CA2653665A1 - Derives d'isoindoline-1-one, d'isoindoline-3-one et d'isoindoline-1,3- dione et leur utilisation - Google Patents

Derives d'isoindoline-1-one, d'isoindoline-3-one et d'isoindoline-1,3- dione et leur utilisation Download PDF

Info

Publication number: CA2653665A1
Authority: CA; Canada
Prior art keywords: substituent; represents hydrogen; group; methyl; alkyl
Prior art date: 2006-05-31
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.): Abandoned

Application number

CA002653665A

Other languages

English (en)

Inventor

Susanne Roehrig

Michael Haerter

Mario Jeske

Elisabeth Perzborn

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.)

Bayer Pharma AG

Original Assignee

Individual

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.)

2006-05-31

Filing date

2007-05-25

Publication date

2007-12-06

2007-05-25 Application filed by Individual filed Critical Individual

2007-12-06 Publication of CA2653665A1 publication Critical patent/CA2653665A1/fr

Status Abandoned legal-status Critical Current

Links

PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title abstract description 6
238000000034 method Methods 0.000 claims abstract description 128
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
239000003814 drug Substances 0.000 claims abstract description 22
201000010099 disease Diseases 0.000 claims abstract description 7
238000004519 manufacturing process Methods 0.000 claims abstract description 5
150000001875 compounds Chemical class 0.000 claims description 217
-1 hydroxy, amino Chemical group 0.000 claims description 167
229910052739 hydrogen Inorganic materials 0.000 claims description 129
239000001257 hydrogen Substances 0.000 claims description 129
125000001424 substituent group Chemical group 0.000 claims description 93
229910052799 carbon Inorganic materials 0.000 claims description 61
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 61
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 56
239000011737 fluorine Chemical group 0.000 claims description 52
229910052731 fluorine Inorganic materials 0.000 claims description 52
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 47
239000000460 chlorine Chemical group 0.000 claims description 44
229910052801 chlorine Inorganic materials 0.000 claims description 41
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 37
150000003839 salts Chemical class 0.000 claims description 36
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 32
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 29
125000000217 alkyl group Chemical group 0.000 claims description 29
125000004432 carbon atom Chemical group C* 0.000 claims description 29
229910052757 nitrogen Inorganic materials 0.000 claims description 29
239000012453 solvate Substances 0.000 claims description 29
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 27
125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical group C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 19
238000011321 prophylaxis Methods 0.000 claims description 18
238000011282 treatment Methods 0.000 claims description 18
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
230000009424 thromboembolic effect Effects 0.000 claims description 16
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 15
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 12
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
125000004093 cyano group Chemical group *C#N 0.000 claims description 11
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 10
125000003282 alkyl amino group Chemical group 0.000 claims description 10
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
125000004043 oxo group Chemical group O=* 0.000 claims description 10
125000003386 piperidinyl group Chemical group 0.000 claims description 10
125000000623 heterocyclic group Chemical group 0.000 claims description 9
125000004193 piperazinyl group Chemical group 0.000 claims description 9
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
230000023555 blood coagulation Effects 0.000 claims description 8
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
230000002429 anti-coagulating effect Effects 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
SYGWYBOJXOGMRU-UHFFFAOYSA-N chembl233051 Chemical compound C1=CC=C2C3=CC(C(N(CCN(C)C)C4=O)=O)=C5C4=CC=CC5=C3SC2=C1 SYGWYBOJXOGMRU-UHFFFAOYSA-N 0.000 claims description 5
125000001153 fluoro group Chemical group F* 0.000 claims description 5
238000000338 in vitro Methods 0.000 claims description 5
125000002757 morpholinyl group Chemical group 0.000 claims description 5
125000003373 pyrazinyl group Chemical group 0.000 claims description 5
125000002098 pyridazinyl group Chemical group 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
125000001544 thienyl group Chemical group 0.000 claims description 5
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
125000001309 chloro group Chemical group Cl* 0.000 claims description 4
125000006317 cyclopropyl amino group Chemical group 0.000 claims description 4
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
229910052736 halogen Inorganic materials 0.000 claims description 4
150000002367 halogens Chemical group 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
241001465754 Metazoa Species 0.000 claims description 3
NFGODEMQGQNUKK-UHFFFAOYSA-M [6-(diethylamino)-9-(2-octadecoxycarbonylphenyl)xanthen-3-ylidene]-diethylazanium;chloride Chemical group [Cl-].CCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C21 NFGODEMQGQNUKK-UHFFFAOYSA-M 0.000 claims description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
229910052794 bromium Inorganic materials 0.000 claims description 3
125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 3
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
231100000252 nontoxic Toxicity 0.000 claims description 3
230000003000 nontoxic effect Effects 0.000 claims description 3
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 2
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical compound C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 claims 2
208000001435 Thromboembolism Diseases 0.000 abstract description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 171
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 100
239000000243 solution Substances 0.000 description 75
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
239000000203 mixture Substances 0.000 description 64
150000002431 hydrogen Chemical class 0.000 description 58
238000005160 1H NMR spectroscopy Methods 0.000 description 54
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
238000004128 high performance liquid chromatography Methods 0.000 description 42
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 40
239000012071 phase Substances 0.000 description 40
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 38
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
239000011541 reaction mixture Substances 0.000 description 36
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
150000001721 carbon Chemical group 0.000 description 35
230000008569 process Effects 0.000 description 35
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
238000012360 testing method Methods 0.000 description 31
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
239000002904 solvent Substances 0.000 description 28
238000006243 chemical reaction Methods 0.000 description 27
239000000126 substance Substances 0.000 description 26
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
108010074860 Factor Xa Proteins 0.000 description 21
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 20
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
239000002585 base Substances 0.000 description 20
208000035475 disorder Diseases 0.000 description 20
235000019253 formic acid Nutrition 0.000 description 20
238000002360 preparation method Methods 0.000 description 20
239000000725 suspension Substances 0.000 description 19
239000012442 inert solvent Substances 0.000 description 17
238000010992 reflux Methods 0.000 description 17
DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
229910052938 sodium sulfate Inorganic materials 0.000 description 16
235000011152 sodium sulphate Nutrition 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
229910052786 argon Inorganic materials 0.000 description 15
238000007429 general method Methods 0.000 description 14
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 14
238000000825 ultraviolet detection Methods 0.000 description 14
239000008346 aqueous phase Substances 0.000 description 13
239000000047 product Substances 0.000 description 13
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
229910000069 nitrogen hydride Inorganic materials 0.000 description 12
239000012074 organic phase Substances 0.000 description 12
229920006395 saturated elastomer Polymers 0.000 description 12
239000000706 filtrate Substances 0.000 description 11
VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 11
238000005191 phase separation Methods 0.000 description 11
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
239000003146 anticoagulant agent Substances 0.000 description 10
238000001914 filtration Methods 0.000 description 10
229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
235000017557 sodium bicarbonate Nutrition 0.000 description 10
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 10
RYKLZUPYJFFNRR-UHFFFAOYSA-N 3-hydroxypiperidin-2-one Chemical compound OC1CCCNC1=O RYKLZUPYJFFNRR-UHFFFAOYSA-N 0.000 description 9
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
150000003254 radicals Chemical class 0.000 description 9
239000012488 sample solution Substances 0.000 description 9
239000007858 starting material Substances 0.000 description 9
239000003826 tablet Substances 0.000 description 9
230000015572 biosynthetic process Effects 0.000 description 8
229960001760 dimethyl sulfoxide Drugs 0.000 description 8
229940079593 drug Drugs 0.000 description 8
239000000284 extract Substances 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 8
229940012957 plasmin Drugs 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
239000000741 silica gel Substances 0.000 description 8
229910002027 silica gel Inorganic materials 0.000 description 8
NWTHBLDDUCVEIQ-UHFFFAOYSA-N 5-chloro-n-[2-[(3-iodo-4-methoxyphenyl)methyl]-1-oxo-3h-isoindol-4-yl]thiophene-2-carboxamide Chemical compound C1=C(I)C(OC)=CC=C1CN1C(=O)C(C=CC=C2NC(=O)C=3SC(Cl)=CC=3)=C2C1 NWTHBLDDUCVEIQ-UHFFFAOYSA-N 0.000 description 7
REKMIVPELXYBIS-UHFFFAOYSA-N 5-chloro-n-[2-[(3-iodophenyl)methyl]-1-oxo-3h-isoindol-4-yl]thiophene-2-carboxamide Chemical compound S1C(Cl)=CC=C1C(=O)NC1=CC=CC2=C1CN(CC=1C=C(I)C=CC=1)C2=O REKMIVPELXYBIS-UHFFFAOYSA-N 0.000 description 7
GAPGSKGSLQRAAB-UHFFFAOYSA-N 5-chloro-n-[2-[(4-iodophenyl)methyl]-3-oxo-1h-isoindol-4-yl]thiophene-2-carboxamide Chemical compound S1C(Cl)=CC=C1C(=O)NC1=CC=CC2=C1C(=O)N(CC=1C=CC(I)=CC=1)C2 GAPGSKGSLQRAAB-UHFFFAOYSA-N 0.000 description 7
LDMKUFMAMHAXFE-UHFFFAOYSA-N 7-amino-2-[(3-iodophenyl)methyl]-3h-isoindol-1-one Chemical compound O=C1C=2C(N)=CC=CC=2CN1CC1=CC=CC(I)=C1 LDMKUFMAMHAXFE-UHFFFAOYSA-N 0.000 description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
108090000631 Trypsin Proteins 0.000 description 7
102000004142 Trypsin Human genes 0.000 description 7
239000012482 calibration solution Substances 0.000 description 7
238000001816 cooling Methods 0.000 description 7
239000012043 crude product Substances 0.000 description 7
239000003112 inhibitor Substances 0.000 description 7
238000002953 preparative HPLC Methods 0.000 description 7
239000012279 sodium borohydride Substances 0.000 description 7
229910000033 sodium borohydride Inorganic materials 0.000 description 7
239000012588 trypsin Substances 0.000 description 7
GEOHZCICFMRUJO-UHFFFAOYSA-N 5-chloro-n-[2-[(3-iodophenyl)methyl]-1,3-dioxoisoindol-4-yl]thiophene-2-carboxamide Chemical compound S1C(Cl)=CC=C1C(=O)NC1=CC=CC2=C1C(=O)N(CC=1C=C(I)C=CC=1)C2=O GEOHZCICFMRUJO-UHFFFAOYSA-N 0.000 description 6
GXLXJHIFJFLJPF-UHFFFAOYSA-N 5-chloro-n-[2-[(4-iodophenyl)methyl]-1-oxo-3h-isoindol-4-yl]thiophene-2-carboxamide Chemical compound S1C(Cl)=CC=C1C(=O)NC1=CC=CC2=C1CN(CC=1C=CC(I)=CC=1)C2=O GXLXJHIFJFLJPF-UHFFFAOYSA-N 0.000 description 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
229910021595 Copper(I) iodide Inorganic materials 0.000 description 6
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
102000012479 Serine Proteases Human genes 0.000 description 6
108010022999 Serine Proteases Proteins 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
229940127219 anticoagulant drug Drugs 0.000 description 6
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
210000004369 blood Anatomy 0.000 description 6
239000008280 blood Substances 0.000 description 6
LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 6
229960002897 heparin Drugs 0.000 description 6
229920000669 heparin Polymers 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
235000019341 magnesium sulphate Nutrition 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
QSBFHJUTZMGUTD-UHFFFAOYSA-N 5-chloro-n-[2-[(3-iodo-4-methoxyphenyl)methyl]-3-oxo-1h-isoindol-4-yl]thiophene-2-carboxamide Chemical compound C1=C(I)C(OC)=CC=C1CN1C(=O)C2=C(NC(=O)C=3SC(Cl)=CC=3)C=CC=C2C1 QSBFHJUTZMGUTD-UHFFFAOYSA-N 0.000 description 5
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
229940123583 Factor Xa inhibitor Drugs 0.000 description 5
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
208000007536 Thrombosis Diseases 0.000 description 5
239000008351 acetate buffer Substances 0.000 description 5
239000000872 buffer Substances 0.000 description 5
229960001701 chloroform Drugs 0.000 description 5
230000015271 coagulation Effects 0.000 description 5
238000005345 coagulation Methods 0.000 description 5
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125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
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CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical class C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
125000000842 isoxazolyl group Chemical group 0.000 description 1
210000004731 jugular vein Anatomy 0.000 description 1
VCMGMSHEPQENPE-UHFFFAOYSA-N ketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1C1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-UHFFFAOYSA-N 0.000 description 1
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239000004310 lactic acid Chemical class 0.000 description 1
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VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Chemical class 0.000 description 1
239000001630 malic acid Chemical class 0.000 description 1
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239000007923 nasal drop Substances 0.000 description 1
229940100662 nasal drops Drugs 0.000 description 1
229920005615 natural polymer Polymers 0.000 description 1
229960003966 nicotinamide Drugs 0.000 description 1
235000005152 nicotinamide Nutrition 0.000 description 1
239000011570 nicotinamide Substances 0.000 description 1
DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
239000003921 oil Substances 0.000 description 1
239000002674 ointment Substances 0.000 description 1
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229940127216 oral anticoagulant drug Drugs 0.000 description 1
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239000001301 oxygen Substances 0.000 description 1
239000006072 paste Substances 0.000 description 1
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230000002085 persistent effect Effects 0.000 description 1
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239000000825 pharmaceutical preparation Substances 0.000 description 1
RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 0.000 description 1
229960004923 phenprocoumon Drugs 0.000 description 1
DQDAYGNAKTZFIW-UHFFFAOYSA-N phenprocoumon Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC)C1=CC=CC=C1 DQDAYGNAKTZFIW-UHFFFAOYSA-N 0.000 description 1
SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
229940127126 plasminogen activator Drugs 0.000 description 1
239000002797 plasminogen activator inhibitor Substances 0.000 description 1
239000000106 platelet aggregation inhibitor Substances 0.000 description 1
229920000573 polyethylene Polymers 0.000 description 1
229940068918 polyethylene glycol 400 Drugs 0.000 description 1
229920002223 polystyrene Polymers 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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239000002243 precursor Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
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125000000168 pyrrolyl group Chemical group 0.000 description 1
238000011002 quantification Methods 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
230000004044 response Effects 0.000 description 1
229940069575 rompun Drugs 0.000 description 1
102220254284 rs755928199 Human genes 0.000 description 1
238000000926 separation method Methods 0.000 description 1
150000003354 serine derivatives Chemical class 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000007787 solid Substances 0.000 description 1
238000007921 solubility assay Methods 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000007940 sugar coated tablet Substances 0.000 description 1
229910021653 sulphate ion Inorganic materials 0.000 description 1
239000001117 sulphuric acid Chemical class 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
239000000829 suppository Substances 0.000 description 1
238000011477 surgical intervention Methods 0.000 description 1
230000008961 swelling Effects 0.000 description 1
229920001059 synthetic polymer Polymers 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
239000011975 tartaric acid Chemical class 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-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
DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
231100001274 therapeutic index Toxicity 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
206010043554 thrombocytopenia Diseases 0.000 description 1
230000002885 thrombogenetic effect Effects 0.000 description 1
229960000103 thrombolytic agent Drugs 0.000 description 1
201000005665 thrombophilia Diseases 0.000 description 1
230000001732 thrombotic effect Effects 0.000 description 1
HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
239000010936 titanium Substances 0.000 description 1
YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
230000001960 triggered effect Effects 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
229940124549 vasodilator Drugs 0.000 description 1
239000003071 vasodilator agent Substances 0.000 description 1
208000004043 venous thromboembolism Diseases 0.000 description 1
238000013022 venting Methods 0.000 description 1
235000019168 vitamin K Nutrition 0.000 description 1
239000011712 vitamin K Substances 0.000 description 1
150000003721 vitamin K derivatives Chemical class 0.000 description 1
229940046010 vitamin k Drugs 0.000 description 1
229940019333 vitamin k antagonists Drugs 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000000230 xanthan gum Substances 0.000 description 1
229920001285 xanthan gum Polymers 0.000 description 1
235000010493 xanthan gum Nutrition 0.000 description 1
229940082509 xanthan gum Drugs 0.000 description 1
QYEFBJRXKKSABU-UHFFFAOYSA-N xylazine hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NC1=NCCCS1 QYEFBJRXKKSABU-UHFFFAOYSA-N 0.000 description 1
239000008096 xylene Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
- 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

Landscapes

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

CA002653665A 2006-05-31 2007-05-25 Derives d'isoindoline-1-one, d'isoindoline-3-one et d'isoindoline-1,3- dione et leur utilisation Abandoned CA2653665A1 (fr)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
DE102006025316A DE102006025316A1 (de)	2006-05-31	2006-05-31	Isoindolin-1-on-, Isoindolin-3-on- und Isoindolin-1,3-dion-Derivate und ihre Verwendung
DE102006025316.7		2006-05-31
PCT/EP2007/004692 WO2007137790A1 (fr)	2006-05-31	2007-05-25	Dérivés d'isoindolin-1-one, d'isoindolin-3-one et d'isoindolin-1,3-dione et leur utilisation

Publications (1)

Publication Number	Publication Date
CA2653665A1 true CA2653665A1 (fr)	2007-12-06

Family

ID=38626434

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002653665A Abandoned CA2653665A1 (fr)	2006-05-31	2007-05-25	Derives d'isoindoline-1-one, d'isoindoline-3-one et d'isoindoline-1,3- dione et leur utilisation

Country Status (5)

Country	Link
EP (1)	EP2029582A1 (fr)
JP (1)	JP2009538845A (fr)
CA (1)	CA2653665A1 (fr)
DE (1)	DE102006025316A1 (fr)
WO (1)	WO2007137790A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP3078378B1 (fr)	2015-04-08	2020-06-24	Vaiomer	Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
MD3762368T2 (ro)	2018-03-08	2022-07-31	Incyte Corp	Compuși diol aminopirazină ca inhibitori ai PI3K-Y
US11046658B2 (en)	2018-07-02	2021-06-29	Incyte Corporation	Aminopyrazine derivatives as PI3K-γ inhibitors

2006
- 2006-05-31 DE DE102006025316A patent/DE102006025316A1/de not_active Withdrawn
2007
- 2007-05-25 JP JP2009512471A patent/JP2009538845A/ja active Pending
- 2007-05-25 CA CA002653665A patent/CA2653665A1/fr not_active Abandoned
- 2007-05-25 WO PCT/EP2007/004692 patent/WO2007137790A1/fr not_active Ceased
- 2007-05-25 EP EP07725588A patent/EP2029582A1/fr not_active Withdrawn

Also Published As

Publication number	Publication date
DE102006025316A1 (de)	2007-12-06
EP2029582A1 (fr)	2009-03-04
JP2009538845A (ja)	2009-11-12
WO2007137790A1 (fr)	2007-12-06

Legal Events

Date	Code	Title	Description
2011-05-25	FZDE	Dead

Publication	Publication Date	Title
JP4598771B2 (ja)	2010-12-15	複素環式化合物
CA2623294C (fr)	2014-05-06	Derives d'acide 2-aminoethoxyacetique et leur utilisation
CA2692178A1 (fr)	2008-12-24	Oxazolidinones substituees et leur utilisation
CA2653666C (fr)	2014-09-16	Heterocycles substitues par un aryle et leur utilisation
CA2653672A1 (fr)	2007-12-06	Derives de dihydro-pyrrolopyridine, de dihydro-pyrrolopyridazine et de dihydro-pyrrolopyrimidine et leur utilisation
US20100048611A1 (en)	2010-02-25	Tetrahydropyrrolopyridine, tetrahydropyrazolopyridine, tetrahydro-imidazopyridine and tetrahydrotriazolopyridine derivatives and use thereof
JP2009538845A (ja)	2009-11-12	イソインドリン−１−オン、イソインドリン−３−オンおよびイソインドリン−１，３−ジオン誘導体ならびにそれらの使用
CA2653673A1 (fr)	2007-12-06	Derives d'isoindolin-1-one, d'isoindolin-3-one et d' isoindoline-1,3-dione et leur utilisation
JP2009507055A (ja)	2009-02-19	イミノオキサゾリジン誘導体およびその使用
CA2589740A1 (fr)	2006-06-08	Iminocarbamates cycliques et leur utilisation
CA2653670A1 (fr)	2007-12-06	Heterocycles substitues et son utilisation
CA2594102A1 (fr)	2006-06-15	Amides d'acide dicarboxylique de pyrazine et leur utilisation
CA2627759A1 (fr)	2007-05-10	Derives de phenylene-bis-oxazolidine et leur utilisation en tant qu'anticoagulant
CA2605492A1 (fr)	2006-10-26	Imino-oxazolidines et leur utilisation
CZ2000293A3 (cs)	2000-06-14	Heterocyklické deriváty, které inhibují faktor Xa