DE19962329A1 - Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel - Google Patents

Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel

Info

Publication number: DE19962329A1
Authority: DE; Germany
Prior art keywords: group; alkyl; substituted; methyl; amino
Prior art date: 1999-12-23
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

DE19962329A

Other languages

German (de)

English (en)

Inventor

Uwe Ries

Iris Kauffmann

Norbert Hauel

Henning Priepke

Herbert Nar

Jean Marie Stassen

Wolfgang Wienen

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Boehringer Ingelheim Pharma GmbH and Co KG

Original Assignee

Boehringer Ingelheim Pharma GmbH and Co KG

Boehringer Ingelheim Pharmaceuticals Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-12-23

Filing date

1999-12-23

Publication date

2001-06-28

1999-12-23 Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG

1999-12-23 Priority to DE19962329A priority Critical patent/DE19962329A1/de

2000-12-12 Priority to US09/735,159 priority patent/US6451832B2/en

2000-12-16 Priority to MXPA02006299A priority patent/MXPA02006299A/es

2000-12-16 Priority to AU20115/01A priority patent/AU2011501A/en

2000-12-16 Priority to JP2001549368A priority patent/JP2003519129A/ja

2000-12-16 Priority to PCT/EP2000/012841 priority patent/WO2001047896A1/de

2000-12-16 Priority to EP00983342A priority patent/EP1244636A1/de

2000-12-16 Priority to CA002393916A priority patent/CA2393916A1/en

2000-12-19 Priority to PE2000001365A priority patent/PE20010954A1/es

2000-12-20 Priority to UY26492A priority patent/UY26492A1/es

2000-12-21 Priority to ARP000106819A priority patent/AR027050A1/es

2001-06-28 Publication of DE19962329A1 publication Critical patent/DE19962329A1/de

2002-07-03 Priority to US10/188,952 priority patent/US6593355B2/en

Status Withdrawn legal-status Critical Current

Links

239000003146 anticoagulant agent Substances 0.000 title description 2
239000000543 intermediate Substances 0.000 title description 2
229940122388 Thrombin inhibitor Drugs 0.000 title 1
229960004676 antithrombotic agent Drugs 0.000 title 1
RICPDSJTBAXDLV-UHFFFAOYSA-N n-(1h-benzimidazol-2-ylmethyl)aniline Chemical class N=1C2=CC=CC=C2NC=1CNC1=CC=CC=C1 RICPDSJTBAXDLV-UHFFFAOYSA-N 0.000 title 1
239000003001 serine protease inhibitor Substances 0.000 title 1
239000003868 thrombin inhibitor Substances 0.000 title 1
-1 pyrrolidinocarbonyl Chemical group 0.000 claims abstract description 229
125000000217 alkyl group Chemical group 0.000 claims abstract description 47
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 36
150000003839 salts Chemical class 0.000 claims abstract description 35
125000003277 amino group Chemical group 0.000 claims abstract description 33
125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract description 28
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
239000000203 mixture Substances 0.000 claims abstract description 23
238000002360 preparation method Methods 0.000 claims abstract description 20
229910052801 chlorine Inorganic materials 0.000 claims abstract description 13
229910052731 fluorine Inorganic materials 0.000 claims abstract description 12
125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
230000004962 physiological condition Effects 0.000 claims abstract description 5
229940002612 prodrug Drugs 0.000 claims abstract description 5
239000000651 prodrug Substances 0.000 claims abstract description 5
125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract 4
150000001875 compounds Chemical class 0.000 claims description 94
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 58
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 38
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
229910021529 ammonia Inorganic materials 0.000 claims description 29
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
239000002253 acid Substances 0.000 claims description 25
239000000460 chlorine Substances 0.000 claims description 18
238000006243 chemical reaction Methods 0.000 claims description 17
238000011282 treatment Methods 0.000 claims description 16
239000011541 reaction mixture Substances 0.000 claims description 15
125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
125000004093 cyano group Chemical group *C#N 0.000 claims description 11
239000011737 fluorine Substances 0.000 claims description 11
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 10
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 10
238000000034 method Methods 0.000 claims description 10
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
229910052740 iodine Inorganic materials 0.000 claims description 9
125000003831 tetrazolyl group Chemical group 0.000 claims description 9
125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims description 8
125000004432 carbon atom Chemical group C* 0.000 claims description 8
230000007062 hydrolysis Effects 0.000 claims description 8
238000006460 hydrolysis reaction Methods 0.000 claims description 8
238000001727 in vivo Methods 0.000 claims description 8
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
150000003254 radicals Chemical class 0.000 claims description 7
239000000126 substance Substances 0.000 claims description 7
150000001556 benzimidazoles Chemical class 0.000 claims description 6
125000006332 fluoro benzoyl group Chemical group 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
125000001841 imino group Chemical group [H]N=* 0.000 claims description 6
125000001424 substituent group Chemical group 0.000 claims description 6
125000003944 tolyl group Chemical group 0.000 claims description 6
230000000694 effects Effects 0.000 claims description 5
238000007327 hydrogenolysis reaction Methods 0.000 claims description 5
238000001149 thermolysis Methods 0.000 claims description 5
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
125000005079 alkoxycarbonylmethyl group Chemical group 0.000 claims description 4
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
230000002401 inhibitory effect Effects 0.000 claims description 4
108090000190 Thrombin Proteins 0.000 claims description 3
239000000969 carrier Substances 0.000 claims description 3
239000003814 drug Substances 0.000 claims description 3
230000032050 esterification Effects 0.000 claims description 3
238000005886 esterification reaction Methods 0.000 claims description 3
150000007522 mineralic acids Chemical class 0.000 claims description 3
150000007524 organic acids Chemical class 0.000 claims description 3
IVYHFJFVBLEKDG-PGUFJCEWSA-N propyl 2-[[(2r)-2-[2-[[4-(n'-benzoylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound O=C([C@](C)(NCC(=O)OCCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC=CC=3)N(C)C2=CC=1)N1CCCC1 IVYHFJFVBLEKDG-PGUFJCEWSA-N 0.000 claims description 3
229960004072 thrombin Drugs 0.000 claims description 3
238000005809 transesterification reaction Methods 0.000 claims description 3
QILXVSWGJTUQLF-PSXMRANNSA-N 2-methylpropyl 2-[[(2r)-2-[2-[[4-(n'-benzoylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound O=C([C@](C)(NCC(=O)OCC(C)C)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC=CC=3)N(C)C2=CC=1)N1CCCC1 QILXVSWGJTUQLF-PSXMRANNSA-N 0.000 claims description 2
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
108010022999 Serine Proteases Proteins 0.000 claims description 2
102000012479 Serine Proteases Human genes 0.000 claims description 2
125000004414 alkyl thio group Chemical group 0.000 claims description 2
125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
125000004429 atom Chemical group 0.000 claims description 2
QYQACUKFOZZIDQ-UHFFFAOYSA-N butyl 2-[[2-[2-[[4-(n'-benzoylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound C=1C=C2N(C)C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC=CC=3)=NC2=CC=1C(C)(NCC(=O)OCCCC)C(=O)N1CCCC1 QYQACUKFOZZIDQ-UHFFFAOYSA-N 0.000 claims description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
125000001153 fluoro group Chemical group F* 0.000 claims description 2
JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 claims description 2
229910052760 oxygen Inorganic materials 0.000 claims description 2
239000001301 oxygen Substances 0.000 claims description 2
230000001681 protective effect Effects 0.000 claims description 2
229910052717 sulfur Inorganic materials 0.000 claims description 2
125000004434 sulfur atom Chemical group 0.000 claims description 2
125000003396 thiol group Chemical class [H]S* 0.000 claims description 2
239000003085 diluting agent Substances 0.000 claims 2
QHCCOYAKYCWDOJ-UHFFFAOYSA-N 2-ethyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CC)=NC2=C1 QHCCOYAKYCWDOJ-UHFFFAOYSA-N 0.000 claims 1
SXWTXMPGXONTDO-UHFFFAOYSA-N 4-[[1-methyl-5-[2-[methyl(2h-tetrazol-5-yl)amino]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]benzimidazol-2-yl]methylamino]benzenecarboximidamide Chemical compound C1CCCN1C(=O)C(C)(C=1C=C2N=C(CNC=3C=CC(=CC=3)C(N)=N)N(C)C2=CC=1)N(C)C1=NN=NN1 SXWTXMPGXONTDO-UHFFFAOYSA-N 0.000 claims 1
241001026509 Kata Species 0.000 claims 1
239000008194 pharmaceutical composition Substances 0.000 claims 1
229910052794 bromium Inorganic materials 0.000 abstract description 4
229940058303 antinematodal benzimidazole derivative Drugs 0.000 abstract 2
125000004457 alkyl amino carbonyl group Chemical group 0.000 abstract 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 188
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 63
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
239000000741 silica gel Substances 0.000 description 60
229910002027 silica gel Inorganic materials 0.000 description 60
238000001819 mass spectrum Methods 0.000 description 52
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
239000000243 solution Substances 0.000 description 38
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
239000002904 solvent Substances 0.000 description 30
239000011734 sodium Substances 0.000 description 26
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 22
229960000583 acetic acid Drugs 0.000 description 22
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
239000012362 glacial acetic acid Substances 0.000 description 19
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
239000002585 base Substances 0.000 description 17
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
239000012071 phase Substances 0.000 description 15
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
230000000875 corresponding effect Effects 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
239000011780 sodium chloride Substances 0.000 description 13
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
239000013543 active substance Substances 0.000 description 11
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
229910052739 hydrogen Inorganic materials 0.000 description 8
239000001257 hydrogen Substances 0.000 description 8
238000004519 manufacturing process Methods 0.000 description 8
239000003208 petroleum Substances 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
239000004480 active ingredient Substances 0.000 description 7
229910000147 aluminium phosphate Inorganic materials 0.000 description 7
239000002775 capsule Substances 0.000 description 7
238000003776 cleavage reaction Methods 0.000 description 7
229910000027 potassium carbonate Inorganic materials 0.000 description 7
230000007017 scission Effects 0.000 description 7
239000003826 tablet Substances 0.000 description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
238000001816 cooling Methods 0.000 description 6
239000012043 crude product Substances 0.000 description 6
150000002148 esters Chemical class 0.000 description 6
239000005457 ice water Substances 0.000 description 6
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
229920002261 Corn starch Polymers 0.000 description 5
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
235000015165 citric acid Nutrition 0.000 description 5
239000008120 corn starch Substances 0.000 description 5
235000019359 magnesium stearate Nutrition 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
229910052763 palladium Inorganic materials 0.000 description 5
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
NMGLVHXJOMBIJW-UHFFFAOYSA-N 1h-benzimidazole;dihydrochloride Chemical compound Cl.Cl.C1=CC=C2NC=NC2=C1 NMGLVHXJOMBIJW-UHFFFAOYSA-N 0.000 description 4
ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
229930195725 Mannitol Natural products 0.000 description 4
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
239000002202 Polyethylene glycol Substances 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
125000002252 acyl group Chemical group 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
239000001099 ammonium carbonate Substances 0.000 description 4
235000012501 ammonium carbonate Nutrition 0.000 description 4
238000009835 boiling Methods 0.000 description 4
239000012267 brine Substances 0.000 description 4
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
229960001760 dimethyl sulfoxide Drugs 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
230000008020 evaporation Effects 0.000 description 4
239000000594 mannitol Substances 0.000 description 4
235000010355 mannitol Nutrition 0.000 description 4
229920001223 polyethylene glycol Polymers 0.000 description 4
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
238000007363 ring formation reaction Methods 0.000 description 4
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 4
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
239000000829 suppository Substances 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
239000008215 water for injection Substances 0.000 description 4
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HMCZLAXKIDEJDE-UHFFFAOYSA-N ethyl 2-[2-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazol-5-yl]-2-methyl-3-oxo-3-pyrrolidin-1-ylpropoxy]acetate Chemical compound C=1C=C2N(C)C(CNC=3C=CC(=CC=3)C#N)=NC2=CC=1C(C)(COCC(=O)OCC)C(=O)N1CCCC1 HMCZLAXKIDEJDE-UHFFFAOYSA-N 0.000 description 1
APUNNQPBXXKEKM-UHFFFAOYSA-N ethyl 2-[2-[4-[benzyl(methyl)amino]-3-nitrophenyl]-2-methyl-3-oxo-3-pyrrolidin-1-ylpropoxy]acetate Chemical compound C=1C=C(N(C)CC=2C=CC=CC=2)C([N+]([O-])=O)=CC=1C(C)(COCC(=O)OCC)C(=O)N1CCCC1 APUNNQPBXXKEKM-UHFFFAOYSA-N 0.000 description 1
XEBPPPZTAHJFND-PGUFJCEWSA-N ethyl 2-[[(2r)-2-[1-methyl-2-[[4-[n'-(4-methylbenzoyl)carbamimidoyl]anilino]methyl]benzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound O=C([C@](C)(NCC(=O)OCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC(C)=CC=3)N(C)C2=CC=1)N1CCCC1 XEBPPPZTAHJFND-PGUFJCEWSA-N 0.000 description 1
SFWNIJSLNBPJQB-UUWRZZSWSA-N ethyl 2-[[(2r)-2-[1-methyl-2-[[4-[n'-[4-(trifluoromethyl)benzoyl]carbamimidoyl]anilino]methyl]benzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound O=C([C@](C)(NCC(=O)OCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC(=CC=3)C(F)(F)F)N(C)C2=CC=1)N1CCCC1 SFWNIJSLNBPJQB-UUWRZZSWSA-N 0.000 description 1
PUIQEACLLJAPJA-KFSCGDPASA-N ethyl 2-[[(2r)-2-[2-[(4-carbamimidoylanilino)methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate;dihydrochloride Chemical compound Cl.Cl.O=C([C@](C)(NCC(=O)OCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(N)=N)N(C)C2=CC=1)N1CCCC1 PUIQEACLLJAPJA-KFSCGDPASA-N 0.000 description 1
CTNDNJBLYKCBTP-UUWRZZSWSA-N ethyl 2-[[(2r)-2-[2-[[4-(n'-benzoylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound O=C([C@](C)(NCC(=O)OCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC=CC=3)N(C)C2=CC=1)N1CCCC1 CTNDNJBLYKCBTP-UUWRZZSWSA-N 0.000 description 1
VLBZKCOKDGMOPZ-UUWRZZSWSA-N ethyl 2-[[(2r)-2-[2-[[4-[n'-(4-fluorobenzoyl)carbamimidoyl]anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]acetate Chemical compound O=C([C@](C)(NCC(=O)OCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC(F)=CC=3)N(C)C2=CC=1)N1CCCC1 VLBZKCOKDGMOPZ-UUWRZZSWSA-N 0.000 description 1
SDIYRVFPQPUNRZ-UHFFFAOYSA-N ethyl 3-[3-amino-4-(methylamino)phenyl]-2-methoxy-3-methyl-4-oxo-4-pyrrolidin-1-ylbutanoate Chemical compound CNC1=C(C=C(C=C1)C(C(=O)N1CCCC1)(C(C(=O)OCC)OC)C)N SDIYRVFPQPUNRZ-UHFFFAOYSA-N 0.000 description 1
QOAOQPPALIPJOX-UHFFFAOYSA-N ethyl 3-[[2-[2-[(4-carbamimidoylanilino)methyl]-1-methylbenzimidazol-5-yl]-2-methyl-3-oxo-3-pyrrolidin-1-ylpropyl]-methylamino]propanoate Chemical compound C=1C=C2N(C)C(CNC=3C=CC(=CC=3)C(N)=N)=NC2=CC=1C(C)(CN(C)CCC(=O)OCC)C(=O)N1CCCC1 QOAOQPPALIPJOX-UHFFFAOYSA-N 0.000 description 1
AGAZSSUKZZBTOM-PSXMRANNSA-N ethyl 4-[[(2r)-2-[2-[[4-(n'-benzoylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]butanoate Chemical compound O=C([C@](C)(NCCCC(=O)OCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC=CC=3)N(C)C2=CC=1)N1CCCC1 AGAZSSUKZZBTOM-PSXMRANNSA-N 0.000 description 1
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
239000000284 extract Substances 0.000 description 1
238000000605 extraction Methods 0.000 description 1
229960004222 factor ix Drugs 0.000 description 1
229940012414 factor viia Drugs 0.000 description 1
229950003499 fibrin Drugs 0.000 description 1
238000001914 filtration Methods 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
239000004220 glutamic acid Substances 0.000 description 1
235000013922 glutamic acid Nutrition 0.000 description 1
235000011187 glycerol Nutrition 0.000 description 1
229960005150 glycerol Drugs 0.000 description 1
229940116364 hard fat Drugs 0.000 description 1
125000000623 heterocyclic group Chemical group 0.000 description 1
125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
230000004054 inflammatory process Effects 0.000 description 1
229910010272 inorganic material Inorganic materials 0.000 description 1
239000011147 inorganic material Substances 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
229960001375 lactose Drugs 0.000 description 1
229960004873 levomenthol Drugs 0.000 description 1
230000007774 longterm Effects 0.000 description 1
210000004072 lung Anatomy 0.000 description 1
229940057948 magnesium stearate Drugs 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
239000000463 material Substances 0.000 description 1
239000000155 melt Substances 0.000 description 1
230000009401 metastasis Effects 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
150000002905 orthoesters Chemical class 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
PQZDXJPHKGFGTG-DIPNUNPCSA-N propyl 4-[[(2r)-2-[2-[[4-(n'-benzoylcarbamimidoyl)anilino]methyl]-1-methylbenzimidazol-5-yl]-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]amino]butanoate Chemical compound O=C([C@](C)(NCCCC(=O)OCCC)C=1C=C2N=C(CNC=3C=CC(=CC=3)C(=N)NC(=O)C=3C=CC=CC=3)N(C)C2=CC=1)N1CCCC1 PQZDXJPHKGFGTG-DIPNUNPCSA-N 0.000 description 1
125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
208000005069 pulmonary fibrosis Diseases 0.000 description 1
238000000746 purification Methods 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
238000010992 reflux Methods 0.000 description 1
208000037803 restenosis Diseases 0.000 description 1
QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
WBHHMMIMDMUBKC-QJWNTBNXSA-N ricinoleic acid Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(O)=O WBHHMMIMDMUBKC-QJWNTBNXSA-N 0.000 description 1
229960003656 ricinoleic acid Drugs 0.000 description 1
239000011833 salt mixture Substances 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
125000005374 siloxide group Chemical group 0.000 description 1
229910001923 silver oxide Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
239000007787 solid Substances 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
238000003756 stirring Methods 0.000 description 1
229960005202 streptokinase Drugs 0.000 description 1
229960004793 sucrose Drugs 0.000 description 1
HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
CIOJQFVISJICOD-UHFFFAOYSA-N tert-butyl N-[2-[2-[(4-cyanoanilino)methyl]-1-methylbenzimidazol-5-yl]-2-methyl-3-oxo-3-pyrrolidin-1-ylpropyl]carbamate Chemical compound N=1C2=CC(C(C)(CNC(=O)OC(C)(C)C)C(=O)N3CCCC3)=CC=C2N(C)C=1CNC1=CC=C(C#N)C=C1 CIOJQFVISJICOD-UHFFFAOYSA-N 0.000 description 1
JXUVLARSSAPUHW-UHFFFAOYSA-N tert-butyl N-[2-[3-amino-4-(methylamino)phenyl]-2-methyl-3-oxo-3-pyrrolidin-1-ylpropyl]carbamate Chemical compound C1=C(N)C(NC)=CC=C1C(C)(CNC(=O)OC(C)(C)C)C(=O)N1CCCC1 JXUVLARSSAPUHW-UHFFFAOYSA-N 0.000 description 1
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
150000003509 tertiary alcohols Chemical class 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
150000003536 tetrazoles Chemical class 0.000 description 1
238000011287 therapeutic dose Methods 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
230000002537 thrombolytic effect Effects 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
239000005051 trimethylchlorosilane Substances 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
229960005356 urokinase Drugs 0.000 description 1
125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000008096 xylene Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Hematology (AREA)
Diabetes (AREA)
Pulmonology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

DE19962329A 1999-12-23 1999-12-23 Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel Withdrawn DE19962329A1 (de)

Priority Applications (12)

Application Number	Priority Date	Filing Date	Title
DE19962329A DE19962329A1 (de)	1999-12-23	1999-12-23	Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel
US09/735,159 US6451832B2 (en)	1999-12-23	2000-12-12	Benzimidazoles with antithrombotic activity
PCT/EP2000/012841 WO2001047896A1 (de)	1999-12-23	2000-12-16	Benzimidazole, deren herstellung und deren verwendung als antithrombotika
AU20115/01A AU2011501A (en)	1999-12-23	2000-12-16	Benzimidazoles, production thereof and the use thereof as antithrombotic
JP2001549368A JP2003519129A (ja)	1999-12-23	2000-12-16	ベンズイミダゾール、その調製及び医薬組成物としての使用
MXPA02006299A MXPA02006299A (es)	1999-12-23	2000-12-16	Bencimidazoles, su obtencion y uso como antibioticos.
EP00983342A EP1244636A1 (de)	1999-12-23	2000-12-16	Benzimidazole, deren herstellung und deren verwendung als antithrombotika
CA002393916A CA2393916A1 (en)	1999-12-23	2000-12-16	Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
PE2000001365A PE20010954A1 (es)	1999-12-23	2000-12-19	Bencimidazoles, su preparacion y su empleo como medicamentos
UY26492A UY26492A1 (es)	1999-12-23	2000-12-20	Bencimidazoles, su preparación y su empleo como medicamentos.
ARP000106819A AR027050A1 (es)	1999-12-23	2000-12-21	Bencimidazoles, su preparacion y su empleo como medicamentos
US10/188,952 US6593355B2 (en)	1999-12-23	2002-07-03	Benzimidazoles with antithrombotic activity

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
DE19962329A DE19962329A1 (de)	1999-12-23	1999-12-23	Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel

Publications (1)

Publication Number	Publication Date
DE19962329A1 true DE19962329A1 (de)	2001-06-28

Family

ID=7934028

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
DE19962329A Withdrawn DE19962329A1 (de)	1999-12-23	1999-12-23	Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel

Country Status (10)

Country	Link
EP (1)	EP1244636A1 (es)
JP (1)	JP2003519129A (es)
AR (1)	AR027050A1 (es)
AU (1)	AU2011501A (es)
CA (1)	CA2393916A1 (es)
DE (1)	DE19962329A1 (es)
MX (1)	MXPA02006299A (es)
PE (1)	PE20010954A1 (es)
UY (1)	UY26492A1 (es)
WO (1)	WO2001047896A1 (es)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP1609784A1 (de) *	2004-06-25	2005-12-28	Boehringer Ingelheim Pharma GmbH & Co.KG	Verfahren zur Herstellung von 4-(Benzimidazolylmethylamino)-Benzamidinen
WO2007071742A1 (en) *	2005-12-21	2007-06-28	Boehringer Ingelheim International Gmbh	Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof
WO2014068587A3 (en) *	2012-10-29	2014-07-17	Biophore India Pharmaceuticals Pvt. Ltd.	An improved process for the synthesis of dabigatran and its intermediates
US10077251B2 (en)	2012-10-29	2018-09-18	Biophore India Pharmaceuticals Pvt. Ltd.	Process for the synthesis of Dabigatran Etexilate and its intermediates

Families Citing this family (7)

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- 2000-12-16 EP EP00983342A patent/EP1244636A1/de not_active Withdrawn
- 2000-12-16 CA CA002393916A patent/CA2393916A1/en not_active Abandoned
- 2000-12-16 JP JP2001549368A patent/JP2003519129A/ja active Pending
- 2000-12-16 WO PCT/EP2000/012841 patent/WO2001047896A1/de not_active Ceased
- 2000-12-16 MX MXPA02006299A patent/MXPA02006299A/es unknown
- 2000-12-19 PE PE2000001365A patent/PE20010954A1/es not_active Application Discontinuation
- 2000-12-20 UY UY26492A patent/UY26492A1/es not_active Application Discontinuation
- 2000-12-21 AR ARP000106819A patent/AR027050A1/es unknown

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Also Published As

Publication number	Publication date
WO2001047896A1 (de)	2001-07-05
PE20010954A1 (es)	2001-10-09
UY26492A1 (es)	2001-07-31
AR027050A1 (es)	2003-03-12
MXPA02006299A (es)	2002-12-09
CA2393916A1 (en)	2001-07-05
AU2011501A (en)	2001-07-09
JP2003519129A (ja)	2003-06-17
EP1244636A1 (de)	2002-10-02

Publication	Publication Date	Title
EP1095025B1 (de)	2002-12-11	Benzimidazole, deren herstellung und deren verwendung als arzneimittel
EP0966454B1 (de)	2003-05-07	Disubstituierte bicyclische heterocyclen, ihre herstellung und ihre verwendung als arzneimittel
EP1100795B1 (de)	2004-06-09	Disubstituierte bicyclische heterocyclen mit insbesondere eine thrombinhemmende wirkung
EP0608858A1 (de)	1994-08-03	5-Gliedrige Heterocyclen als Aggregationshemmer
WO1999040072A1 (de)	1999-08-12	5-gliedrige benzokondensierte heterocyclen als antithrombotika
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EP1414790A1 (de)	2004-05-06	Substituierte n-acyl-anilinderivate, deren herstellung und deren verwendung als arzneimittel
DE19816983A1 (de)	1999-10-21	Bicyclen, deren Herstellung und deren Verwendung als Arzneimittel
WO2001014342A1 (de)	2001-03-01	Aminocarbonyl-substituierte benzimidazolderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
EP1370540A1 (de)	2003-12-17	Antithrombotische carbonsäureamide, deren herstellung und deren verwendung als arzneimittel
DE19804085A1 (de)	1999-08-05	5-Gliedrige heterocyclische kondensierte Benzoderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE19907813A1 (de)	2000-08-31	Substituierte bicyclische Heterocyclen, deren Herstellung und deren Verwendung als Arzneimittel
WO1999029670A2 (de)	1999-06-17	Aminocarbonyltetralin- und -dihydronapthalinderivate als thrombinhemmer
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DE19945787A1 (de)	2001-03-29	Arylsulfonamid-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE10230012A1 (de)	2004-01-22	Neue 5,6-Dihydro-4H-imidazo[4,5,1-ij]chinoline,ihre Herstellung und ihre Verwendung als Arzneimittel
DE19834325A1 (de)	2000-02-17	5-Gliedrige heterocyclische kondensierte Derivate, deren Herstellung und deren Verwendung als Arzneimittel
DE19706229A1 (de)	1998-08-20	Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19948101A1 (de)	2001-04-12	Substituierte Aryl- und Heteroarylderivate, deren Herstellung und deren Verwendung als Arzneimittel
WO2004013128A1 (de)	2004-02-12	Neue substituierte benzoesäureamide, deren herstellung und deren verwendung als arzneimittel
DE19858029A1 (de)	2000-06-21	Substituierte Aryl- und Heteroarylderivate, deren Herstellung und deren Verwendung als Arzneimittel

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2003-04-24	8127	New person/name/address of the applicant	Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG, 55218 IN
2004-10-21	8139	Disposal/non-payment of the annual fee