soc . 89, 5012 (1967); or the DCC/HOBT protocol
described by Konig, and Geiger, Chem . Ber . 103, 788 (1970) to form the requisite amide bond. Also, the DCC/DMAP esterification procedure, reported by Hassner, and Alexanian, Tetrahedron Let t . 19, 4475 (1978) has proved useful for performing the second acylation reaction. Finally, one may choose an ester other than benzyl which might be removed hydrolytically or
photilytically, such as photlytic deprotection. For example, with a methyl ester of (II), treatment of an alcoholic solution of the compound with a solution of sodium hydroxide so as to deliver 1 equivalent amount of NaOH followed by acidification should provide the carboxylic acid.
The N-acyl-4-(alkoxy)proline intermediates can prepared as shown in Scheme 2.
Scheme 2
The hydroxyl function of an N-protected 4-hydroxyproline (V) can be alkylated according to the method of Smith et al., JV Med . Chem . 31, 875 (1988), by treatment with an alkali metal hydride, such as but not limited to sodium hydride and an alkyl halide (R3X) to give (VI). Removal
of the N-protecting group by an appropriate method know to one of skill in the art can provide (VII): the t-butyl carbamate can be cleaved upon treating with acid under anhydrous conditions; for example, trifluoroacetic acid in dichloromethane solution removes the t-butyl urethane of derivatives of (IV) at ambient temperature as reported by Bryan et. al., J. Am . Chem . Soc . 99, 2353 (1977); alternatively anhydrous hydrogen chloride in dioxane may be used to prepare the HCI salt. Other methods for protection of the amine are delineated in Greene and Wuts (1991). The use of benzyl urethane is also viable where hydrogenation over palladium catalyst deliveres the free amine (VII). Acydlation by one of the methods discussed previously can provide (VIII).
The 4-amino and 4-mercaptoproline intermediates useful for the synthesis of compounds of the formula (I), wherein V is S, NH or derivatives thereof, can be prepared according to Scheme 3. The hydroxyproline ester (IX), wherein the amine is protected as the BOC or CBZ, can be reacted with carbon tetrachloride/
triphenylphosphine according to the method of Webb and Eigenbrot, J. Org . Chem . , 56, 3009 (1991), to provide the chloride (X) with inversion of stereochemistry. The chloride can be displaced by a sulfur nucleophile, again with inversion of sterochemistry in a manner similar to that reported by Smith et al . (1988) to provide the displacement product (Xllb) , sulfur-containing prolines. Similarly, the chloride can be displaced by sodium azide, which is reduced to the primary amine and
converted by reductive amination to provide the
displacement products (Xlla), nitrogen-containing prolines. The R3 group in (XII) used in the
displacement reaction need not be the ultimate R3 of formula (I); methods for their removal are well known to those skilled in the art of organic synthesis. Methods for the attachment cf preferred R3 are described herein.
Scheme 3
These disubstituted prolines (XIIa,b) can be used in an analogous manner to that of (IV) or (VIII) described hereafter.
The construction of thrombin inhibitors of the present invention requires the coupling of either of the aforementioned intermediates, (IV), (VIII), or (XII) with a boron-containing fragment followed by
manipulation of the pendant functionalities, as shown in Scheme 4.
Scheme 4
The synthesis of borolysine-containing thrombin
inhibitors (XVII) begins with the coupling of amine hydrochloride (XIII), disclosed by Kettner and Shenvi U.S. Patent No. 5.187.147, to provide amide (XIV). In practice, one may choose from several well-known methods to prepare (XIV) in suitably pure form, as purification of this intermediate is oftentimes impractical. One method calls for the combination of (XIII) and the acid chloride derived from (IV), (VIII) or (XII) in the presence of an amine base, such as but not limited to pyridine. Alternatively, one may employ either the mixed anhydride method, which involves mixing the acid to be coupled with an alkylchloroformate and an tertiary amine base, such as, but not limited to, i-butyl chloroformate and 4-methylmorpholine, followed by
addition of the amine discussed previously, to prepare (XIV) from (IV), (VIII) or (XII); additionally the
DCC/HOBT method may be used to access amines XIV and/or XII
Conversion of the bromide to the X group in R1 of formula (I) can be accomplished by first reaction of bromide (X) with an inorganic azide, such as sodium or potassium azide, in an anhydrous polar aprotic solvent, such as acetone, N,Ν-dimethylformamide or methyl
sulfoxide at temperatures ranging from ambient to 130°C; typically reaction with sodium azide in N,N-dimethylformamide at 65-70 °C for several hours provides (XV). Subsequent reduction of the azide function to the amine (XVI) is effected by catalytic hydrogenation of the azide in a solvent, such as an alcohol or ethyl acetate using a suitable transition metal catalyst under an atmosphere of hydrogen gas. Reduction of the azide (XX) in the presence of sulfur-containing prolines (XV, where V is S) can be done according to the method of Knowles et al., Tetrahedron Lett . , p. 3663 (1978) to provide the amines (XXI). A variety of alternative methods can be found in the monograph by Hudlicky,
Reductions In Organi c Synthesis, John Wiley and Sons, pp. 134 (1984). The amine (XVI) can be isolated as the free base or a salt, typically, but not exclusively hydrochloride or benzenesulfonate; other salts which impart improved physical properties may be preferred.
The method described by Matteson et al., J. Am . Chem . Soc . 102, 7590 (1980) discloses a procedure for removing the pinanediol ester, however, the method employs reagents which may decompose the desired
product. The preferred method for preparation of the free boronic acid (XVII) involves transesterification in the presence of excess phenylboric acid.
The amidine-type analogs, where the X group in R1 of formula (I) is modified, can be prepared as shown in
Scheme 5.
Scheme 5
The guanidinium analogs can be prepared in a similar manner starting from amine hydrochloride (XVIII) . Amide bond formation using one of the methods previously described provides (XIX), which can be converted to the azide (XX) by nucleophilic displacement of the bromide. Reduction of the azide using conditions already
described can provide the amine (XXI) . Preparation of formamidine (XXII) can be accomplished by reaction of amine (XXI) with ethyl formimidate hydrochloride in the presence of DMAP according to the method of Ohme and Schmitz, Angew, Chem mt. Ed 6,566 (1967) . Elaboration of (XXI) to guanidine (XXIII) can be accomplished by reaction with formamidinesulfonic acid in the presence of DMAP, according to that described in Kim et al., Tetrahedron Let t . 29, 3183 (1988), whereas the analogous N-methylguanidine (XXIV) can be produced when N-methylformamidinesulfonic acid is employed according to the method of Walter and Rauden, Liebig Ann. Chem. 722, 98(1969). As before, transesterification with
phenylboric acid yields acids (XXV)-(XXVIII) .
The compounds of formula (I), wherein X is
isothiouronium can be prepared as shown in Scheme 6.
Scheme 6
~ ι
Starting from intermediate bromide (XIX), the X group in formula (I) can be introduced directly by displacement of the halide using thiourea as the nucleophilic species thereby providing boronic ester (XXVIII) . As described previously, transesterification using phenylboric acid yields (XXIX) .
Examples Example 78
N1- [(4R)-N-Acetyl-4-(3-phenylpropionyl)oxy-(L)-prolyl]-R- borolysine, (+)-pinanediol ester
Part A: To a solution of ( 4R)-4-hydroxy-(L)-proline benzyl ester hydrochloride (2.67 g, 1.04 mol) in
dichloromethane (CH2Cl2, 50 mL) at 0 °C was added 4-methylmorpholine (2.50 mL, 2.28 mmol) followed by acetyl chloride (0.72 mL, 1.09 mmol) . The reaction mixture was warmed to room temperature over 12 hours and ethyl acetate (EtOAc, ca. 200 mL) was added. The organic layer was washed with saturated aqueous sodium
bicarbonate (NaHCO3, 1 × 30 mL), water (H2O, 1 × 30 mL), saturated aqueous sodium chloride (NaCl, 1 × 30 mL), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting oil (1.94 g, 71 % yield) solidified on standing at room temperature. A sample of (4R)-Ν-acetyl-4-hydroxy-(L)-proline benzyl ester was recrystallized from hexanes : EtOAc to give white plates, mp 99-102 °C (orthorhombic, P212121, a = 9.216, b = 9.315, c 15.420 A). 1H NMR (300 MHz, CDCl3) δ
7.35 (comp, 5H), 5.17 (s, 2H), 4.63 (m, 1H), 3.79 (dd, J= 10.6,4.6 Hz, 1H), 3.50 (d, J= 10.6 Hz, 1H), 2.29 (d, J= 4.4 Hz, 1H), 2.24 (m, 1H) , 2.11 (m, 1H), 2.09 (s, 3H) ; LRMS 264 (M+H, base), 281 (M+NH4); Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.84; K, 6.41; N, 5.38.
Part B: To a solution of the product from Part A (370 mg, 1.41 mmol) and pyridine (0.17 mL, 2.10 mmol) in CH2Cl2 (14 mL) at 0 °C was added 3-phenylpropionyl chloride (0.23 mL, 1.55 mmol). The reaction mixture was warmed to room temperature over 3 hours and added to EtOAc (ca. 75 mL). The organic layer was washed with sat. aq. NaHCO3 (1 × 25 mL), half-saturated aqueous copper (II) sulfate (1 × 25 mL), sat. aq. NaCl (1 × 25 mL), dried (Na2SO4) and was concentrated under reduced pressure. The residue was purified by flash
chromatography, elution with 2:1 EtOAc-hexanes to give
(4R)-Ν-acetyl-4-(3-phenylpropionyl)oxy-(L)-proline benzyl ester (340 mg) as an oil in 61% yield. 1H NMR (300 MHz, CDCl3) δ 7.37 (comp, 5H), 7.28 (m, 2H), 7.19 (m, 3H),
5.30 (m, 1H), 5.18 (m, 2H), 4.51 (dd, J= 8.4, 8.0 Hz,
1H), 3.84 (dd, J= 11.7, 4.7 Hz, 1H), 3.46 (d, J= 11.7
Hz, 1H), 2.93 (t, J= 7.5 Hz, 2H), 2.64 (t, J= 7.5 Hz,
2H) 2.28 (m, 1H), 2.13 (m, 1H), 2.03 (s, 3H); LRMS 396 (M+H, base).
Part C: A solution of the product from Part E (340 mg, 0.86 mmol) together with palladium on charcoal (50 mg) in methanol (MeOH, 9 mL) was stirred under hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give (4R)-Ν-acetyl-4-(3-phenylpropionyl)oxy-(L)-proline (245 mg) as a foam in 93% yield. 1H NMR (300 MHz, CDCI3) δ 7.27 (comp, 5H), 5.28 (m, 1H), 4.57 (t, J=
7.7 Hz, 1H), 4.38 (br s, 1H), 3.76 (dd, J= 11.9, 4.5 Hz, 1H), 3.49 (s, 1H), 2.95 (t, J= 7.3 Hz, 2H), 2.66 (t, J= 7.3 Hz, 2H), 2.56 (m, 1H), 2.26 (m, 1H), 2.07 (s, 3H); LRMS 306 (M+H), 173 (base).
Part D: To a solution of the product from Part C (240 mg, 0.79 mmol) and 4-methylmorpholine (0.26 mL, 2.36 mmol) in tetrahydrofuran (THF, 6 mL) at -20 °C was added i-butyl chloroformate (0.11 mL, 0.87 mmol) after which the reaction mixture was stirred for 2 minutes. A solution of (1R)-5-bromoaminopentane-1-boronic acid (+)-pinanediol ester (299 mg, 0.79 mmol) in N, N-dimethylformamide (DMF, 2 mL) was added, the reaction was stirred at -20 °C for 15 minutes and warmed to room temperature over 18 hours. The reaction mixture was poured into EtOAc (ca. 50 mL) and washed with H2O (3 × 15 mL), and sat. aq. NaCl (1 × 15 mL) dried (Na2SO4) and concentrated under reduced pressure to give (1R)-5-bromo-[(4R)-Ν-acetyl-4-(3-phenylpropionyl)oxy-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester (475 mg) as an oil in 96=s yield. LRMS 631,633 (M+H), 551 (base).
Part E: A mixture of the product from Part D (470 mg, 0.75 mmol) and sodium azide (NaN3, 97 mg, 1.50 mmol) in DMF (8 mL) was heated at 65-70 °C for 4 hours. The mixture was poured into EtOAc (ca. 75 mL). and washed with H2O (3 × 20 mL), sat. aq. NaCl (1 × 20 mL), dried (Na2SO4), and concentration under reduced pressure to give (1R)-5-azido-[( 4R)-N-acetyl-4-(3-phenylpropionyl)oxy-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester. (403 mg) as an oil in 91% yield. LRMS 594 (M+H, base). Part F: A solution of the product from Part E (388 mg, 0.65 mmol) in MeOH (7 mL) together with palladium hydroxide on charcoal (35 mg) was stirred under hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give 320 mg of the title compound as a foam in 86'ε
yield. LRMS 568 (M + 1, base); HRMS Cacld for
C31H47BN3O6: 568.3558. Found: 568.3558.
Example 154
N1- [ ( 4R) -N-(3-Phenylpropionyl)-4-(benzyl)oxy-(L)-prolyl]- R-borolysine, benzenesulfonate
To a mixture of Example 303 (1.95 g, 2.52 mmol) in H2O (10 mL), Et2O (15 mL), and sufficient MeOH (ca. 1.5 mL) to maintain a clear, biphasic system was added phenylboric acid (1.54 g, 12.6 mmol). The mixture was stirred for 14 hours, the layers were separated and the aqueous phase was extracted with Et2O (5 × 20 mL). The aqueous layer was concentrated under reduced pressure to give the title compound (1.20 g) as an amorphous powder in 75% yield. LRMS 482 (M+H), 464 (base); HRMS Calcd for C28H39BN3O5 (ethylene gycol ester): 508.2983. Found:
508.2999.
Example 302
N1- [(4R)-Ν-(3-Phenylρropionyl)-4-(phenyl)thio-(L)-prolyl]-R-borolysine (+)-pinanediol ester, hydrochloride Part A: The commercially available starting material,
(4R)-Ν-BOC-4-hydroxy-(L)-proline methyl ester was dissolved in CH2Cl2 (140 mL) and carbon tetrachloride (140 mL) and triphenylphosphine (42.56 g, 162.2 mmol) was added. The mixture was allowed to stir for 2 hours, ethanol (15 mL) was added and stirring was continued for an additional 16 hours. The mixture was concentrated under reduced pressure to 100 mL, cooled to -20 °C and Et2O (200 mL) was added. The resulting precipitate was suction filtered and washed with Et2O. The solid was further purified by flash chromatography, elution with
1:1 Et2O-hexanes gave (4S)-Ν-BOC-4-chloro-(L)-proline methyl ester (17.03 g) as an oil in 84% yield. 1H NMR (300 MHz, CDCl3) δ 4.37 (m, 2H), 3.95 (m, 1H), 3.75 (s,
3H), 3.63 (m, 1H), 2.63 (m, 1H), 2.38 (m, 1H), 1.45 (s, 9H).
Part B: A solution of the product from Part A (17.03 g, 64.5 mmol) in trifluoroacetic acid (20 mL) and CH2Cl2 (20 mL) was stirred 18 hours. The reaction mixture was concentrated under reduced pressure to give (4S)-4-chloro-(L)-proline methyl ester (18.05 g) as an oil in quanitative yield. 1H NMR (300 MHz, CDCI3) δ 4.75 (comp,
2H), 3.87 (comp, 2H), 3.94 (s, 3H), 2.99 (m, 1H), 2.77 (m, 1H).
Part C: A solution of the product from Part B (30.28 g, 109 mmol) in CH2Cl2 (50 mL) was cooled to 0 °C and Et3N (45.6 mL, 327 mmol) followed by hydrocinnamoyl chloride (17.8 mL, 120 mmol) were added slowly in order to maintain an internal temperature less than 10 °C .
After stirring six hours, H2O (50 mL) was added to the reaction mixture. The resulting solution was extracted with CH2Cl2 (3 × 50 mL). The organics were washed with H2O (25 mL), dried with MgSO4 and concentrated under reduced pressure to give (4S)-Ν-(3-phenylpropionyl)-4-chloro-(L)-proline methyl ester (17.44 g) as a waxy solid in 54% yield. LRMS 296.1 (base, M+H).
Part D: EtOH (50 mL) was cooled to 0 °C and sodium (0.78 g, 33.8 mmol) was added. After the hydrogen evolution ceased, thiophenol (3.72 g, 33.8 mmol) was added and the reaction mixture stirred for 15 minutes at 0 °C, and the product from Part C (5 g, 16.9 mmol) was added. The stirring was continued for an additional 16 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and acidified with 1N HCI to pH 4. The aqueous solution was
extracted with EtOAc (3 × 30 mL), the organics dried with Na2SO4 and concentrated under reduced pressure.
The residue was further purified by flash
chromatography, elution with chromatographed with 1:3 EtOAc-hexanes gave 2.06 g of ( 4R) -N-(3-phenylpropionyl)-4-(phenyl)thio-(L)-proline in 25% yield. LRMS 356.1 (M+H, base).
Part E: Using the method described above for the preparation of Example 78, Part D, ( 1R)-5-bromo-[(4R) -N-(3-phenylpropionyl)-4-(phenyl)thio-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (2.43 g) as an oil in 85% yield. LRMS 681.2 683.2 (M+H, base).
Part F: Using the method described above for Example 78, Part E, the intermediate ( 1R)-5-azido-[(4R)-Ν-(3-phenylpropionyl)-4-(phenyl)thio-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (2.42 g) as an oil in quantitative yield.
Part G: A solution of the product from Part F (2.42 g, 3.76 mmol) in 1,3-propanedithiol (1.62 g, 15 mmol), triethylamine (1.52 g, 15 mmol) and methanol (20 mL) was stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduce pressure and purified by flash chromatography through florosil, eluting with 1:9 MeOH-CH2Cl2. The concentrated residue was dissolved in diethyl ether (10 mL), acidified with 1 equivalent of IN HCI in Et2O and concentrated to give the title compound
(0.73 g) as a solid in 31% yield. LRMS 617.3 (M+H, base). HRMS Cacld for C35H48BN3O4S : 617.34583. Found: 617.34580.
Example 303
N1- {(4R)-Ν-(3-Phenylpropionyl)-4-(benzyl)oxy-(L)-prolyl]- R-borolysine, (+) -pinanediol ester
Part A: A solution of the commercially available starting material, (4R)-Ν-BOC-4-(benzyl)oxy-(L)-proline, previously reported by Smith et al., J. Med . Chem . 31, 875 (1988); (2.11 g, 6.57 mmol), in CH2Cl2 (27 mL) was treated with anhydrous hydrogen chloride in dioxanes (4 M, 6.60 mL). The reaction mixture was stirred for 18 hours, during which time a white precipitate formed. The reaction was diluted with diethyl ether (Et2O, ca. 100 mL) and the solid material was collected by suction filtration to afford (4R)-4-(benzyl)oxy-(L)-proline hydrochloride (1.60 g) as a white powder in 95% yield. 1H NMR (300 MHz, DMSO-d6) δ 10.2 (br s, 1H), 7.36 (comp,
5H), 4.52 (s, 2H), 4.37 (dd, J= 10.8,7.5 Hz, 1H), 4.31
(m, 1H), 3.43 (dd, J= 12.5,4.4 Hz, 1H), 3.33 (d, J= 12.5
Hz, 1H), 2.48 (m, 1H), 2.11 (m, 1H); LRMS 222 (M+H, base).
Part B: A suspension of the product from Part A (1.50 g, 5.83 mmol) in CH2Cl2 (58 mL) at 0 °C was treated with
3-phenylpropiόnyl chloride (0.95 mL, 6.41 mmol) followed by 4-methylmorpholine (1.92 mL, 17.5 mmol). The
reaction mixture was warmed to room temperature over 20 hours, treated with 2M aqueous hydrochloric acid (HCI) until pH = 2, and added to EtOAc (ca. 200 mL). The organic layer was washed with H2O (3 × 50 mL), sat. aq. NaCl (1 × 50 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting solid was
recrystallized from hexanes-EtOAc and gave a first crop (1.33 g, mp 127-129 °C) and a second crop (0.37 g, mp 122-125 °C) of (4R)-Ν-(3-phenylpropionyl)-4-(benzyl)oxy- (L)-proline as colorless plates in a total of 82% yield, (monoclinic, P21 , a = 6.196, b = 9.101, c = 16.477A, β =
98.98 °) 1H NMR (300 MHz, CDCl3) δ 7.29 (comp, 10H),
4.95 (br s, 1H), 4.69 (dd, J= 8.1, 6.2 Hz, 1H), 4.50 (ABq, ΔαAB = 32.5 Hz, JAB= 11.7 Hz, 2H) , 4.20 (quin, J=
4.8 Hz, 1H), 3.46 (d, J= 4.8 Hz, 2H), 2.98 (t, J= 7.7 Hz, 2H), 2.59 (t, J= 7.4 Hz, 2H), 2.50 (m, 1H) , 2.23 (ddd, J= 13.5, 8.4, 5.0 Hz, 1H) ; LRMS 354 (M+H, base) ; Anal. Calcd for C21H23NO4: %C, 71.37; %H, 6.56; %N, 3.96.
Found: %C, 71.39; %H, 6.57; %N, 3.92.
Part C: Using the method described above for the preparation of Example 78, Part D, (1R)-5-bromo-[(4R)-N-(3-phenylpropionyl)-4-(benzyl)oxy-(L)-prolyl]aminopentane-1-boronic acid (+)-pinanediol ester was isolated (2.80 g) as an oil in 90% yield. LRMS 679, 681 (M+H, base).
Part D: Using the method described above for Example
78, Part E, (1R)-5-azido-[(4R)-Ν-(3-phenylpropionyl)-4- (benzyl)oxy-(L)-prolyl]aminoρentane-1-boronic acid (+)-pinanediol ester was isolated (2.31 g) as an oil in 94% yield. LRMS 642 (M+H, base).
Part E: A solution of product from Part D (2.24 g, 3.50 mmol) in MeOH (35 mL) together with palladium on charcoal (225 mg) was stirred under hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 30 mL) and the filtrate was concentrated under reduced pressure to give a foam which contained a small amount of unreacted azide. This material was resubjected to the
hydrogenation conditions described above to afford the title compound (2.00 g) as a white foam in 93% yield. LRMS 616 (M+H, base).
Example 303a
N1- [(4R)-N-(3-Phenylpropionyl)-4-(benzyl)oxy-(L)-prolyl]- R-borolysine, (+)-pinanediol ester, benzenesulfonate
A solution of Example 303 (2.00 g, 3.25 mmol) in methanol (25 mL) was treated with a solution of
benzenesulfonic acid (0.514 g, 3.25 mmol) in methanol (8 mL) . The mixture was allowed to stand at room
temperature for 15 minutes and concentrated under reduced pressure to give a foam. The residue was washed with Et2O (2 × 25 mL), which was decanted, then
dissolved in EtOAc (ca. 20 mL) and triturated with Et2O
(ca. 75 mL) to afford an oily material which was washed with Et2O (2 × 25 mL). The excess solvent was removed in vacuo to give the title compound (2.00 g) as a powder in 79% yield. LRMS 616 (M+H, base); HRMS Calcd for C36H51BN3O5: 616.3922. Found: 616.3921.
Example 375
N1-[( 4R) -N-(3-Phenylpropionyl)-4-(benzyl)amino-(L)- prolyl]-R-borolysine, (+)-pinanediol ester,
hydrochloride
Part A: A mixture of the product from Example 302, Part C (3.00g, 10.1 mmol) and NaN3 (3.30 g, 50.7 mmol) in DMF (15 mL) was heated to 75 °C for 18 hours. Tne reaction mixture was dissolved in H2O (25 mL). The aqueous solution was extracted with Et2O (3 × 25 mL), dried with MgSO4 and concentrated to give (4R)-Ν-(3-phenylpropionyl)-4-azido-(L)-proline methyl ester (2.13 g) as an oil in 83% yield. 1H NMR (300 MHz, CDCl3) δ
7.25 (comp, 5H), 4.56 (m, 1H), 4.26 (m, 1H), 3.77 (s,
3H), 3.75 (m, 1H), 3.40 (dd, J = 8, 2 Hz, 1H), 2.97 (m,
2H), 2,60 (m, 2H), 2.32 (comp, 2H). LRMS 303.1 (M+H, base).
Part B: Using the method described above for the preparation of Example 78, Part F, ( 4R) -N- ( 3-phenylpropionyl)-4-amino-(L)-proline methyl ester was isolated (2.43 g) as an oil in 85% yield. 1H ΝMR (300 MHz, CDCI3) δ 7.24 (comp, 5H), 4.58 (m, 1H), 3.74
(m, 2H), 3.73 (s, 3H), 3.01 (m, 3H), 2.60 (m, 2H), 2.12 (m, 1H), 1.94 (m, 1H). LRMS 277.1 (M+H, base).
Part C: A mixture of the product from Part B (1.51 g, 5.46 mmol), benzaldehyde (0.58 g, 5.46 mmol), potassium acetate (0.54 g, 5.46 mmol) and 5% palladium on charcoal (0.21 g) was stirred in MeOH (25 mL) under hydrogen (3 atm) for 5 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate concentrated under reduced pressure to give (4R)-Ν-(3-phenylpropionyl)-4-(benzyl)amino-(L)-proline methyl ester (2.00 g) as an oil in quantitative yield. 1H ΝMR (300 MHz, CDCI3) δ 7.27 (comp, 10H), 4.58
(m, 1H), 3.73 (comp, 4H) , 3.50 (m, 1H), 3.44 (s, 3H), 3.15 (m, 1H), 2.96 (t, J = 7 Hz, 2H), 2.55 (m, 2H), 2.09 (m, 2H). LRMS 367.2 (M+H, base).
Part D: A solution of the product from Part C (2.00 g, 5.46 mmol) methanol (15 mL) and IN sodium hydroxide (9 mL) was stirred for 24 hours. The pH of the solution was adjusted to 6 with 1N HCI and a white precipitate formed. The solid material was collected by suction filtration to give (4R)-Ν-(3-phenylpropionyl)-4- (benzyl)amino-(L)-proline (1.31 g) as a white powder in 68% yield. LRMS 353.2 (M+H, base).
Part E: Using the method described above for the preparation of Example 78, Part D, ( 1R)-5-bromo-[(4R)-Ν- (3-phenylpropionyl)-4-(benzyl)amino-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (0.71 g) as an oil in 49% yield. LRMS 678.3 680.3 (M+H, base).
Part F: Using the method described above for Example 78, Part E, the intermediate (1R)-5-azido-[(4R)-N-(3-phenylpropionyl)-4-(benzyl)amino-(L)-prolyl]aminopentane-1-boronic acid, (+)-pinanediol ester was isolated (0.45 g) as an oil in 67% yield.
Part G: A solution of the product from Part F (0.45 g, 0.70 mmol) in MeOH (5 mL) together with 20% palladium hydroxide on charcoal (0.04 g) was stirred under
hydrogen (1 atm) for 4 hours. The reaction mixture was filtered through a pad of Celite with EtOAc (ca. 10 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography through florosil, eluting with 1:9 MeOH-CH2Cl2. The concentrated residue was dissolved in Et2O (10 mL), acidified with 2
equivalents of 1N HCI in Et2O and concentrated to give the title compound (0.27 g) as a oil in 56% yield. LRMS 615.4 (M+H, base).
Example 1641
N1- [(4R)-N-(Benzyloxy)carbonyl-4-(benzyl)oxy-(L)-prolyl]- R-borothioarginine, ( +)-pinanediol ester
Part A: Using the method described above for Example 78, (1R)-4-bromo-[(4R)-Ν-(benzyloxy)carbonyl-4-(benzyl)oxy-(L)-prolyl]aminobutane-1-boronic acid, ( + )-pinanediol ester (370 mg) was prepared as an oil in 99% yield. LRMS 667, 669 (M+H), 587 (base).
Part B: A mixture of the product from Part A (365 mg, 0.55 mmol) and thiourea (83 mg, 1.10 mmol) in ethanol (EtOH, 10 mL) was heated at reflux for 16 hours and cooled to room temperature. The reaction was poured into Et2O (ca. 120 mL) and concentrated under reduced
pressure. The residue was triturated with Et2O (ca. 50 mL), which was decanted. Purification of the residue by size exclusion chromatography on Sephadex LH-20, elution with MeOH, gave a glass which was dissolved in THF (1.5 mL) and treated with Et2O (ca. 20 mL) to give a solid. The solid was washed with Et2O (ca. 10 mL) and dried to afford the title compound (125 mg) as a white solid in 31% yield, mp 79-82 °C. LRMS 663 (M+H, base); HRMS Calcd for C35H48BN4O6S : 663.3388. Found: 663.3374.
Based on the representative examples detailed above, the following compounds of the invention can be prepared, as shown in Tables 1-20
Table 4
Table 5
Table 9
Table 12
DATA
A HRMS Calcd for C29H42BN3O6: 540.3241 Found:
540.3248.
B HRMS Calcd for C30H44BN3O6: 554.3401 Found:
554.3404.
C HRMS Calcd for C31H47BN3O6 : 568.3558. Found:
568.3558.
D HRMS Calcd for C29H42BN3O6: 540.3245 Found:
540.3248.
E HRMS Calcd for C33H51BN3O6: 596.3871. Found:
596.3870.
F HRMS Calcd for C33H51BN3O6: 596.3871. Found:
596.3857.
G HRMS Calcd for C36H48BN3O6: 630.3714. Found:
630.3709.
H HRMS Calcd for C30H44BN3O7: 570.3351. Found:
570.3353.
I LRMS Calcd for C30H45BN3O8S : 618.3. Found: 618.4. J HRMS Calcd for C31H46BFN3O6 : 586.3464. Found:
586.3456.
K HRMS Calcd for C30H46BN4O6: 569.3510. Found:
569.3501.
L HRMS Calcd for C3eH52BN3O6: 658.4027. Found:
658.4036.
M HRMS Calcd for C28H39BN3O5 (ethylene glycol ester) :
508.2983. Found: 508.2999.
N HRMS Calcd for C27H39BN3O5 (ethylene glycol ester):
522.3139. Found: 522.3123.
O LRMS Calcd for C26H36BFN3O5 (ethylene glycol ester) :
526. Found: 526.
P HRMS Calcd for C35H49BN3O4S : 618.3537. Found:
618.3537.
Q HRMS Calcd for C36H51BN3O5: 616.3922. Found:
616.3910.
R HRMS Calcd for C37H53BN3O5 : 630.4078. Found:
630.4060.
S HRMS Calcd for C35H50BN4O5 : 617.3874. Found:
617.3876.
T LRMS Calcd for C36H50BFN3O5 : 634. Found: 634.5.
U LRMS Calcd for C36H52BN4O5: 631. Found: 631.3. V HRMS Calcd for C37H53BN3O5 : 630.4078. Found:
630.4071.
W HRMS Calcd for C36H48BN3O6: 618.3714. Found:
618.3713.
X HRMS Calcd for C36H51BN3O6 : 632.3871. Found:
632.3857.
Y LRMS Calcd for C36H51BN4O4: 615. Found: 615.5. Z HRMS Calcd for C29H44BN4O5: 526.3452. Found:
526.3460.
AA HRMS Calcd for C30H46BN3O5: 540.3609. Found:
540.3604.
BB HRMS Calcd for C30H47BN3O5: 540.3609. Found:
540.3620.
CC HRMS Calcd for C31H49BN3O5: 554.3765. Found:
554.3769.
DD HRMS Calcd for C33H53BN4O7 : 582.4078. Found:
582.4071.
EE HRMS Calcd for C30H48BN4O5: 555.3718. Found:
555.3735.
FF HRMS Calcd for C35H56BN4O7: 655.4242. Found:
655.4234.
GG HRMS Calcd for C26H47BN3O5: 492.3609. Found:
492.3600.
HH HRMS Calcd for C33H47BN3O5: 576.3609. Found:
576.3593.
II HRMS Calcd for C33H53BN3O5: 582.4078. Found:
582.4092.
JJ HRMS Calcd for C40H53BN3O5: 666.4078. Found:
666.4089.
KK LRMS Calcd for C26H36BFN5O5 : 528.3. Found: 528.3. LL HRMS Calcd for C36H51BN5O5: 644.3983. Found:
644.3977.
MM LRMS Calcd for C36H50BFN5O5 : 662. Found: 662. NN HRMS Calcd for C28H42BN4O6S : 573.2918. Found:
573.2919.
OO HRMS Calcd for C32H50BN4O6S : 629.3544. Found:
629.3524.
PP HRMS Calcd for C29H42BN3O5S : 571.3126. Found:
571.3138.
QQ HRMS Calcd for C35H48BN4O6S : 663.3388. Found:
663.3374.
RR HRMS Calcd for C29H43BN3O5: 524.3300. Found:
524.3305.
SS LRMS Calcd for C37H53BN5O5 : 653. Found: 658
TT LRMS Calcd for C36H50BN4O5: 629. Found: 629
UU LRMS Calcd for C27H39BN5O5: 524. Found: 524
W LRMS Calcd for C26H36BN4O5: 495. Found: 495
WW HRMS Calcd for C35H48BFN3O6 : 636.3620. Found:
636.3612.
Utility
The compounds of formula (I) are useful as
inhibitors of serine proteases and notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes.
Inhibition constants .were determined by the method described by Kettner et al. in J. Bi ol . Chem . 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis cf the chromogenic substrate S2238 (Helena Laboratories,
Beaumont, TX) was monitored spectrophotometrically .
Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research
Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% polyethylene glycol 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the
reaction velocity as a function of substrate
concentration using the standard method of Lineweaver and Burk.
Using the methodology described above,
representative compounds of this invention were
evaluated and found to exhibit a Ki of less than 1 mM, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.
The ability of the compounds to inhibit coagulation was assayed in normal rabbit plasma which was prepared by diluting blood 1:10 with 3.2% aqueous citric acid followed by centrifugation. Bovine thrombin was
obtained from Sigma and diluted to 24 NIH units/mL.
Plasma ( 0.2 mL) and buffer (0.05 mL, 0.10 M
Tris [hydroxymethyl] -aminomethane hydrochloride, pH 7.4, 0.9% (w/v) sodium chloride, and 2.5 mg/mL bovine serum albumin) containing inhibitor were incubated 3 min at 37 °C in a fibrameter. Reactions were initiated by adding thrombin (0.05 mL) to achieve a final concentration of 4 NIH units/mL. The effectiveness of compounds as
anticoagulants is reported as the level of inhibitor required to prolong clotting to that observed for 2 NIH units/mL of thrombin in the absence of inhibitor. In this assay then, better inhibitors require lower
concentrations to delay clot formation. Representative compounds of this invention were evaluated and found to be active.
Since the compounds of formula (I) have anti-thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for the control of the coagulation of the fibrinolysis system in mammals or they may be added to blood for the
purpose of preventing coagulation of the blood due to contact with blood collecting or distribution
containers, tubing or apparatus.
Generally, these compounds may be administered orally, parenterally or intravenously to a host to obtain an anti-thrombogenic effect. The dosage of the active compound depends on the mammalian species, body weight, age, and mode of administration as determined by one skilled in the art. In the case of large mammals such as humans, the compounds may be
administered alone or in combination with
pharmaceutical carriers or diluents at a dose of from 0.02 to 15 mg/kg to obtain the anti-thrombogenic effect, and may be given as a single dose or in
divided doses or as a sustained release formulation. Pharmaceutical carriers or diluents are well known and include sugars, starches and water, which may be used tc make tablets, capsules, injectable solutions or the like which can serve as suitable dosage forms for
administration of the compounds of this invention.
Remington's Pharmaceutical Sciences. A. Osol, is a standard reference text which discloses suitable pharmaceutical carriers and dosage forms. The
disclosure of this text is hereby incorporated by reference for a more complete teaching of suitable dosage forms "for administration of the compounds of this invention.
Claims
WHAT IS CLAIMED IS
A compound of formula ( i ;
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is
a) - (C1-C12 alkyl)-X, or
b) - (C2-C12 alkenyl)-X, or
c)
X is
a) halogen,
b) -CN,
c) -NO2,
d) -CF3,
e) -S(O)pR2,
f> -NHR2,
g) -NHS(O)pR2,
h) -NHC(=NH)H, i) -NHC (=NH) NHOH,
j) -NHC(=NH)NHCN,
k) -NHC(=NH)NHR2,
1) -NHC(=NH)NHC(=O)R2,
m) -C(=NH)H,
n) -C(=NH)NHR2,
O) -C(=NH)NHC(=O)R2,
p) -C(=O)NHR2,
q) -C(=O)NHC(=O)R2,
r) -C(=O)OR2,
s) -OR2,
t) -OC(=O)R2,
u) -OC(=O)OR2,
v) -OC(=O)NHR2,
w) -OC(=O)NHC (=O)R2,
x) -SC (=NH)NHR2;
R2 is
a) hydrogen,
b) -CF3
c) C1-C4 alkyl,
d) -(CH2)q-aryl;
R3 and R10 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) halogen,
c) -(CR6R7)tW(CR8R9)u-R9,
d) -(CR6R7)tW(CR8R9)u-aryl,
e) -(CR6R7)tW(CR8R9)u-heteroaryl,
f) -(CR6R7)tW(CR8R9)u-heterocycle,
g) -(CR6R7)tW(CR8R9)u-adamantyl,
h) -(CR6R7)tW(CR8R9)u(C5-C7)cycloalkyl,
i) 
j)
o) 
p) 
q) 
r)
s)
a) -(CR6R7)t(CR8R9)u-W-(CR8R9)u(CR6R7)t;
b) -(CR6R7)tW(CR8R9)u-aryl-(CR8R9)uW(CR6R7)t-;
c) -(CR6R7)tW(CR8R9)u-heteroaryl-(CR8R9)uW(CR6R7)t-; d) -(CR6R7)tW(CR8R9)u-heterocycle-(CR8R9)uW(CR6R7)t-; e) -(CR6R7)tW(CR8R9)u-W-(CR8R9)uW(CR6R7)t-;
R4 and R5 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) C1-C4 alkyl,
c) C1-C4 alkoxy,
d) C5-C7 cycloalkyl,
e) phenyl,
f) benzyl;
R6, R7, R8 and R9 are independently selected at each
occurrence from the group consisting of:
a) hydrogen,
b) C1-C6 alkyl,
c) C1-C6 alkoxy,
d) C3-C8 cycloalkyl,
e) aryl,
f) heterocycle,
g) heteroaryl,
h) -W-aryl,
i) -(CH2)wC(=O)OR4,
j) R6 or R7 can alternatively be taken
together with R6 or R7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or
k) R8 or R9 can alternatively be taken
together with R8 or R9 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons;
R11 is
a) hydrogen,
b) C1-C4 alkyl,
c) C1-C4 thioalkyl,
d) -(CR6R7)tW(CR8R9)u-aryl,
e) -(CR6R7)tW(CR8R9)u-heteroaryl,
f) -(CR6R7)tW(CR8R9)u-heterocycle, or
g) -(CR6R7)tW(CR8R9)u-R9;
R11 and V, when taken together, can also be:
a) keto,
b) =NR10,
c) =C[(CR6R7)tW(CR8R9)uR2]2, or
d) -(CR6R7)tW(CR8R9)u-W-(CR6R7)tW(CR8R9)u-
A is
a) -BY1Y2,
b) -C(=O)CF3,
c) -C(=O)CF2CF3,
d) -PO3H2
d) -C(=O)H,
e) -C(=O)-1-piperdinyl,
f) -C(=O)CH2OCH2CF3,
g) CH2Cl
h) SO2F; Y1 and Y2 are
a) -OH,
b) -F,
c) -NR4R5 -,
d) -C1-C8 alkoxy, or;
when taken together Y1 and Y2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
W can be independently selected at each occurence from the group consisting of:
a) -(CH2)x-,
b) -C(=O)-,
c) -C(=O)O-,
d) -C(=O)NR4-,
e) -O-,
f) -OC(=O)-,
g) -OC(=O)O-,
h) -OC(=O)NR4-,
i) -NR4-,
j) -NR4C(=O)-,
k) -NR4C(=O)O-,
1) -NR4C(=O)NR5-,
m) -NR4S(O)p- n) -S(O)p-,
o) -S(O)pO-,
p) -S(O)pNR4-,
q) -S(O)pNR4C(=O)-,
r) -S(O)pNR4C(=O)NR5-; V is selected from the group consisting of:
a) -(CH2)x-, b) -(CH2)xC(=O)-,
c) -(CH2)xC(=O)O-,
d) -C(=O) (CH2)x-,
e) -O-(CH2)x-,
f) -O(CH2)xC(=O)-,
g) -O(CH2)xC(=O)O-,
h) -O(CH2)xC(=O)NR4-,
i) -O(CH2)xS(O)p-,
j) -(CH2)xS(O)p-,
k) -(CH2)xS(O)pO-,
1) -(CH2)xS(O)pNR4-,
m) -(CH2)xS(O)pNR4C(=O)-,
n) -(CH2)xS(O)pNR4C(=O)NR5-]
o) -(CH2)xNR4-,
p) -(CH2)xNR4C(=O)-,
q) -(CH2)xNR4C(=O)O-,
r) -(CH2)xNR4C(=O)NR5-,
s) -(CH2)xNR4S(O)p-; Z is selected from the group consisiting of a) -(CH2)x- ,
b) -(CH2)xC(=O)-,
c) -C(=O) (CH2)x-,
d) -(CH2)xC(=O)O-,
e) -(CH2)xC(=O)NR4-,
f) -(CH2)xNR4-,
g) -(CH2)xNR4C(=O)-,
h) -(CH2)xNR4C(=O)O-,
i) -(CH2)xNR4C(=O)NR5-,
j) -(CH2)xNR4S(O)p-,
k) -(CH2)xS(O)p-,
1) -(CH2)xS(O)pNR4-, m can be 0 to 4; n can be 0 to 4; p can be 0 to 2 q can be 0 to 4; r, s, t, u, and v are independently selected at each
occurrence from 0 to 6, w and x are independently selected at each occurence
from 0 to 4; with the following provisos: (a) when V is (CH2)x, x cannot be 0 when R3 is
hydrogen;
(b) when Z is -(CH2)xC(=O)- and -C(=O) (CH2)x and x is C, R10 cannot be halogen; wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents; heteroaryl is 2-, or 3-, or 4-pyridyi; 2-or 3-furyl; 2-or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ; 2-or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4-or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring; said ring(s) may be unsubstitued or include optional substitution with one to three
substituents; heterocycle is 2- or 3-pyrrolidinyl, a 2-, 3-, or 4-piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4-tetrahydroquinoiinyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothioρhene, 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino; said ring(s) which may be unsubstituted or include optional substitution with one to three substituents; cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl; the substituents which may be attached to the ring(s) above may be independently selected at each occurrence from the group selected from:
halogen, -CF3, C1-C4 alkyl, nitro, phenyl, -(CH2)rR4,
-(CH2)rC(=O) (CH2)sR4, -(CH2)rC(=O)O(CH2)sR4,
-(CH2)rC(=O)N[(CH2)sR4][(CH2)sR5], methylenedioxy, C1-C4 alkoxy, -CH2)rO(CH2)sR4, -(CH2)rOC(=O) (CH2)sR4 -(CH2)rOC(=O)O(CH2)sR4,
-(CH2)rOC(=O)N[ (CH2)sR4] [ (CH2)sR5] ,
-(CH2)rOC(=O)N[ (CH2)sR4] [C(=O) (CH2)sR5] ,
-(CH2)rS(O)p(CH2)SR4, - (CH2)rS(O)p(CH2)sC(=O)R4, -(CH2)rS(O)p(CH2)sC(=O)OR4,
-(CH2)rS(O)pN[ (CH2)sR4] [ (CH2)sR5J ,
-(CH2)rS(O)pN[ (CH2)sR4] [C(=O) (CH2)sR5] ,
-(CH2)rN[(CH2)sR4] [ (CH2)sR5],
-(CH2)rN[(CH2)sR4] [C(=O) (CH2)sR5],
-(CH2)rN[(CH2)sR4] [C(=O)0(CH2)sR5],
-(CH2)rN[(CH2)sR4]CON[ (CH2)sR4] [ (CH2)sR5] .
-(CH2)rN[(CH2)sR4]C(=O)-N[ (CH2)sR4] [C(=O) (CH2)sR5] -(CH2)rN[ (CH2)sR4] [S(O)p(CH2)sR5] .
2. A compound of claim 1 wherein: R1 is (C3-C4 alkyl); X is selected from the group consisting of:
-NHC(=NH)H, -NHC(=NH)NHR2, -NH2 or -SC(=NH)NHR2;
R2 is hydrogen or C1-C4 alkyl.
3 . A compound of claim 2 having formula ( Ia ) wherein :
X is selected from the group consisting of:
-NHC(=NH)H, -NHC(=NH)NHR2, -NH2 or -SC(=NH)NHR2; R2 is hydrogen or C1-C4 alkyl ;
R3 and R10 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) halogen, c) - (CR6R7)tW(CR8R9)u-R9
d) -(CR6R7)tW(CR8R9)u-aryl
e) - (CR6R7)tW(CR8R9)u-heteroaryl; R4 and R5 are independently selected at each occurrence from the group consisting of:
a) hydrogen,
b) C1-C4 alkyl,
c) C1-C4 alkoxy,
d) phenyl, or
e) benzyl;
R6, R7, R8, R9 are independently selected at each
occurrence from the group consisting of:
a) hydrogen
b) C1-C6 alkyl,
c) aryl,
d) -(CH2)wC(=O)OR4, or; Y1 and Y2 are
a) -OH,
b) -F,
c) -NR4R5 -,
d) -C1-C8 alkoxy, or;
when taken together Y1 and Y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
W can be independently selected at each occurrence from the group consisting of:
a) -(CH2)x-,
b) -O-,
c) -S(O)p-,
d) -NR4-,
e) -NR4C(=O)-,
f) -NR4C(=O)O-,
V is selected from the group consisting of:
a) -(CH2)x-,
b) -O(CH2)x-,
c) -O(CH2)x(C=O)-,
d) -(CH2)xS(O)P-,
e) -(CH2)xNR4- f) -(CH2)xNR4C(=O)-,
g) -(CH2)xNR4C(=O)O-;
Z is selected from the group consisiting of:
a) -(CH2)xC(=O)-,
b) -C(=O) (C(2)x-,
c) -(CH2)xC(=O)O-, p can be 0 or 2; r can be independently selected at each occurrence from 0 to 3; s can be independently selected at each occurrence from 0 to 3; t can be independently selected at each occurrence from 0 to 2; u can be independently selected at each occurrence from 0 to 2; w can be independently selected at each occurrence from 0 to 2; x can be independently selected at each occurrence from 0 to 3; with the following provisos:
(a) when V is (CH2)x, x can not be 0 when R3 is
hydrogen;
(b) when Z is -(CH2)xC(=O)- and -C(=O) (CH2)x and x is 0, R10 can not be halogen; wherein aryl is phenyl, fluorenyl, biphenyl and
naphthyl, which may be unsubstituted or include optional substitution with one to three substituents; heteroaryl is 2-, 3-, or 4-pyridyl; 2-, or 3-furyi; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl, which may be unsubstitued or include optional substitution with one to three substituents; heterocycle is 1-, 3-, or 4-tetrahdroisoquinolinyl, 2-or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl, which may be unsubstituted or include optional substitution with one to three substituents; cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl; the substituents which may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group selected from:
halogen, -CF3, C1-C4 alkyl, nitro, phenyl, -(CH2)rR4,
-(CH2)rC(=O)(CH2)SR4, -(CH2)rC(=O)O(CH2)sR4,
~(CH2)rC(=O)N[ (CH2)sR4] [ (CH2)sR5], methylenedioxy, C1-C4 alkoxy, -CH2)rO(CH2)sR4, -(CH2)rOC(=O) (CH2)sR4, -(CH2)rOC(=O)O(CH2)sR4,
-(CH2)rOC(=O)N[ (CH2)sR4] [ (CH2)sR5],
"(CH2)rOC(=O)N[ (CH2)sR4] [C(=O) (CH2)sR5],
-(CH2)rS(O)p(CH2)SR4, -(CH2)rS(O)p(CH2)SC(=O)R4, -(CH2)rS(O)p(CH2)sC(=O)OR4,
-(CH2)rS(O)pN[ (CH2)sR4] [ (CH2)sR5],
-(CH2)rS(O)pN[ (CH2)sR4] [C(=O) (CH2)sR5] .
"(CH2) N[ (CH2)sR4] [ (CH2)sR5],
~(CH2) N[ (CH2)sR4] [C(=O) (CH2)sR5],
-(CH2) N[ (CH2)sR4] [C(=O)O(CH2)sR5],
-(CH2)rN[ (CH2)sR4]CON[ (CH2)sR4] [ (CH2)sR5] ,
~(CH2)rN[ (CH2)sR4]C(=O)-N[ (CH2)sR4] [C(=O) (CH2)sR5] , -(CH2)rN[ (CH2)sR4] [S(O)p(CH2)sR5] .
4. A compound of claim 3 wherein:
R3 is independently selected from the group consisting of:
benzyl, phenyl, phenethyl, (3-phenyl)prop-1-yl, (2- methyl-1-phenyl)prop-2-yl, (2-methyl-2-phenyl)prop- 1-yl, 1,1-diphenylmethyl, phenoxymethyl,
phenylsulfonylmethyl, 2-(m-fluorophenyl)ethyl,, 2- (3-pyridyl)ethyl, (m-aminophenyl)methyl, (m- methylphenyl)methyl, (p-methylphenyl)methyl, 1- naphthylmethyl; R10 is independently selected from the group consisting of:
methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl-Ν-t- butoxycarbonylaminomethyl, N-methylaminomethyl, (m- methyl)phenethyl, (m-fluoro)phenethyl, (m- methyl)phenoxymethyl, (3-pyridyl)ethyl;
R11 is hydrαgen;
V is independently selected from the group consisting of:
O, -OC(=O)-, S, -ΝH-;
Z is -C(=O)-.
5. A compound of claim 4 of the formula (lb) selected from the group consisting of:
6. A compound of claim 4 of the formula (Ic) selected from the group consisting of:
R3 is (m-rnethylphenyl)methyl and R10 is methyl; the compound of formula (Ic) wherein V is oxygen,
R3 is (p-methylphenyl)methyl and R10 is methyl; the compound of formula (Ic) wherein V is oxygen, R3 is (1-naphthyl)methyl and R10 is methyl; the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is N-methyl -N-t-butoxycarbonylaminomethyl; the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is N-methylaminomethyl.
7. A compound of claim 4 of the formula (Id) selected from the group consisting of:
8. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 1.
9. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 2.
10. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 3.
11. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 4.
12. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 5.
13. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 6.
14. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 7.
15. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 1.
16. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 2.
17. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 3.
18. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 4.
19. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 5.
20. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 6.
21. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 7.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU79227/94A AU7922794A (en) | 1993-10-07 | 1994-10-06 | Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring |
| EP94929943A EP0722449A1 (en) | 1993-10-07 | 1994-10-06 | Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13325093A | 1993-10-07 | 1993-10-07 | |
| US08/133,250 | 1993-10-07 | ||
| US13944393A | 1993-10-20 | 1993-10-20 | |
| US08/139,443 | 1993-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995009859A1 true WO1995009859A1 (en) | 1995-04-13 |
Family
ID=26831201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1994/011049 WO1995009859A1 (en) | 1993-10-07 | 1994-10-06 | Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0722449A1 (en) |
| AU (1) | AU7922794A (en) |
| CA (1) | CA2174311A1 (en) |
| WO (1) | WO1995009859A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578574A (en) * | 1994-03-04 | 1996-11-26 | Eli Lilly And Company | Antithrombotic agents |
| US5599793A (en) * | 1994-03-04 | 1997-02-04 | Eli Lilly And Company | Antithromobotic agents |
| US5602101A (en) * | 1994-03-04 | 1997-02-11 | Eli Lilly And Company | Antithrombotic agents |
| US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5885967A (en) * | 1994-03-04 | 1999-03-23 | Eli Lilly And Company | Antithrombotic agents |
| US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
| US6638950B2 (en) | 2000-06-21 | 2003-10-28 | Bristol-Myers Squibb Pharma Company | Piperidine amides as modulators of chemokine receptor activity |
| EP1396270A1 (en) * | 2002-09-09 | 2004-03-10 | Trigen Limited | Boronic acid salts and use thereof in the preparation of medicaments for treating thrombosis |
| US7112572B2 (en) | 2002-09-09 | 2006-09-26 | Trigen Limited | Multivalent metal salts of boronic acids |
| WO2014058538A1 (en) * | 2012-08-27 | 2014-04-17 | Merck Sharp & Dohme Corp. | Substituted pyrrolidine thrombin inhibitors |
| US10370388B2 (en) * | 2012-01-06 | 2019-08-06 | Novartis Ag | Heterocyclic compounds and methods of their use |
| US10590084B2 (en) | 2016-03-09 | 2020-03-17 | Blade Therapeutics, Inc. | Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof |
| US10934261B2 (en) | 2016-09-28 | 2021-03-02 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
| US11292801B2 (en) | 2016-07-05 | 2022-04-05 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
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|---|---|---|---|---|
| EP0293881A2 (en) * | 1987-06-05 | 1988-12-07 | The Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| EP0471651A2 (en) * | 1990-08-13 | 1992-02-19 | Sandoz Ltd. | Peptide boronic acid derivatives having protease inhibiting activity |
| WO1992007869A1 (en) * | 1990-11-06 | 1992-05-14 | Thrombosis Research Institute | Inhibitors and substrates of thrombin |
| EP0504064A1 (en) * | 1991-03-15 | 1992-09-16 | Merrell Pharmaceuticals Inc. | Novel thrombin inhibitors |
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1994
- 1994-10-06 EP EP94929943A patent/EP0722449A1/en not_active Withdrawn
- 1994-10-06 CA CA002174311A patent/CA2174311A1/en not_active Abandoned
- 1994-10-06 WO PCT/US1994/011049 patent/WO1995009859A1/en not_active Application Discontinuation
- 1994-10-06 AU AU79227/94A patent/AU7922794A/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0293881A2 (en) * | 1987-06-05 | 1988-12-07 | The Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| EP0471651A2 (en) * | 1990-08-13 | 1992-02-19 | Sandoz Ltd. | Peptide boronic acid derivatives having protease inhibiting activity |
| WO1992007869A1 (en) * | 1990-11-06 | 1992-05-14 | Thrombosis Research Institute | Inhibitors and substrates of thrombin |
| EP0504064A1 (en) * | 1991-03-15 | 1992-09-16 | Merrell Pharmaceuticals Inc. | Novel thrombin inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5599793A (en) * | 1994-03-04 | 1997-02-04 | Eli Lilly And Company | Antithromobotic agents |
| US5602101A (en) * | 1994-03-04 | 1997-02-11 | Eli Lilly And Company | Antithrombotic agents |
| US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| US5578574A (en) * | 1994-03-04 | 1996-11-26 | Eli Lilly And Company | Antithrombotic agents |
| US5885967A (en) * | 1994-03-04 | 1999-03-23 | Eli Lilly And Company | Antithrombotic agents |
| US6090787A (en) * | 1994-03-04 | 2000-07-18 | Eli Lilly And Company | Antithrombotic agents |
| US6124277A (en) * | 1994-03-04 | 2000-09-26 | Eli Lilly And Company | Antithrombotic agents |
| US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
| US6638950B2 (en) | 2000-06-21 | 2003-10-28 | Bristol-Myers Squibb Pharma Company | Piperidine amides as modulators of chemokine receptor activity |
| US6984651B2 (en) | 2000-06-21 | 2006-01-10 | Bristol-Myers Squibb Pharma, Company | Piperidine amides as modulators of chemokine receptor activity |
| WO2004022071A1 (en) * | 2002-09-09 | 2004-03-18 | Trigen Limited | Multivalent metal salts of boronic acids for treating thrombosis |
| EP1561466A3 (en) * | 2002-09-09 | 2006-08-23 | Trigen Limited | Boronic acid salts and use thereof in the preparation of medicaments for treating thrombosis |
| WO2004022072A1 (en) * | 2002-09-09 | 2004-03-18 | Trigen Limited | Boronic acid salts ant their use in the treatment of thrombosis |
| EP1396269A1 (en) | 2002-09-09 | 2004-03-10 | Trigen Limited | Boronic acid salts of multivalent metals used in the preparation of a medicament for treating thrombosis |
| EP1400245A1 (en) * | 2002-09-09 | 2004-03-24 | Trigen Limited | Boronic acid salts useful in parenteral formulations for selective thrombin inhibition |
| EP1466917A1 (en) | 2002-09-09 | 2004-10-13 | Trigen Limited | Method for making peptide boronic acids and acids obtainable thereby |
| EP1561466A2 (en) * | 2002-09-09 | 2005-08-10 | Trigen Limited | Boronic acid salts and use thereof in the preparation of medicaments for treating thrombosis |
| EP1396270A1 (en) * | 2002-09-09 | 2004-03-10 | Trigen Limited | Boronic acid salts and use thereof in the preparation of medicaments for treating thrombosis |
| JP2006503903A (en) * | 2002-09-09 | 2006-02-02 | トライジェン・リミテッド | Boronic acid polyvalent metal salt for the treatment of thrombosis |
| WO2004022070A1 (en) * | 2002-09-09 | 2004-03-18 | Trigen Limited | Boronic acid salts useful in parenteral formulations for selective thrombin inhibition |
| US7112572B2 (en) | 2002-09-09 | 2006-09-26 | Trigen Limited | Multivalent metal salts of boronic acids |
| US7371729B2 (en) | 2002-09-09 | 2008-05-13 | Trigen Limited | Boronic acid salts useful in parenteral formulations |
| CN100447151C (en) * | 2002-09-09 | 2008-12-31 | 特里根有限公司 | Peptide boronic acids useful in making salts thereof |
| CN100553639C (en) | 2002-09-09 | 2009-10-28 | 特里根有限公司 | Be used for the treatment of thrombotic boronic acid polyvalent salts |
| US10370388B2 (en) * | 2012-01-06 | 2019-08-06 | Novartis Ag | Heterocyclic compounds and methods of their use |
| WO2014058538A1 (en) * | 2012-08-27 | 2014-04-17 | Merck Sharp & Dohme Corp. | Substituted pyrrolidine thrombin inhibitors |
| US10590084B2 (en) | 2016-03-09 | 2020-03-17 | Blade Therapeutics, Inc. | Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof |
| US11292801B2 (en) | 2016-07-05 | 2022-04-05 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
| US10934261B2 (en) | 2016-09-28 | 2021-03-02 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
| US11339130B1 (en) | 2016-09-28 | 2022-05-24 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7922794A (en) | 1995-05-01 |
| EP0722449A1 (en) | 1996-07-24 |
| CA2174311A1 (en) | 1995-04-13 |
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