ZA200110558B - Tricyclic compounds having spiro union. - Google Patents

Tricyclic compounds having spiro union. Download PDF

Info

Publication number: ZA200110558B
Authority: ZA; South Africa
Prior art keywords: group; compound; diaza; piperidin; bicyclo
Prior art date: 1999-06-30

Application number

ZA200110558A

Other languages

English (en)

Inventor

Hidemitsu Nishida

Fumihiko Saitoh

Kousuke Harada

Ikuya Shiromizu

Original Assignee

Mochida Pharm Co Ltd

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

1999-06-30

Filing date

2001-12-21

Publication date

2002-09-12

2001-12-21 Application filed by Mochida Pharm Co Ltd filed Critical Mochida Pharm Co Ltd

2002-09-12 Publication of ZA200110558B publication Critical patent/ZA200110558B/en

Links

150000001875 compounds Chemical class 0.000 title claims description 891
125000003003 spiro group Chemical group 0.000 title claims description 35
150000003839 salts Chemical class 0.000 claims description 222
238000000034 method Methods 0.000 claims description 189
-1 6-chloronaphthalen-2-ylsulfonyl Chemical group 0.000 claims description 150
125000000217 alkyl group Chemical group 0.000 claims description 144
239000000203 mixture Substances 0.000 claims description 140
VRQDPNKOUPEWOC-UHFFFAOYSA-N spiro[bicyclo[2.2.2]octane-3,3'-piperidine] Chemical compound C1CCNCC21C(CC1)CCC1C2 VRQDPNKOUPEWOC-UHFFFAOYSA-N 0.000 claims description 131
125000001424 substituent group Chemical group 0.000 claims description 107
239000003112 inhibitor Substances 0.000 claims description 73
230000002401 inhibitory effect Effects 0.000 claims description 72
125000005843 halogen group Chemical group 0.000 claims description 50
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 49
229920006395 saturated elastomer Polymers 0.000 claims description 49
125000003545 alkoxy group Chemical group 0.000 claims description 43
125000000623 heterocyclic group Chemical group 0.000 claims description 41
125000002947 alkylene group Chemical group 0.000 claims description 40
230000002209 hydrophobic effect Effects 0.000 claims description 36
125000003277 amino group Chemical group 0.000 claims description 33
229910052757 nitrogen Inorganic materials 0.000 claims description 30
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
125000000753 cycloalkyl group Chemical group 0.000 claims description 26
125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
125000004430 oxygen atom Chemical group O* 0.000 claims description 24
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 23
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 19
230000003993 interaction Effects 0.000 claims description 18
125000006239 protecting group Chemical group 0.000 claims description 18
125000001841 imino group Chemical group [H]N=* 0.000 claims description 17
125000004076 pyridyl group Chemical group 0.000 claims description 17
230000036961 partial effect Effects 0.000 claims description 15
239000008194 pharmaceutical composition Substances 0.000 claims description 15
239000013078 crystal Substances 0.000 claims description 14
230000001747 exhibiting effect Effects 0.000 claims description 11
125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 11
238000004166 bioassay Methods 0.000 claims description 9
125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 9
108090000317 Chymotrypsin Proteins 0.000 claims description 8
229960002376 chymotrypsin Drugs 0.000 claims description 8
239000012634 fragment Substances 0.000 claims description 8
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 7
230000003287 optical effect Effects 0.000 claims description 7
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
125000000539 amino acid group Chemical group 0.000 claims description 6
150000001413 amino acids Chemical class 0.000 claims description 6
229910052698 phosphorus Inorganic materials 0.000 claims description 6
ATVLKVRIWUZBSN-UHFFFAOYSA-N spiro[3,3a,5,6,7,7a-hexahydro-1H-indene-2,4'-piperidine]-4-one Chemical compound C1C2C(=O)CCCC2CC21CCNCC2 ATVLKVRIWUZBSN-UHFFFAOYSA-N 0.000 claims description 6
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
238000003556 assay Methods 0.000 claims description 5
230000005764 inhibitory process Effects 0.000 claims description 5
241000124008 Mammalia Species 0.000 claims description 4
150000007942 carboxylates Chemical class 0.000 claims description 3
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
NRWRNGAIXQYSKM-UHFFFAOYSA-N 7-(6-chloronaphthalen-2-yl)sulfonyl-1'-pyridin-4-ylspiro[3,6,8,8a-tetrahydro-[1,3]oxazolo[3,2-a]pyrazine-2,4'-piperidine]-5-one Chemical compound C1=CC2=CC(Cl)=CC=C2C=C1S(=O)(=O)N(CC(=O)N1C2)CC1OC2(CC1)CCN1C1=CC=NC=C1 NRWRNGAIXQYSKM-UHFFFAOYSA-N 0.000 claims 1
GNXLMCCZZCSKGL-UHFFFAOYSA-N 7-(6-chloronaphthalen-2-yl)sulfonyl-8a-(methoxymethyl)-1-methyl-1'-pyridin-4-ylspiro[6,8-dihydro-3h-imidazo[1,2-a]pyrazine-2,4'-piperidine]-5-one Chemical compound CN1C2(COC)CN(S(=O)(=O)C=3C=C4C=CC(Cl)=CC4=CC=3)CC(=O)N2CC1(CC1)CCN1C1=CC=NC=C1 GNXLMCCZZCSKGL-UHFFFAOYSA-N 0.000 claims 1
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
125000001183 hydrocarbyl group Chemical group 0.000 claims 1
239000000651 prodrug Substances 0.000 claims 1
229940002612 prodrug Drugs 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 388
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 257
230000015572 biosynthetic process Effects 0.000 description 218
238000003786 synthesis reaction Methods 0.000 description 218
239000000243 solution Substances 0.000 description 141
239000002904 solvent Substances 0.000 description 120
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 100
230000002829 reductive effect Effects 0.000 description 99
238000006243 chemical reaction Methods 0.000 description 97
239000011541 reaction mixture Substances 0.000 description 88
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 86
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
238000004519 manufacturing process Methods 0.000 description 71
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 64
239000003480 eluent Substances 0.000 description 63
238000010898 silica gel chromatography Methods 0.000 description 61
238000001816 cooling Methods 0.000 description 60
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 53
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
239000012044 organic layer Substances 0.000 description 51
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
125000006615 aromatic heterocyclic group Chemical group 0.000 description 45
230000008569 process Effects 0.000 description 45
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
239000007864 aqueous solution Substances 0.000 description 44
239000003814 drug Substances 0.000 description 44
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
125000003118 aryl group Chemical group 0.000 description 43
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
238000010992 reflux Methods 0.000 description 35
125000004453 alkoxycarbonyl group Chemical group 0.000 description 32
238000012360 testing method Methods 0.000 description 30
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 29
238000004896 high resolution mass spectrometry Methods 0.000 description 29
238000003756 stirring Methods 0.000 description 28
XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 27
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 26
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
125000004429 atom Chemical group 0.000 description 25
230000003647 oxidation Effects 0.000 description 25
238000007254 oxidation reaction Methods 0.000 description 25
229940079593 drug Drugs 0.000 description 24
235000019441 ethanol Nutrition 0.000 description 24
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 24
229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
235000017557 sodium bicarbonate Nutrition 0.000 description 24
239000003795 chemical substances by application Substances 0.000 description 22
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 21
125000002252 acyl group Chemical group 0.000 description 21
125000003342 alkenyl group Chemical group 0.000 description 21
125000004432 carbon atom Chemical group C* 0.000 description 21
201000010099 disease Diseases 0.000 description 21
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
239000000725 suspension Substances 0.000 description 21
125000004043 oxo group Chemical group O=* 0.000 description 20
239000002253 acid Substances 0.000 description 19
238000001914 filtration Methods 0.000 description 19
125000005842 heteroatom Chemical group 0.000 description 19
238000006467 substitution reaction Methods 0.000 description 19
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 18
230000015271 coagulation Effects 0.000 description 17
238000005345 coagulation Methods 0.000 description 17
229960004132 diethyl ether Drugs 0.000 description 17
229910052717 sulfur Inorganic materials 0.000 description 17
125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 16
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 16
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
230000000704 physical effect Effects 0.000 description 16
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
239000003146 anticoagulant agent Substances 0.000 description 15
FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 15
125000002950 monocyclic group Chemical group 0.000 description 15
125000004434 sulfur atom Chemical group 0.000 description 15
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 14
229940127219 anticoagulant drug Drugs 0.000 description 14
230000000694 effects Effects 0.000 description 14
229910052739 hydrogen Inorganic materials 0.000 description 14
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 14
125000000304 alkynyl group Chemical group 0.000 description 13
125000004093 cyano group Chemical group *C#N 0.000 description 13
238000013461 design Methods 0.000 description 13
125000003710 aryl alkyl group Chemical group 0.000 description 12
239000010410 layer Substances 0.000 description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
230000003449 preventive effect Effects 0.000 description 12
230000000069 prophylactic effect Effects 0.000 description 12
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
208000007536 Thrombosis Diseases 0.000 description 11
125000000392 cycloalkenyl group Chemical group 0.000 description 11
229910052736 halogen Inorganic materials 0.000 description 11
150000002367 halogens Chemical class 0.000 description 11
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
108090000190 Thrombin Proteins 0.000 description 10
HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 10
125000004122 cyclic group Chemical group 0.000 description 10
239000001257 hydrogen Substances 0.000 description 10
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
229940124597 therapeutic agent Drugs 0.000 description 10
229960004072 thrombin Drugs 0.000 description 10
229910052721 tungsten Inorganic materials 0.000 description 10
PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 10
229960005080 warfarin Drugs 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
102000004190 Enzymes Human genes 0.000 description 9
108090000790 Enzymes Proteins 0.000 description 9
208000032843 Hemorrhage Diseases 0.000 description 9
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
208000034158 bleeding Diseases 0.000 description 9
230000000740 bleeding effect Effects 0.000 description 9
229910052801 chlorine Inorganic materials 0.000 description 9
229940088598 enzyme Drugs 0.000 description 9
239000000706 filtrate Substances 0.000 description 9
150000002430 hydrocarbons Chemical group 0.000 description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
239000007858 starting material Substances 0.000 description 9
239000000758 substrate Substances 0.000 description 9
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
208000005189 Embolism Diseases 0.000 description 8
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 8
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
102000012479 Serine Proteases Human genes 0.000 description 8
108010022999 Serine Proteases Proteins 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
238000010521 absorption reaction Methods 0.000 description 8
239000003153 chemical reaction reagent Substances 0.000 description 8
238000011161 development Methods 0.000 description 8
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 8
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 8
229960002897 heparin Drugs 0.000 description 8
229920000669 heparin Polymers 0.000 description 8
NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
229910000027 potassium carbonate Inorganic materials 0.000 description 8
230000002265 prevention Effects 0.000 description 8
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
125000003282 alkyl amino group Chemical group 0.000 description 7
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
239000008280 blood Substances 0.000 description 7
210000004369 blood Anatomy 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 7
230000009881 electrostatic interaction Effects 0.000 description 7
229940102223 injectable solution Drugs 0.000 description 7
238000005259 measurement Methods 0.000 description 7
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 7
229910052760 oxygen Inorganic materials 0.000 description 7
238000012216 screening Methods 0.000 description 7
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
229940122388 Thrombin inhibitor Drugs 0.000 description 6
235000011054 acetic acid Nutrition 0.000 description 6
125000005115 alkyl carbamoyl group Chemical group 0.000 description 6
229910052799 carbon Inorganic materials 0.000 description 6
125000001309 chloro group Chemical group Cl* 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
238000004590 computer program Methods 0.000 description 6
238000010908 decantation Methods 0.000 description 6
238000000605 extraction Methods 0.000 description 6
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
239000004615 ingredient Substances 0.000 description 6
230000000302 ischemic effect Effects 0.000 description 6
239000008101 lactose Substances 0.000 description 6
229910052751 metal Inorganic materials 0.000 description 6
239000002184 metal Substances 0.000 description 6
239000011259 mixed solution Substances 0.000 description 6
230000003389 potentiating effect Effects 0.000 description 6
239000000047 product Substances 0.000 description 6
125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 6
230000009467 reduction Effects 0.000 description 6
238000006722 reduction reaction Methods 0.000 description 6
239000006228 supernatant Substances 0.000 description 6
125000003396 thiol group Chemical class [H]S* 0.000 description 6
239000003868 thrombin inhibitor Substances 0.000 description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
LJCBAPRMNYSDOP-LVCYMWGESA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydron;chloride;pentahydrate Chemical compound O.O.O.O.O.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 LJCBAPRMNYSDOP-LVCYMWGESA-N 0.000 description 5
GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
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FTKASJMIPSSXBP-UHFFFAOYSA-N ethyl 2-nitroacetate Chemical compound CCOC(=O)C[N+]([O-])=O FTKASJMIPSSXBP-UHFFFAOYSA-N 0.000 description 1
UVSPVEYCSVXYBB-UHFFFAOYSA-N ethyl 3-amino-3-oxopropanoate Chemical compound CCOC(=O)CC(N)=O UVSPVEYCSVXYBB-UHFFFAOYSA-N 0.000 description 1
VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
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239000007888 film coating Substances 0.000 description 1
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238000010579 first pass effect Methods 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
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238000009472 formulation Methods 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
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239000008103 glucose Substances 0.000 description 1
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229940093915 gynecological organic acid Drugs 0.000 description 1
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238000010438 heat treatment Methods 0.000 description 1
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150000004677 hydrates Chemical class 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
XJTQJERLRPWUGL-UHFFFAOYSA-N iodomethylbenzene Chemical compound ICC1=CC=CC=C1 XJTQJERLRPWUGL-UHFFFAOYSA-N 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
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125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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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
230000005923 long-lasting effect Effects 0.000 description 1
230000007774 longterm Effects 0.000 description 1
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239000011777 magnesium Substances 0.000 description 1
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VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
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230000009401 metastasis Effects 0.000 description 1
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125000005394 methallyl group Chemical group 0.000 description 1
125000000718 methaneimidamido group Chemical group C(=N)N* 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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IWVKTOUOPHGZRX-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-N 0.000 description 1
KQKMCRNWIOKXNL-UHFFFAOYSA-N methyl 6-[(6-chloronaphthalen-2-yl)sulfonyl-(2-ethoxy-2-oxoethyl)amino]-5-oxohexanoate Chemical compound C1=C(Cl)C=CC2=CC(S(=O)(=O)N(CC(=O)CCCC(=O)OC)CC(=O)OCC)=CC=C21 KQKMCRNWIOKXNL-UHFFFAOYSA-N 0.000 description 1
UJAAJBIJFQPFBC-UHFFFAOYSA-N methyl 6-bromo-5-oxohexanoate Chemical compound COC(=O)CCCC(=O)CBr UJAAJBIJFQPFBC-UHFFFAOYSA-N 0.000 description 1
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125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
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HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
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BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
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235000020824 obesity Nutrition 0.000 description 1
239000002674 ointment Substances 0.000 description 1
239000004006 olive oil Substances 0.000 description 1
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229960003104 ornithine Drugs 0.000 description 1
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230000007170 pathology Effects 0.000 description 1
230000037361 pathway Effects 0.000 description 1
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XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
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239000011591 potassium Substances 0.000 description 1
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239000002243 precursor Substances 0.000 description 1
238000012746 preparative thin layer chromatography Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002335 preservative effect Effects 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
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230000001681 protective effect Effects 0.000 description 1
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125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound 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
125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
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210000000813 small intestine Anatomy 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
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
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239000012453 solvate Substances 0.000 description 1
208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
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230000002459 sustained effect Effects 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
235000012222 talc Nutrition 0.000 description 1
235000002906 tartaric acid Nutrition 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
MMQMQEVGUNJVHN-UHFFFAOYSA-N tert-butyl n-[(4-hydroxy-1-pyridin-4-ylpiperidin-4-yl)methyl]carbamate Chemical compound C1CC(CNC(=O)OC(C)(C)C)(O)CCN1C1=CC=NC=C1 MMQMQEVGUNJVHN-UHFFFAOYSA-N 0.000 description 1
ZVUCOORWSKRJII-UHFFFAOYSA-N tert-butyl n-[(4-hydroxypiperidin-4-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1(O)CCNCC1 ZVUCOORWSKRJII-UHFFFAOYSA-N 0.000 description 1
125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
206010043554 thrombocytopenia Diseases 0.000 description 1
229960000103 thrombolytic agent Drugs 0.000 description 1
201000005060 thrombophlebitis Diseases 0.000 description 1
RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
229960000187 tissue plasminogen activator Drugs 0.000 description 1
NNBZCPXTIHJBJL-UHFFFAOYSA-N trans-decahydronaphthalene Natural products C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
238000012546 transfer Methods 0.000 description 1
201000010875 transient cerebral ischemia Diseases 0.000 description 1
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
230000001960 triggered effect Effects 0.000 description 1
UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
238000011144 upstream manufacturing Methods 0.000 description 1
229960005356 urokinase Drugs 0.000 description 1
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210000003556 vascular endothelial cell Anatomy 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
239000000273 veterinary drug Substances 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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230000009385 viral infection Effects 0.000 description 1
230000008673 vomiting Effects 0.000 description 1
229920003169 water-soluble polymer Polymers 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/20—Spiro-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96433—Serine endopeptidases (3.4.21)
- G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
- G01N2333/96444—Factor X (3.4.21.6)
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value

Landscapes

Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Bioinformatics & Cheminformatics (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
Cardiology (AREA)
Diabetes (AREA)
Hematology (AREA)
Heart & Thoracic Surgery (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Prostheses (AREA)
External Artificial Organs (AREA)

ZA200110558A 1999-06-30 2001-12-21 Tricyclic compounds having spiro union. ZA200110558B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
JP22288399		1999-06-30

Publications (1)

Publication Number	Publication Date
ZA200110558B true ZA200110558B (en)	2002-09-12

Family

ID=16789385

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ZA200110558A ZA200110558B (en)	1999-06-30	2001-12-21	Tricyclic compounds having spiro union.

Country Status (21)

Country	Link
EP (1)	EP1191028B1 (fr)
JP (1)	JP4890707B2 (fr)
KR (1)	KR20020015061A (fr)
CN (1)	CN1371375A (fr)
AT (1)	ATE281457T1 (fr)
AU (1)	AU774397B2 (fr)
BR (1)	BR0012093A (fr)
CA (1)	CA2380852C (fr)
CZ (1)	CZ20014696A3 (fr)
DE (1)	DE60015541T2 (fr)
HK (1)	HK1049157A1 (fr)
HU (1)	HUP0202188A3 (fr)
IL (1)	IL147348A0 (fr)
MX (1)	MXPA02000003A (fr)
NO (1)	NO20016402L (fr)
NZ (1)	NZ516363A (fr)
PL (1)	PL352862A1 (fr)
SK (1)	SK19292001A3 (fr)
TR (1)	TR200103853T2 (fr)
WO (1)	WO2001002397A1 (fr)
ZA (1)	ZA200110558B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP1302462A4 (fr) *	2000-07-17	2007-07-18	Takeda Pharmaceutical	Derives de sulfonate, procede de production et utilisation de ces derives
JPWO2002053568A1 (ja) *	2000-12-28	2004-05-13	持田製薬株式会社	スピロ結合を有する三環系化合物を有効成分とするコレステロール生合成阻害剤
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2000
- 2000-06-30 WO PCT/JP2000/004374 patent/WO2001002397A1/fr not_active Application Discontinuation
- 2000-06-30 CN CN00811976A patent/CN1371375A/zh active Pending
- 2000-06-30 CZ CZ20014696A patent/CZ20014696A3/cs unknown
- 2000-06-30 JP JP2001507834A patent/JP4890707B2/ja not_active Expired - Fee Related
- 2000-06-30 AU AU55720/00A patent/AU774397B2/en not_active Ceased
- 2000-06-30 KR KR1020017016658A patent/KR20020015061A/ko not_active Application Discontinuation
- 2000-06-30 NZ NZ516363A patent/NZ516363A/en unknown
- 2000-06-30 SK SK1929-2001A patent/SK19292001A3/sk unknown
- 2000-06-30 PL PL00352862A patent/PL352862A1/xx not_active Application Discontinuation
- 2000-06-30 IL IL14734800A patent/IL147348A0/xx unknown
- 2000-06-30 BR BR0012093-6A patent/BR0012093A/pt not_active IP Right Cessation
- 2000-06-30 HU HU0202188A patent/HUP0202188A3/hu unknown
- 2000-06-30 DE DE60015541T patent/DE60015541T2/de not_active Expired - Lifetime
- 2000-06-30 CA CA002380852A patent/CA2380852C/fr not_active Expired - Fee Related
- 2000-06-30 MX MXPA02000003A patent/MXPA02000003A/es unknown
- 2000-06-30 AT AT00940912T patent/ATE281457T1/de not_active IP Right Cessation
- 2000-06-30 TR TR2001/03853T patent/TR200103853T2/xx unknown
- 2000-06-30 EP EP00940912A patent/EP1191028B1/fr not_active Expired - Lifetime
2001
- 2001-12-21 ZA ZA200110558A patent/ZA200110558B/en unknown
- 2001-12-28 NO NO20016402A patent/NO20016402L/no not_active Application Discontinuation
2003
- 2003-01-28 HK HK03100716.0A patent/HK1049157A1/zh unknown

Also Published As

Publication number	Publication date
JP4890707B2 (ja)	2012-03-07
EP1191028A4 (fr)	2002-10-23
HUP0202188A2 (en)	2002-10-28
EP1191028B1 (fr)	2004-11-03
KR20020015061A (ko)	2002-02-27
CA2380852A1 (fr)	2001-01-11
WO2001002397A9 (fr)	2001-04-05
DE60015541T2 (de)	2005-12-08
HK1049157A1 (zh)	2003-05-02
CN1371375A (zh)	2002-09-25
EP1191028A1 (fr)	2002-03-27
CZ20014696A3 (cs)	2002-05-15
MXPA02000003A (es)	2003-07-21
AU5572000A (en)	2001-01-22
SK19292001A3 (sk)	2002-06-04
TR200103853T2 (tr)	2002-11-21
NO20016402D0 (no)	2001-12-28
BR0012093A (pt)	2002-07-16
CA2380852C (fr)	2009-10-20
ATE281457T1 (de)	2004-11-15
NZ516363A (en)	2004-05-28
AU774397B2 (en)	2004-06-24
WO2001002397A1 (fr)	2001-01-11
NO20016402L (no)	2002-02-27
PL352862A1 (en)	2003-09-08
DE60015541D1 (de)	2004-12-09
IL147348A0 (en)	2002-08-14
HUP0202188A3 (en)	2004-04-28

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