ZA200607606B - Novel pyrrolidine-3, 4-dicarboxamide derivatives - Google Patents

Novel pyrrolidine-3, 4-dicarboxamide derivatives Download PDF

Info

Publication number: ZA200607606B
Authority: ZA; South Africa
Prior art keywords: amide; phenyl; alkyl; fluoro; pyrrolidine
Prior art date: 2004-03-26

Application number

ZA200607606A

Other languages

English (en)

Inventor

Anselm Lilli

Haap Wolfgang

Christoph Martin Stahl

Zbinden Katrin Groebke

Himber Jacques

Thomi Stefan

Original Assignee

Hoffmann La Roche

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.)

2004-03-26

Filing date

2006-09-11

Publication date

2008-05-28

2006-09-11 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2008-05-28 Publication of ZA200607606B publication Critical patent/ZA200607606B/en

Links

HEHBWXUFYYBHME-UHFFFAOYSA-N pyrrolidine-3,4-dicarboxamide Chemical class NC(=O)C1CNCC1C(N)=O HEHBWXUFYYBHME-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims description 228
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 122
125000000217 alkyl group Chemical group 0.000 claims description 114
-1 Ci. alkylsufonyl Chemical group 0.000 claims description 107
238000000034 method Methods 0.000 claims description 102
239000000203 mixture Substances 0.000 claims description 67
ILAIIURYCZSHPA-WHFBIAKZSA-N (3r,4r)-1-methylsulfonylpyrrolidine-3,4-dicarboxylic acid Chemical compound CS(=O)(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 ILAIIURYCZSHPA-WHFBIAKZSA-N 0.000 claims description 65
229910052739 hydrogen Inorganic materials 0.000 claims description 37
239000001257 hydrogen Substances 0.000 claims description 36
125000001072 heteroaryl group Chemical group 0.000 claims description 33
229910052736 halogen Inorganic materials 0.000 claims description 32
150000002367 halogens Chemical class 0.000 claims description 32
125000003118 aryl group Chemical group 0.000 claims description 28
125000003545 alkoxy group Chemical group 0.000 claims description 26
150000003839 salts Chemical class 0.000 claims description 25
125000000623 heterocyclic group Chemical group 0.000 claims description 23
125000004432 carbon atom Chemical group C* 0.000 claims description 20
150000002431 hydrogen Chemical class 0.000 claims description 20
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
206010047249 Venous thrombosis Diseases 0.000 claims description 17
108010074860 Factor Xa Proteins 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
125000000753 cycloalkyl group Chemical group 0.000 claims description 16
229910052757 nitrogen Inorganic materials 0.000 claims description 14
230000008569 process Effects 0.000 claims description 14
238000011321 prophylaxis Methods 0.000 claims description 13
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
230000001225 therapeutic effect Effects 0.000 claims description 12
RUESXRXDNLNITM-WHFBIAKZSA-N (3r,4r)-1-(2,2-difluoroethyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound OC(=O)[C@H]1CN(CC(F)F)C[C@@H]1C(O)=O RUESXRXDNLNITM-WHFBIAKZSA-N 0.000 claims description 11
208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 10
239000003146 anticoagulant agent Substances 0.000 claims description 10
201000010099 disease Diseases 0.000 claims description 10
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
238000011282 treatment Methods 0.000 claims description 10
206010003178 Arterial thrombosis Diseases 0.000 claims description 9
206010051055 Deep vein thrombosis Diseases 0.000 claims description 9
208000007536 Thrombosis Diseases 0.000 claims description 9
206010003210 Arteriosclerosis Diseases 0.000 claims description 8
206010003658 Atrial Fibrillation Diseases 0.000 claims description 8
206010061218 Inflammation Diseases 0.000 claims description 8
208000010378 Pulmonary Embolism Diseases 0.000 claims description 8
208000006011 Stroke Diseases 0.000 claims description 8
208000007814 Unstable Angina Diseases 0.000 claims description 8
230000001154 acute effect Effects 0.000 claims description 8
208000011775 arteriosclerosis disease Diseases 0.000 claims description 8
208000029078 coronary artery disease Diseases 0.000 claims description 8
230000004054 inflammatory process Effects 0.000 claims description 8
238000004519 manufacturing process Methods 0.000 claims description 8
208000010125 myocardial infarction Diseases 0.000 claims description 8
208000037803 restenosis Diseases 0.000 claims description 8
125000001424 substituent group Chemical group 0.000 claims description 8
238000002560 therapeutic procedure Methods 0.000 claims description 8
230000002537 thrombolytic effect Effects 0.000 claims description 8
150000001408 amides Chemical class 0.000 claims description 7
229910052799 carbon Inorganic materials 0.000 claims description 7
BFSHEKRTOWIVOA-BQBZGAKWSA-N (3r,4r)-1-propan-2-ylpyrrolidine-3,4-dicarboxylic acid Chemical compound CC(C)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 BFSHEKRTOWIVOA-BQBZGAKWSA-N 0.000 claims description 6
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
206010028980 Neoplasm Diseases 0.000 claims description 6
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
125000006193 alkinyl group Chemical group 0.000 claims description 6
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
125000001041 indolyl group Chemical group 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
239000001301 oxygen Substances 0.000 claims description 6
125000004076 pyridyl group Chemical group 0.000 claims description 6
238000006467 substitution reaction Methods 0.000 claims description 6
FLBWMDZFGGRSBK-WDSKDSINSA-N (3r,4r)-1-ethylsulfonylpyrrolidine-3,4-dicarboxylic acid Chemical compound CCS(=O)(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 FLBWMDZFGGRSBK-WDSKDSINSA-N 0.000 claims description 5
KMHDKGFRYVKQNW-IMJSIDKUSA-N (3r,4r)-pyrrolidine-3,4-dicarboxylic acid Chemical compound OC(=O)[C@H]1CNC[C@@H]1C(O)=O KMHDKGFRYVKQNW-IMJSIDKUSA-N 0.000 claims description 5
239000013543 active substance Substances 0.000 claims description 5
125000002947 alkylene group Chemical group 0.000 claims description 5
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 5
239000011737 fluorine Substances 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 5
238000002360 preparation method Methods 0.000 claims description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
VSCXGGLYCBATKH-WHFBIAKZSA-N (3r,4r)-1-(2,2,2-trifluoroethyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound OC(=O)[C@H]1CN(CC(F)(F)F)C[C@@H]1C(O)=O VSCXGGLYCBATKH-WHFBIAKZSA-N 0.000 claims description 4
COKLFPIGBAZDGN-WDSKDSINSA-N (3r,4r)-1-(dimethylsulfamoyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound CN(C)S(=O)(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 COKLFPIGBAZDGN-WDSKDSINSA-N 0.000 claims description 4
ITHXWJIJFAOUCC-BQBZGAKWSA-N (3r,4r)-1-propan-2-ylsulfonylpyrrolidine-3,4-dicarboxylic acid Chemical compound CC(C)S(=O)(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 ITHXWJIJFAOUCC-BQBZGAKWSA-N 0.000 claims description 4
MCPKNFPGHPYQBK-IMJSIDKUSA-N (3r,4r)-1-sulfamoylpyrrolidine-3,4-dicarboxylic acid Chemical compound NS(=O)(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 MCPKNFPGHPYQBK-IMJSIDKUSA-N 0.000 claims description 4
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
CFYNPNGXNLFANO-RFZPGFLSSA-N NC(=O)CN1C[C@@H](C(O)=O)[C@H](C(O)=O)C1 Chemical compound NC(=O)CN1C[C@@H](C(O)=O)[C@H](C(O)=O)C1 CFYNPNGXNLFANO-RFZPGFLSSA-N 0.000 claims description 4
125000003342 alkenyl group Chemical group 0.000 claims description 4
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
125000000068 chlorophenyl group Chemical group 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 4
125000002757 morpholinyl group Chemical group 0.000 claims description 4
125000003386 piperidinyl group Chemical group 0.000 claims description 4
125000001422 pyrrolinyl group Chemical group 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
KXLSZWWJSXCMSJ-WHFBIAKZSA-N (3r,4r)-1-(2,2,2-trifluoroethylsulfonyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound OC(=O)[C@H]1CN(S(=O)(=O)CC(F)(F)F)C[C@@H]1C(O)=O KXLSZWWJSXCMSJ-WHFBIAKZSA-N 0.000 claims description 3
YOWSBQUHCYBLMK-WDSKDSINSA-N (3r,4r)-1-(2-fluoroethyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound OC(=O)[C@H]1CN(CCF)C[C@@H]1C(O)=O YOWSBQUHCYBLMK-WDSKDSINSA-N 0.000 claims description 3
BKMROVXWJCKVND-YUMQZZPRSA-N (3r,4r)-1-(pyrrolidine-1-carbonyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound C1[C@H](C(O)=O)[C@@H](C(=O)O)CN1C(=O)N1CCCC1 BKMROVXWJCKVND-YUMQZZPRSA-N 0.000 claims description 3
ITRCERWAFLQAPZ-WDSKDSINSA-N (3r,4r)-1-acetylpyrrolidine-3,4-dicarboxylic acid Chemical compound CC(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 ITRCERWAFLQAPZ-WDSKDSINSA-N 0.000 claims description 3
HDGFMXHMUINWHS-WHFBIAKZSA-N (3r,4r)-1-formylpyrrolidine-3,4-dicarboxylic acid Chemical compound OC(=O)[C@H]1CN(C=O)C[C@@H]1C(O)=O HDGFMXHMUINWHS-WHFBIAKZSA-N 0.000 claims description 3
CQCUXFZSFNBZMP-BQBZGAKWSA-N (3r,4r)-1-propylsulfonylpyrrolidine-3,4-dicarboxylic acid Chemical compound CCCS(=O)(=O)N1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 CQCUXFZSFNBZMP-BQBZGAKWSA-N 0.000 claims description 3
125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 3
125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
WCVNMDMFUJJCOV-PHDIDXHHSA-N OC(=O)[C@@H]1CN(CCC(F)(F)F)C[C@H]1C(O)=O Chemical compound OC(=O)[C@@H]1CN(CCC(F)(F)F)C[C@H]1C(O)=O WCVNMDMFUJJCOV-PHDIDXHHSA-N 0.000 claims description 3
239000005864 Sulphur Substances 0.000 claims description 3
125000004429 atom Chemical group 0.000 claims description 3
125000002393 azetidinyl group Chemical group 0.000 claims description 3
125000002619 bicyclic group Chemical group 0.000 claims description 3
125000002883 imidazolyl group Chemical group 0.000 claims description 3
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
125000001786 isothiazolyl group Chemical group 0.000 claims description 3
125000000842 isoxazolyl group Chemical group 0.000 claims description 3
125000002950 monocyclic group Chemical group 0.000 claims description 3
125000001624 naphthyl group Chemical group 0.000 claims description 3
125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
125000002971 oxazolyl group Chemical group 0.000 claims description 3
125000004193 piperazinyl group Chemical group 0.000 claims description 3
125000003226 pyrazolyl group Chemical group 0.000 claims description 3
125000002098 pyridazinyl group Chemical group 0.000 claims description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
125000000168 pyrrolyl group Chemical group 0.000 claims description 3
239000011593 sulfur Substances 0.000 claims description 3
125000003831 tetrazolyl group Chemical group 0.000 claims description 3
125000000335 thiazolyl group Chemical group 0.000 claims description 3
125000001544 thienyl group Chemical group 0.000 claims description 3
125000001425 triazolyl group Chemical group 0.000 claims description 3
LITHIIBGISYOSX-WDSKDSINSA-N (3r,4r)-1-(2-hydroxyethyl)pyrrolidine-3,4-dicarboxylic acid Chemical compound OCCN1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 LITHIIBGISYOSX-WDSKDSINSA-N 0.000 claims description 2
ZQIVESXGUBDYJX-WDSKDSINSA-N (3r,4r)-1-[2-(methylamino)-2-oxoethyl]pyrrolidine-3,4-dicarboxylic acid Chemical compound CNC(=O)CN1C[C@H](C(O)=O)[C@@H](C(O)=O)C1 ZQIVESXGUBDYJX-WDSKDSINSA-N 0.000 claims description 2
ILAIIURYCZSHPA-RFZPGFLSSA-N (3s,4s)-1-methylsulfonylpyrrolidine-3,4-dicarboxylic acid Chemical compound CS(=O)(=O)N1C[C@@H](C(O)=O)[C@H](C(O)=O)C1 ILAIIURYCZSHPA-RFZPGFLSSA-N 0.000 claims description 2
125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 2
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 2
239000002671 adjuvant Substances 0.000 claims description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
239000008194 pharmaceutical composition Substances 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 8
125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
125000004448 alkyl carbonyl group Chemical group 0.000 claims 2
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 2
125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 99
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
239000011541 reaction mixture Substances 0.000 description 42
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
239000000243 solution Substances 0.000 description 32
238000006243 chemical reaction Methods 0.000 description 30
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
229940093499 ethyl acetate Drugs 0.000 description 17
235000019439 ethyl acetate Nutrition 0.000 description 17
239000012074 organic phase Substances 0.000 description 17
239000011734 sodium Substances 0.000 description 17
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
239000002904 solvent Substances 0.000 description 15
238000002953 preparative HPLC Methods 0.000 description 14
239000007787 solid Substances 0.000 description 14
125000004356 hydroxy functional group Chemical group O* 0.000 description 13
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
239000003112 inhibitor Substances 0.000 description 12
238000003756 stirring Methods 0.000 description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
238000007127 saponification reaction Methods 0.000 description 11
150000001412 amines Chemical class 0.000 description 10
239000012267 brine Substances 0.000 description 10
239000012876 carrier material Substances 0.000 description 10
238000010898 silica gel chromatography Methods 0.000 description 10
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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239000012043 crude product Substances 0.000 description 9
239000003153 chemical reaction reagent Substances 0.000 description 8
HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 8
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SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
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239000000706 filtrate Substances 0.000 description 7
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FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 7
KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 6
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239000000758 substrate Substances 0.000 description 6
VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
238000005160 1H NMR spectroscopy Methods 0.000 description 5
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
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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 1
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Classifications

- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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ZA200607606A 2004-03-26 2006-09-11 Novel pyrrolidine-3, 4-dicarboxamide derivatives ZA200607606B (en)

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Application Number	Priority Date	Filing Date	Title
EP04101265		2004-03-26

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Publication Number	Publication Date
ZA200607606B true ZA200607606B (en)	2008-05-28

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ZA200607606A ZA200607606B (en)	2004-03-26	2006-09-11	Novel pyrrolidine-3, 4-dicarboxamide derivatives

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US (1)	US7550487B2 (ko)
EP (1)	EP1732918B1 (ko)
JP (1)	JP4533428B2 (ko)
KR (1)	KR100847191B1 (ko)
CN (1)	CN1938294B (ko)
AR (1)	AR048589A1 (ko)
AT (1)	ATE414075T1 (ko)
AU (2)	AU2005225523B2 (ko)
BR (1)	BRPI0509256B1 (ko)
CA (1)	CA2560669C (ko)
DE (1)	DE602005010986D1 (ko)
DK (1)	DK1732918T3 (ko)
ES (1)	ES2314632T3 (ko)
HK (1)	HK1101856A1 (ko)
HR (1)	HRP20090050T3 (ko)
IL (1)	IL177662A (ko)
MX (1)	MXPA06010827A (ko)
MY (1)	MY144101A (ko)
NO (1)	NO338531B1 (ko)
NZ (1)	NZ549395A (ko)
PL (1)	PL1732918T3 (ko)
PT (1)	PT1732918E (ko)
RU (1)	RU2379288C2 (ko)
SI (1)	SI1732918T1 (ko)
TW (1)	TWI295290B (ko)
WO (1)	WO2005092881A1 (ko)
ZA (1)	ZA200607606B (ko)

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MX2007005113A (es)	2004-11-03	2007-06-26	Hoffmann La Roche	Nuevos derivados de dicarboxamida.
US20110144271A1 (en)	2005-06-16	2011-06-16	Jsr Corporation	Radioactive ray-curable liquid resin composition for use in optical stereolithography, and optically shaped article produced by curing the composition
WO2007053610A2 (en) *	2005-11-01	2007-05-10	The Regents Of The University Of California	Methods of treating atrial fibrillation wtih pirfenidone
EP2097401A1 (en) *	2006-12-22	2009-09-09	F. Hoffmann-Roche AG	Processes for the preparation of (3r, 4r) -n- (4 -chlorophenyl) -1- (2, 2-difluoroethyl) -n' - [2-fluoro-4- (2-oxo-1 (2h) -pyridinyl) phenyl]-3, 4-pyrrolidinedicarboxamide
EP2155723A2 (en) *	2007-05-10	2010-02-24	F. Hoffmann-Roche AG	New solid forms of fxa inhibitors
US8354444B2 (en) *	2008-09-18	2013-01-15	Hoffmann-La Roche Inc.	Substituted pyrrolidine-2-carboxamides
US20110152233A1 (en) *	2009-12-18	2011-06-23	Henner Knust	Pyrrolidine compounds
WO2012109996A1 (zh)	2011-02-18	2012-08-23	上海璎黎科技有限公司	一种芳基糖苷类化合物及其制备方法和应用
EP4171547A1 (en) *	2020-05-27	2023-05-03	Axial Therapeutics, Inc.	Tlr2 modulator compounds, pharmaceutical compositions and uses thereof

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JP2002518368A (ja) *	1998-06-17	2002-06-25	デュポンファーマシューティカルズカンパニー	メタロプロテイナーゼ阻害剤としての環式ヒドロキサム酸類
CA2382751A1 (en) *	1999-05-24	2000-11-30	Cor Therapeutics, Inc.	Inhibitors of factor xa
AU2001288819A1 (en)	2000-09-11	2002-03-26	Genentech, Inc.	Amidine inhibitors of serine proteases
US7030141B2 (en) *	2001-11-29	2006-04-18	Christopher Franklin Bigge	Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
US7205318B2 (en) *	2003-03-18	2007-04-17	Bristol-Myers Squibb Company	Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors
MX2007005113A (es)	2004-11-03	2007-06-26	Hoffmann La Roche	Nuevos derivados de dicarboxamida.
US7361672B2 (en)	2004-12-23	2008-04-22	Hoffmann-La Roche Inc.	Heteroarylacetamide inhibitors of factor Xa
US7820699B2 (en)	2005-04-27	2010-10-26	Hoffmann-La Roche Inc.	Cyclic amines
EP1907388A1 (en)	2005-07-15	2008-04-09	F. Hoffmann-Roche AG	Novel heteroaryl fused cyclic amines
US7678917B2 (en)	2005-09-01	2010-03-16	Hoffman-La Roche Inc.	Factor Xa inhibitors
WO2007054453A2 (en)	2005-11-11	2007-05-18	F. Hoffmann-La Roche Ag	Carbocyclic fused cyclic amines as inhibitors of the coagulation factor xa
WO2007057317A1 (en)	2005-11-16	2007-05-24	F. Hoffmann-La Roche Ag	Novel pyrrolidine derivatives as inhibitors of coagulation factor xa
EP1847537A1 (en)	2006-04-21	2007-10-24	F. Hoffmann-La Roche Ag	Dicarboxamide derivatives

2005
- 2005-03-09 US US11/076,162 patent/US7550487B2/en not_active Expired - Fee Related
- 2005-03-17 MX MXPA06010827A patent/MXPA06010827A/es active IP Right Grant
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- 2005-03-17 CA CA2560669A patent/CA2560669C/en not_active Expired - Fee Related
- 2005-03-17 DE DE602005010986T patent/DE602005010986D1/de active Active
- 2005-03-17 RU RU2006137661/04A patent/RU2379288C2/ru not_active IP Right Cessation
- 2005-03-17 EP EP05716166A patent/EP1732918B1/en active Active
- 2005-03-17 BR BRPI0509256-6A patent/BRPI0509256B1/pt not_active IP Right Cessation
- 2005-03-17 NZ NZ549395A patent/NZ549395A/en not_active IP Right Cessation
- 2005-03-17 CN CN2005800098333A patent/CN1938294B/zh not_active Expired - Fee Related
- 2005-03-17 PL PL05716166T patent/PL1732918T3/pl unknown
- 2005-03-17 WO PCT/EP2005/002862 patent/WO2005092881A1/en active Application Filing
- 2005-03-17 AU AU2005225523A patent/AU2005225523B2/en not_active Ceased
- 2005-03-17 DK DK05716166T patent/DK1732918T3/da active
- 2005-03-17 ES ES05716166T patent/ES2314632T3/es active Active
- 2005-03-17 PT PT05716166T patent/PT1732918E/pt unknown
- 2005-03-17 JP JP2007504314A patent/JP4533428B2/ja not_active Expired - Fee Related
- 2005-03-17 KR KR1020067019740A patent/KR100847191B1/ko active IP Right Grant
- 2005-03-17 AT AT05716166T patent/ATE414075T1/de active
- 2005-03-22 TW TW094108790A patent/TWI295290B/zh not_active IP Right Cessation
- 2005-03-23 AR ARP050101146A patent/AR048589A1/es not_active Application Discontinuation
- 2005-03-24 MY MYPI20051293A patent/MY144101A/en unknown
2006
- 2006-08-23 IL IL177662A patent/IL177662A/en active IP Right Grant
- 2006-09-11 ZA ZA200607606A patent/ZA200607606B/en unknown
- 2006-10-24 NO NO20064821A patent/NO338531B1/no not_active IP Right Cessation
2007
- 2007-09-03 HK HK07109535.6A patent/HK1101856A1/xx not_active IP Right Cessation
2009
- 2009-01-27 HR HR20090050T patent/HRP20090050T3/xx unknown
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Also Published As

Publication number	Publication date
DK1732918T3 (da)	2009-01-12
NO338531B1 (no)	2016-08-29
KR20060124781A (ko)	2006-12-05
HRP20090050T3 (en)	2009-03-31
AR048589A1 (es)	2006-05-10
IL177662A (en)	2011-11-30
NO20064821L (no)	2006-10-24
MXPA06010827A (es)	2006-12-15
AU2012200212A1 (en)	2012-02-02
ATE414075T1 (de)	2008-11-15
MY144101A (en)	2011-08-15
AU2005225523B2 (en)	2011-10-13
RU2379288C2 (ru)	2010-01-20
BRPI0509256A (pt)	2007-09-11
CN1938294B (zh)	2012-09-26
JP2007530479A (ja)	2007-11-01
TWI295290B (en)	2008-04-01
TW200534849A (en)	2005-11-01
EP1732918A1 (en)	2006-12-20
PT1732918E (pt)	2009-01-08
AU2012200212A8 (en)	2012-02-16
SI1732918T1 (sl)	2009-02-28
AU2005225523A1 (en)	2005-10-06
IL177662A0 (en)	2006-12-31
CA2560669C (en)	2012-09-18
NZ549395A (en)	2010-07-30
EP1732918B1 (en)	2008-11-12
JP4533428B2 (ja)	2010-09-01
BRPI0509256B1 (pt)	2019-02-12
DE602005010986D1 (de)	2008-12-24
PL1732918T3 (pl)	2009-04-30
US7550487B2 (en)	2009-06-23
KR100847191B1 (ko)	2008-07-17
CN1938294A (zh)	2007-03-28
HK1101856A1 (en)	2007-10-26
ES2314632T3 (es)	2009-03-16
WO2005092881A1 (en)	2005-10-06
RU2006137661A (ru)	2008-05-10
CA2560669A1 (en)	2005-10-06
US20050215599A1 (en)	2005-09-29

Publication	Publication Date	Title
US7550487B2 (en)	2009-06-23	Pyrrolidine-3,4-dicarboxamide derivatives
KR100933231B1 (ko)	2009-12-22	새로운 환식 아민
AU2001277754B2 (en)	2005-09-29	Proline derivatives and use thereof as drugs
EP1720844B1 (de)	2009-04-29	Pyrrolidin-1,2-dicarbonsäure-1-(phenylamid)-2-(4-(3-oxo-morpholin-4-yl)-phenylamid) derivate und verwandte verbindungen als inhibitoren des koagulationsfaktors xa zur behandlung von thromboembolischen erkrankungen
WO2006032342A2 (de)	2006-03-30	Arzneimittel enthaltend carbonylverbindungen sowie deren verwendung
US20050148637A1 (en)	2005-07-07	Heterocyclic ketone and thioester compounds and uses
MXPA05010445A (es)	2005-11-04	Derivados de azaprolina.
KR20160064100A (ko)	2016-06-07	치환된 페닐알라닌 유도체
DE10315377A1 (de)	2004-10-14	Carbonylverbindungen
KR20070054807A (ko)	2007-05-30	Ｄｐｐ－ⅳ 저해 활성을 갖는 베타 아미노기를 포함하는헤테로사이클 화합물, 이의 제조방법, 및 이를유효성분으로 함유하는 약학적 조성물
AU2005289184A1 (en)	2006-04-06	Proline derivatives
KR19990015206A (ko)	1999-03-05	선택적 트롬빈 억제활성을 갖는 치환된 방향족 유도체
DE10329295A1 (de)	2005-02-03	Carbonylverbindungen