HRP990396A2 - NITROGEN CONTAINING HETEROBICYCLES AS FACTOR Xa INHIBITORS - Google Patents

NITROGEN CONTAINING HETEROBICYCLES AS FACTOR Xa INHIBITORS

Info

Publication number: HRP990396A2
Authority: HR; Croatia
Prior art keywords: biphen; alkyl; trifluoromethyl; dihydropyrazolo; methyl
Prior art date: 1998-12-23

Application number

HR990396A

Other languages

English (en)

Croatian (hr)

Inventor

John Matthew Fevig

Joseph Cacciola

Charles G Clark

Lam Patrick Yuk-Sun

Donald Joseph Phillip Pinto

James Russell Pruitt

Karen Anita Rossi

Original Assignee

Du Pont Pharm Co

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.)

1998-12-23

Filing date

1999-12-21

Publication date

2000-08-31

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26811284&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HRP990396(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1999-12-21 Application filed by Du Pont Pharm Co filed Critical Du Pont Pharm Co

2000-08-31 Publication of HRP990396A2 publication Critical patent/HRP990396A2/hr

Links

229910052757 nitrogen Inorganic materials 0.000 title claims description 71
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title description 26
229940123583 Factor Xa inhibitor Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims description 261
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 164
-1 methylenedioxy Chemical group 0.000 claims description 153
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 86
229910052760 oxygen Inorganic materials 0.000 claims description 71
229910052717 sulfur Inorganic materials 0.000 claims description 71
238000000034 method Methods 0.000 claims description 61
125000005842 heteroatom Chemical group 0.000 claims description 57
150000003839 salts Chemical class 0.000 claims description 55
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 50
229910052799 carbon Inorganic materials 0.000 claims description 49
102100022631 Glutamate receptor ionotropic, NMDA 2C Human genes 0.000 claims description 48
108091008646 testicular receptors Proteins 0.000 claims description 48
229920006395 saturated elastomer Polymers 0.000 claims description 41
125000000623 heterocyclic group Chemical group 0.000 claims description 38
108020002076 NR2 subfamily Proteins 0.000 claims description 36
125000000217 alkyl group Chemical group 0.000 claims description 36
125000002837 carbocyclic group Chemical group 0.000 claims description 33
229910052739 hydrogen Inorganic materials 0.000 claims description 33
229910052794 bromium Inorganic materials 0.000 claims description 30
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 28
229910052731 fluorine Inorganic materials 0.000 claims description 28
229910052740 iodine Inorganic materials 0.000 claims description 28
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 28
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 26
229910052801 chlorine Inorganic materials 0.000 claims description 25
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
125000004076 pyridyl group Chemical group 0.000 claims description 20
125000000714 pyrimidinyl group Chemical group 0.000 claims description 20
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 19
125000004429 atom Chemical group 0.000 claims description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 16
125000003118 aryl group Chemical group 0.000 claims description 15
125000002541 furyl group Chemical group 0.000 claims description 14
125000003226 pyrazolyl group Chemical group 0.000 claims description 14
108020004021 3-ketosteroid receptors Proteins 0.000 claims description 12
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
125000002883 imidazolyl group Chemical group 0.000 claims description 11
125000000842 isoxazolyl group Chemical group 0.000 claims description 10
125000001544 thienyl group Chemical group 0.000 claims description 10
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 9
125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 9
125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 9
125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 9
125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 9
125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 9
125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims description 9
125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 9
125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 9
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
125000001041 indolyl group Chemical group 0.000 claims description 9
125000005438 isoindazolyl group Chemical group 0.000 claims description 9
125000001786 isothiazolyl group Chemical group 0.000 claims description 9
125000002757 morpholinyl group Chemical group 0.000 claims description 9
125000001715 oxadiazolyl group Chemical group 0.000 claims description 9
125000002971 oxazolyl group Chemical group 0.000 claims description 9
125000004193 piperazinyl group Chemical group 0.000 claims description 9
125000003386 piperidinyl group Chemical group 0.000 claims description 9
125000003373 pyrazinyl group Chemical group 0.000 claims description 9
125000002098 pyridazinyl group Chemical group 0.000 claims description 9
125000000168 pyrrolyl group Chemical group 0.000 claims description 9
125000000335 thiazolyl group Chemical group 0.000 claims description 9
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 8
125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 8
108020000002 NR3 subfamily Proteins 0.000 claims description 8
125000002947 alkylene group Chemical group 0.000 claims description 8
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
230000009424 thromboembolic effect Effects 0.000 claims description 8
125000001425 triazolyl group Chemical group 0.000 claims description 8
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
229910052727 yttrium Inorganic materials 0.000 claims description 8
125000005843 halogen group Chemical group 0.000 claims description 7
125000004430 oxygen atom Chemical group O* 0.000 claims description 7
125000004434 sulfur atom Chemical group 0.000 claims description 7
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 5
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 5
125000004104 aryloxy group Chemical group 0.000 claims description 5
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 4
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
229940079593 drug Drugs 0.000 claims description 4
125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 4
125000003971 isoxazolinyl group Chemical group 0.000 claims description 4
239000003937 drug carrier Substances 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
239000000825 pharmaceutical preparation Substances 0.000 claims description 3
ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 2
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
230000002265 prevention Effects 0.000 claims description 2
125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 claims description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 366
239000000243 solution Substances 0.000 description 212
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 203
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 200
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 187
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 163
235000019439 ethyl acetate Nutrition 0.000 description 150
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
238000006243 chemical reaction Methods 0.000 description 125
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 113
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 104
229910052943 magnesium sulfate Inorganic materials 0.000 description 100
235000019341 magnesium sulphate Nutrition 0.000 description 100
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 96
239000000203 mixture Substances 0.000 description 82
239000007787 solid Substances 0.000 description 79
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
238000005160 1H NMR spectroscopy Methods 0.000 description 66
239000012267 brine Substances 0.000 description 62
239000000741 silica gel Substances 0.000 description 62
229910002027 silica gel Inorganic materials 0.000 description 62
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 62
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 59
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
239000000047 product Substances 0.000 description 57
230000002829 reductive effect Effects 0.000 description 57
238000000746 purification Methods 0.000 description 51
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
238000007792 addition Methods 0.000 description 49
239000000543 intermediate Substances 0.000 description 48
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 48
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 48
125000002619 bicyclic group Chemical group 0.000 description 47
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 45
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
238000010992 reflux Methods 0.000 description 45
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
238000003756 stirring Methods 0.000 description 41
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 38
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
239000002585 base Substances 0.000 description 34
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 34
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 32
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
239000011541 reaction mixture Substances 0.000 description 32
150000002148 esters Chemical group 0.000 description 30
230000002441 reversible effect Effects 0.000 description 30
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 28
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 27
238000002953 preparative HPLC Methods 0.000 description 27
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 26
239000010410 layer Substances 0.000 description 26
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 26
235000017557 sodium bicarbonate Nutrition 0.000 description 26
229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
239000012266 salt solution Substances 0.000 description 25
229910000027 potassium carbonate Inorganic materials 0.000 description 24
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 22
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 22
239000002904 solvent Substances 0.000 description 22
230000015572 biosynthetic process Effects 0.000 description 21
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 21
238000010511 deprotection reaction Methods 0.000 description 21
238000010438 heat treatment Methods 0.000 description 21
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
235000010288 sodium nitrite Nutrition 0.000 description 19
238000004587 chromatography analysis Methods 0.000 description 18
238000002360 preparation method Methods 0.000 description 18
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 18
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 18
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 17
229960000583 acetic acid Drugs 0.000 description 17
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
150000002576 ketones Chemical group 0.000 description 16
239000000651 prodrug Substances 0.000 description 16
229940002612 prodrug Drugs 0.000 description 16
230000009467 reduction Effects 0.000 description 16
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 15
150000001721 carbon Chemical group 0.000 description 15
238000006722 reduction reaction Methods 0.000 description 15
239000000377 silicon dioxide Substances 0.000 description 15
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 14
238000010958 [3+2] cycloaddition reaction Methods 0.000 description 14
150000001540 azides Chemical class 0.000 description 14
239000003153 chemical reaction reagent Substances 0.000 description 14
238000007254 oxidation reaction Methods 0.000 description 14
235000011181 potassium carbonates Nutrition 0.000 description 14
239000000126 substance Substances 0.000 description 14
125000001424 substituent group Chemical group 0.000 description 14
125000001302 tertiary amino group Chemical group 0.000 description 14
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 13
108010074860 Factor Xa Proteins 0.000 description 13
235000019253 formic acid Nutrition 0.000 description 13
238000004128 high performance liquid chromatography Methods 0.000 description 13
230000003647 oxidation Effects 0.000 description 13
238000003786 synthesis reaction Methods 0.000 description 13
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
239000002253 acid Substances 0.000 description 12
150000001412 amines Chemical class 0.000 description 12
150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
125000004093 cyano group Chemical group *C#N 0.000 description 12
150000004820 halides Chemical class 0.000 description 12
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 12
229960000549 4-dimethylaminophenol Drugs 0.000 description 11
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
150000001299 aldehydes Chemical class 0.000 description 11
238000009833 condensation Methods 0.000 description 11
230000005494 condensation Effects 0.000 description 11
239000006260 foam Substances 0.000 description 11
238000004007 reversed phase HPLC Methods 0.000 description 11
DGUWACLYDSWXRZ-UHFFFAOYSA-N (2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C=O DGUWACLYDSWXRZ-UHFFFAOYSA-N 0.000 description 10
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 description 10
229960001171 acetohydroxamic acid Drugs 0.000 description 10
239000012954 diazonium Substances 0.000 description 10
238000003818 flash chromatography Methods 0.000 description 10
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
239000012044 organic layer Substances 0.000 description 10
235000015320 potassium carbonate Nutrition 0.000 description 10
150000003217 pyrazoles Chemical class 0.000 description 10
239000012279 sodium borohydride Substances 0.000 description 10
229910000033 sodium borohydride Inorganic materials 0.000 description 10
150000003852 triazoles Chemical class 0.000 description 10
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 9
125000000524 functional group Chemical group 0.000 description 9
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 9
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238000006460 hydrolysis reaction Methods 0.000 description 8
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SHRRRNSPESGSCM-UHFFFAOYSA-N 4-amino-1h-pyrazole-5-carboxylic acid Chemical compound NC1=CNN=C1C(O)=O SHRRRNSPESGSCM-UHFFFAOYSA-N 0.000 description 7
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238000004458 analytical method Methods 0.000 description 3
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ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 3
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AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
OYQVQWIASIXXRT-UHFFFAOYSA-N ethyl 2,4-dioxopentanoate Chemical compound CCOC(=O)C(=O)CC(C)=O OYQVQWIASIXXRT-UHFFFAOYSA-N 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-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
ZHOPKHNLYOLWLE-UHFFFAOYSA-N ethynethiol Chemical class SC#C ZHOPKHNLYOLWLE-UHFFFAOYSA-N 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
238000001125 extrusion Methods 0.000 description 1
229960000301 factor viii Drugs 0.000 description 1
229950003499 fibrin Drugs 0.000 description 1
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
238000009472 formulation Methods 0.000 description 1
DNXDYHALMANNEJ-UHFFFAOYSA-N furan-2,3-dicarboxylic acid Chemical class OC(=O)C=1C=COC=1C(O)=O DNXDYHALMANNEJ-UHFFFAOYSA-N 0.000 description 1
ICGWWCLWBPLPDF-UHFFFAOYSA-N furan-2-ol Chemical class OC1=CC=CO1 ICGWWCLWBPLPDF-UHFFFAOYSA-N 0.000 description 1
125000003838 furazanyl group Chemical group 0.000 description 1
230000004927 fusion Effects 0.000 description 1
150000002366 halogen compounds Chemical class 0.000 description 1
230000026030 halogenation Effects 0.000 description 1
238000005658 halogenation reaction Methods 0.000 description 1
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 description 1
125000001072 heteroaryl group Chemical group 0.000 description 1
125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
125000000592 heterocycloalkyl group Chemical group 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
125000002632 imidazolidinyl group Chemical group 0.000 description 1
125000002636 imidazolinyl group Chemical group 0.000 description 1
ZIPLUEXSCPLCEI-UHFFFAOYSA-N iminomethylideneazanide Chemical compound [NH-]C#N ZIPLUEXSCPLCEI-UHFFFAOYSA-N 0.000 description 1
230000000415 inactivating effect Effects 0.000 description 1
238000010348 incorporation Methods 0.000 description 1
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
125000004926 indolenyl group Chemical group 0.000 description 1
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
230000002452 interceptive effect Effects 0.000 description 1
238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
230000007794 irritation Effects 0.000 description 1
125000004936 isatinoyl group Chemical group N1(C(=O)C(=O)C2=CC=CC=C12)C(=O)* 0.000 description 1
125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
150000003854 isothiazoles Chemical class 0.000 description 1
150000002596 lactones Chemical class 0.000 description 1
229940040102 levulinic acid Drugs 0.000 description 1
239000007788 liquid Substances 0.000 description 1
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
238000004949 mass spectrometry Methods 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000011707 mineral Substances 0.000 description 1
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
DSFPLGRTIPURCS-UHFFFAOYSA-N n-[[2-[6-(4-bromo-2-fluorophenyl)-7-oxo-3-(trifluoromethyl)-4,5-dihydropyrazolo[3,4-c]pyridin-1-yl]phenyl]methyl]-2,2,2-trifluoroacetamide Chemical compound FC1=CC(Br)=CC=C1N1C(=O)C(N(N=C2C(F)(F)F)C=3C(=CC=CC=3)CNC(=O)C(F)(F)F)=C2CC1 DSFPLGRTIPURCS-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
230000000802 nitrating effect Effects 0.000 description 1
238000006396 nitration reaction Methods 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000003199 nucleic acid amplification method Methods 0.000 description 1
239000012038 nucleophile Substances 0.000 description 1
RCALDWJXTVCBAZ-UHFFFAOYSA-N oct-1-enylbenzene Chemical compound CCCCCCC=CC1=CC=CC=C1 RCALDWJXTVCBAZ-UHFFFAOYSA-N 0.000 description 1
125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000005457 optimization Methods 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
125000000160 oxazolidinyl group Chemical group 0.000 description 1
QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 1
238000007243 oxidative cyclization reaction Methods 0.000 description 1
238000007248 oxidative elimination reaction Methods 0.000 description 1
150000002923 oximes Chemical class 0.000 description 1
125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
238000006213 oxygenation reaction Methods 0.000 description 1
229920002866 paraformaldehyde Polymers 0.000 description 1
239000002245 particle Substances 0.000 description 1
230000037361 pathway Effects 0.000 description 1
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
RYFZYYUIAZYQLC-UHFFFAOYSA-N perchloromethyl mercaptan Chemical compound ClSC(Cl)(Cl)Cl RYFZYYUIAZYQLC-UHFFFAOYSA-N 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
150000003904 phospholipids Chemical class 0.000 description 1
125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
CNMOHEDUVVUVPP-UHFFFAOYSA-N piperidine-2,3-dione Chemical compound O=C1CCCNC1=O CNMOHEDUVVUVPP-UHFFFAOYSA-N 0.000 description 1
125000004928 piperidonyl group Chemical group 0.000 description 1
229960005235 piperonyl butoxide Drugs 0.000 description 1
125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011698 potassium fluoride Substances 0.000 description 1
235000003270 potassium fluoride Nutrition 0.000 description 1
239000002243 precursor Substances 0.000 description 1
230000008569 process Effects 0.000 description 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
230000017854 proteolysis Effects 0.000 description 1
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
125000003072 pyrazolidinyl group Chemical group 0.000 description 1
DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
125000002755 pyrazolinyl group Chemical group 0.000 description 1
ANTNKSBMJNVROF-UHFFFAOYSA-N pyrazolo[4,3-c]diazepine-3,6-dione Chemical class C1=CC(=O)N=NC2=C1N=NC2=O ANTNKSBMJNVROF-UHFFFAOYSA-N 0.000 description 1
DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical class N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 description 1
VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
150000003235 pyrrolidines Chemical group 0.000 description 1
125000001422 pyrrolinyl group Chemical group 0.000 description 1
150000003242 quaternary ammonium salts Chemical class 0.000 description 1
238000010791 quenching Methods 0.000 description 1
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
238000012552 review Methods 0.000 description 1
MNOALXGAYUJNKX-UHFFFAOYSA-N s-chloro chloromethanethioate Chemical compound ClSC(Cl)=O MNOALXGAYUJNKX-UHFFFAOYSA-N 0.000 description 1
230000007017 scission Effects 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
230000019491 signal transduction Effects 0.000 description 1
235000012239 silicon dioxide Nutrition 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
229910000342 sodium bisulfate Inorganic materials 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
150000003413 spiro compounds Chemical class 0.000 description 1
239000001119 stannous chloride Substances 0.000 description 1
229910052682 stishovite Inorganic materials 0.000 description 1
125000003107 substituted aryl group Chemical group 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
239000011885 synergistic combination Substances 0.000 description 1
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
238000001149 thermolysis Methods 0.000 description 1
125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
WZMPOCLULGAHJR-UHFFFAOYSA-N thiophen-2-ol Chemical class OC1=CC=CS1 WZMPOCLULGAHJR-UHFFFAOYSA-N 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
HIHKYDVSWLFRAY-UHFFFAOYSA-N thiophene-2,3-dicarboxylic acid Chemical class OC(=O)C=1C=CSC=1C(O)=O HIHKYDVSWLFRAY-UHFFFAOYSA-N 0.000 description 1
QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
229910052905 tridymite Inorganic materials 0.000 description 1
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
MDCWDBMBZLORER-UHFFFAOYSA-N triphenyl borate Chemical compound C=1C=CC=CC=1OB(OC=1C=CC=CC=1)OC1=CC=CC=C1 MDCWDBMBZLORER-UHFFFAOYSA-N 0.000 description 1
229910052722 tritium Inorganic materials 0.000 description 1
108010036927 trypsin-like serine protease Proteins 0.000 description 1
229910052720 vanadium Inorganic materials 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Vascular Medicine (AREA)
Urology & Nephrology (AREA)
Diabetes (AREA)
Hematology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

HR990396A 1998-12-23 1999-12-21 NITROGEN CONTAINING HETEROBICYCLES AS FACTOR Xa INHIBITORS HRP990396A2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US11362898P	1998-12-23	1998-12-23
US12763399P	1999-04-02	1999-04-02

Publications (1)

Publication Number	Publication Date
HRP990396A2 true HRP990396A2 (en)	2000-08-31

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ID=26811284

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR990396A HRP990396A2 (en)	1998-12-23	1999-12-21	NITROGEN CONTAINING HETEROBICYCLES AS FACTOR Xa INHIBITORS

Country Status (26)

Country	Link
US (2)	US6413980B1 (fr)
EP (1)	EP1140941B1 (fr)
JP (1)	JP2002533465A (fr)
KR (1)	KR100628407B1 (fr)
CN (1)	CN100340559C (fr)
AR (1)	AR024242A1 (fr)
AT (1)	ATE280171T1 (fr)
AU (1)	AU759711B2 (fr)
BR (1)	BR9917080A (fr)
CA (1)	CA2349330C (fr)
DE (1)	DE69921358T2 (fr)
DK (1)	DK1140941T3 (fr)
EA (1)	EA004515B1 (fr)
ES (1)	ES2232202T3 (fr)
HK (1)	HK1052508B (fr)
HR (1)	HRP990396A2 (fr)
IL (2)	IL142959A0 (fr)
MX (1)	MXPA01006502A (fr)
MY (1)	MY138239A (fr)
NO (1)	NO319816B1 (fr)
NZ (1)	NZ511674A (fr)
PT (1)	PT1140941E (fr)
SI (1)	SI1140941T1 (fr)
TW (1)	TWI225862B (fr)
WO (1)	WO2000039131A1 (fr)
ZA (1)	ZA200103795B (fr)

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EP1140941B1 (fr)	2004-10-20
US20030004167A1 (en)	2003-01-02
DE69921358D1 (de)	2004-11-25
KR20010092754A (ko)	2001-10-26
AU759711B2 (en)	2003-04-17
NO319816B1 (no)	2005-09-19
JP2002533465A (ja)	2002-10-08
NZ511674A (en)	2003-11-28
EA004515B1 (ru)	2004-04-29
EA200100688A1 (ru)	2001-12-24
EP1140941A1 (fr)	2001-10-10
HK1052508A1 (zh)	2003-09-19
PT1140941E (pt)	2005-02-28
ATE280171T1 (de)	2004-11-15
IL142959A (en)	2010-05-31
MY138239A (en)	2009-05-29
AU2371700A (en)	2000-07-31
WO2000039131A1 (fr)	2000-07-06
US6673810B2 (en)	2004-01-06
CN1391575A (zh)	2003-01-15
US6413980B1 (en)	2002-07-02
CA2349330C (fr)	2009-09-29
AR024242A1 (es)	2002-09-25
DE69921358T2 (de)	2006-03-09
NO20013072L (no)	2001-06-20
CN100340559C (zh)	2007-10-03
IL142959A0 (en)	2002-04-21
TWI225862B (en)	2005-01-01
ES2232202T3 (es)	2005-05-16
MXPA01006502A (es)	2002-04-08
NO20013072D0 (no)	2001-06-20
KR100628407B1 (ko)	2006-09-26
DK1140941T3 (da)	2005-02-14
ZA200103795B (en)	2002-08-12
HK1052508B (zh)	2008-08-01
SI1140941T1 (en)	2005-04-30
BR9917080A (pt)	2002-03-12
CA2349330A1 (fr)	2000-07-06

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