ZA200106454B - Imidazo[4,5-c]-pyridine-4-on-derivatives. - Google Patents
Imidazo[4,5-c]-pyridine-4-on-derivatives. Download PDFInfo
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- ZA200106454B ZA200106454B ZA200106454A ZA200106454A ZA200106454B ZA 200106454 B ZA200106454 B ZA 200106454B ZA 200106454 A ZA200106454 A ZA 200106454A ZA 200106454 A ZA200106454 A ZA 200106454A ZA 200106454 B ZA200106454 B ZA 200106454B
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- -1 pyrrolidin-l-yl Chemical group 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 40
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 108010074860 Factor Xa Proteins 0.000 claims description 14
- 235000010290 biphenyl Nutrition 0.000 claims description 14
- 239000004305 biphenyl Substances 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- 208000007536 Thrombosis Diseases 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 206010022562 Intermittent claudication Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 238000002399 angioplasty Methods 0.000 claims description 5
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 5
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 208000021156 intermittent vascular claudication Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 150000004866 oxadiazoles Chemical class 0.000 claims description 2
- 238000003797 solvolysis reaction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 8
- 239000007788 liquid Substances 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 description 12
- 108090000190 Thrombin Proteins 0.000 description 9
- 229960004072 thrombin Drugs 0.000 description 9
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 108010054265 Factor VIIa Proteins 0.000 description 5
- 230000002785 anti-thrombosis Effects 0.000 description 5
- 108010048049 Factor IXa Proteins 0.000 description 4
- 230000002429 anti-coagulating effect Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 229940012414 factor viia Drugs 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 230000009424 thromboembolic effect Effects 0.000 description 4
- 206010053567 Coagulopathies Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- 108010014173 Factor X Proteins 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000004362 3,4,5-trichlorophenyl group Chemical group [H]C1=C(Cl)C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical class OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- NDPNAZHCBKSFAP-UHFFFAOYSA-N benzyl N-[[(butylsulfonylamino)-[(ethylsulfonylamino)-(methanesulfonamido)-(propylsulfonylamino)methyl]sulfonylamino]methyl]sulfamate Chemical group C(C1=CC=CC=C1)OS(=O)(=O)NCN(S(=O)(=O)C(NS(=O)(=O)CCC)(NS(=O)(=O)CC)NS(=O)(=O)C)NS(=O)(=O)CCCC NDPNAZHCBKSFAP-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- HUXULLJDEXUMOP-UHFFFAOYSA-N carbamimidoyl fluoride Chemical compound NC(F)=N HUXULLJDEXUMOP-UHFFFAOYSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000011737 fluorine Substances 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
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003607 serino group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Imidazo([4,5-c]pyridin-4-one derivatives
The invention relates to compounds of the formula I
R3
Ss
AN N (CH,) —R1
R? n 0 in which
R is H or unbranched or branched alkyl having 1-6
C atoms or cycloalkyl having 3-6 C atoms,
R? is Ar,
R? is Ar',
R’ is H, R, R*, Hal, CN, COOH, COOA or CONH,,
Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another unsubstituted or mono-, di- or trisubstituted by R, OH, Hal, CN,
NO», CFs, NH», NHR, NR,, pyrrolidin-1-vyl, piperidin-1-yl1, benzyloxy, SO,NH,, SO,NHR,
SO,NR;, -CONHR, =-CONR,, =-(CHz)n-NH;, -(CH:)a-NHR, - (CH2) n=NR2, =0~ (CHz) n~NHaz, —-0= (CHz2) n—NHR, -0-(CH3) a—-NR>, R? or together by -0-(CH3),-0-, or are NH,-substituted isoquinolinyl,
R* is -C(=NH)-NH, which is unsubstituted or monosubstituted by -COR, -COOR, -OH or by a conventional amino protective group or -NH-C (=NH) =NH,, -C(=0)-N=C (NH;) 2, ~Mo ~¢™o
HN— or N= 0 CH,
A is alkyl having 1-4 C atoms,
Hal is F, Cl, Br or I, m is 1 or 2, n is 0 or 1, and their salts and solvates.
The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. alcoholates, of these compounds.
The invention is based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very useful pharmacological properties together with good tolerability. In particular, they show factor Xa-inhibiting properties and can therefore be employed for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
The compounds of the formula I according to the invention can furthermore be inhibitors of the clotting factors factor VIIa, factor IXa and thrombin of the blood clotting cascade.
Aromatic amidine derivatives having antithrombotic action are disclosed, for example, in EP 0 540 051 Bl.
Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165.
Aromatic heterocycles having factor Xa-inhibitory activity are disclosed, for example, in WO 96/10022.
Substituted N-[(aminoiminomethyl)phenylalkyl]- azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibiting action against the activated clotting protease, known under the name factor Xa, or to the
: inhibition of other activated serine proteases such as factor VIIa, factor IXa or thrombin.
Factor Xa is one of the proteases which is involved in the complex process of blood clotting. Factor Xa catalyses the conversion of prothrombin into thrombin.
Thrombin cleaves fibrinogen into fibrin monomers which, after crosslinking, contribute elementarily to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. Inhibition of thrombin, however, can inhibit the fibrin formation involved in thrombus formation.
The inhibition of thrombin can be measured, for example, by the method of G.F. Cousins et al. in
Circulation 1996, 94, 1705-1712.
Inhibition of factor Xa can thus prevent thrombin being formed.
The compounds of the formula I according to the invention and their salts intervene in the blood clotting process by inhibition of factor Xa and thus inhibit the formation of thrombi.
The inhibition of factor Xa by the compounds according to the invention and the anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable procedure is described, for example, by J. Hauptmann et al. in
Thrombosis and Haemostatis 1990, 63, 220-223.
The inhibition of factor Xa can be measured, for example, by the method of T. Hara et al. in Thromb.
Haemostas. 1994, 71, 314-319.
After binding to tissue factor, the clotting factor
VIIa initiates the extrinsic part of the «clotting cascade and contributes to the activation of factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus subsequent thrombin formation.
The inhibition of factor VIIa by the compounds according to the invention and the anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A customary procedure for the measurement of the inhibition of factor VIIa is described, for example, by H.F. Ronning et al. in
Thrombosis Research 1996, 84, 73-81.
The clotting factor IXa is generated in the intrinsic clotting cascade and is likewise involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore prevent factor Xa being formed in another way.
The inhibition of factor IXa by the compounds according to the invention and the anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable procedure is described, for example, by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
The invention relates to the compounds of the formula I and their salts, and to a process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) they are set free from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent, by o - 5 - 2! * i) liberating an amidino group from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, ii) replacing a conventional amino protective group by hydrogen by treating with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protective group, or b) in a compound of the formula I, one or more radicals R, R!, R? and/or R® are converted into one or more radicals R, R!, R? and/or R?, by, for example i) hydrolysing an ester group to a carboxyl group ii) reducing a nitro group iii) acylating an amino group iv) converting a cyano group into an amidino group and/or
Cc) a base or acid of the formula I is converted into one of its salts.
For all radicals which occur a number of times, it is a condition that their meanings are independent of one another.
Above and below, the radicals and parameters R, R', R?,
R® and n have the meanings indicated in the formula I, if not expressly stated otherwise.
@® - 6 - ! tT R is alkyl, is unbranched (linear) or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6, C atoms. R is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, in addition also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- cr 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1l-ethyl-1- methylpropyl, 1l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2- trimethylpropyl. R is also cycloalkyl and is preferably cyclopropyl, cyclobutyl, «cyclopentyl, cyclohexyl or cycloheptyl.
A is alkyl having 1, 2, 3 or 4 C atoms and is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Hal is preferably F, Cl or Br, but also I.
Ar and Ar' are phenyl, benzodioxol-5-yl, naphthyl or biphenyl, in each case independently of one another unsubstituted or mono-, di- or trisubstituted by R, OH,
OR, Hal, CN, NO, CF;, NH;, NHR, NR, pyrrolidin-1-yl, piperidin-1-yl1, benzyloxy, SO,NH,, SO,NHA, SO,NR,, phenylsulfonamido, -(CH;),-NHz, =(CHz),-NHR, -(CH3z),-NRy, -0- (CH) n~NH;, -0-(CH;)n—-NHR, ~0O-(CH;),-NRy, -0-(CHj3)n-0- or R*, naphthyl or biphenyl monosubstituted by amidino being preferred. Preferred substituents for biphenyl are amidino, fluorine, SO,NH; or SO;NHR.
Ar and Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another preferably unsubstituted, phenyl, naphthyl or biphenyl, furthermore preferably, for example, mono-, di- or trisubstituted by methyl, ethyl, propyl, isopropyl, butyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoexy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino,
® | - 7 - ' _ dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl1, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfon- amido, aminomethyl, aminoethyl, N-methylaminomethyl, N- ethylaminomethyl, N,N-dimethylaminomethyl, amino- methyloxy, aminoethyloxy or R' and in addition benzodioxolyl.
Ar and Ar' are therefore, in each case independently of one another, very particularly preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylamino- carbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (N,N-dimethylamino) phenyl, o-, m- or p- (N,N- dimethylaminocarbonyl)phenyl, o-, m- or p- (N- ethylamino) phenyl, o-, m- or p-(N,N- diethylamino) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m~- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) phenyl, o-, m- or p-amidinophenyl, 7J-amidino-2-naphthyl, 2'-amidinobiphenyl-3-vy1, 3- fluoro-2'-sulfamoylbiphenyl-4-vyl, 3-fluoro-2'-N-tert- butylsulfamoylbiphenyl-4-yl, 2'-sulfamoylbiphenyl-4-yl, 2'-N-tert-butylsulfamoylbiphenyl-4-yl, o-, m- or p- (pyrrolidin-1-yl) phenyl, o-, m- or p=-(piperidin-1- vyl)phenyl, o-, m- or p-{5-methyl[l,2,4]oxadiazol-3~ yl) }phenyl, 7-{5-methyl[1l,2,4]oxadiazol-3-yl) }naphth-2- yl, o-, m- or p-{5-oxo[1l,2,4]oxadiazol-3-yl) }phenyl, 7- {5-oxo([1l,2,4)oxadiazol-3-yl) }naphth-2-yl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4- dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4- chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-
® - 8 - ‘ : S5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N- dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4~-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2- hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro- 4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4- bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6- methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro~4- acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6- methylphenyl, 3-chloro-4-acetamidophenyl or 2,5- dimethyl-4-chlorophenyl.
R® is preferably, for example, H, Hal, COOH, COOA or
CONH,.
R* is preferably, for example, unsubstituted -C (=NH) -NH,;, =-NH-C(=NH)-NH;, -C(=0)-N=C(NH;),, which can also be monosubstituted by OH, t~Mo t~¢™o
HN— or N={ o CH, very particularly preferably unsubstituted or OH- substituted -C(=NH)~NH, or ~"o =
CH, m is 1 or 2. n is preferably 0 or 1.
R3 R3
N N
_N | Ker, a ASI "
R2 n 1s R2 \ © © (CHR!
9 - 9 -
RY FHI
N nM JR or RZ N (1B). 0
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms.
Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae
Ia to Ii, which correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which in Ia Ar is phenyl, naphthyl or biphenyl which is monosubstituted by RY; in Ib Ar’ is phenyl, naphthyl or biphenyl which is monosubstituted by SO;NH; or RY; in Ic Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another monosubstituted by SO;NH; or RY; in Id Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another monosubstituted by -CONR;, SO;NH; or
RY; in Ie R’ is H, R, Hal, COOH or COOA; in If RR is SO;NH, or -C(=NH)-NH, or (~Mo v=
CH,
! in Ig R is unbranched or branched alkyl having 1-6 C atoms or cycloalkyl having 3-6 C atoms,
Rr? is Ar,
R? is Ar'
R’ is H, R, Hal, COOH or COOA,
Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another monosubstituted by -CONR,;, SO;NH; or
RY,
Rr is -C(=NH)-NH; or (~Mo v=
CH,
A is alkyl having 1-4 C atoms,
Hal is F, Cl, Br or I, m is 1 or 2, n is 0 or in Ih R is H or unbranched or branched alkyl having 1-6 C atoms or cycloalkyl having 3-6 C atoms, rR} is Ar,
R? is Ar',
R’ is H, R, Hal, COOH or COOA,
Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another monosubstituted by SO;NH; or RY,
R* is -C(=NH)-NH; or (~Mo =
CH,
A is alkyl having 1-4 C atoms,
Hal is F, Cl, Br or I, m is 1 or 2, n is 0 or 1; in Ii R is H or unbranched or branched alkyl having 1-6 C atoms or cycloalkyl having 3-6 C atoms,
. ® - 11 ~ ‘ rR} is Ar,
R? is Ar', rR? is H, R, Hal, COOH or COOA,
Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another monosubstituted by SO,NHR or RY, or are NHj;-substituted isoquinolinyl,
Rr? is unsubstituted or OH-substituted -C(=NH) -NH, or (~Mo
N= i" CH,
A is alkyl having 1-4 C atoms,
Hal is F, Cl, Br or I, m is 1 or 2, n is 0 or 1.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-
Weyl, Methoden der organischen Chemie [Methods of
Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
The starting substances can, if desired, also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by setting compounds of the formula I free from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent.
Claims (19)
1. Compounds of the formula I R3
—. AN N “(CH,) —R! R2 2/n . Oo in which R is H or unbranched or branched alkyl having 1-6 C atoms or cycloalkyl having 3-6 C atoms, Rr! is Ar, R? is Ar', R’ is H, R, R!, Hal, CN, COOH, COOA or CONHy, Ar, Ar' are phenyl, naphthyl or biphenyl, in each case independently of one another unsubstituted or mono-, di- or trisubstituted by R, OH, Hal, CN, NO, CFj, NH,, NHR, NR;, pyrrolidin-l-yl, piperidin- 1-vy1, benzyloxy, SO,NH,, SO,NHR, SO,NR,, —CONHR, -CONR2, - (CH) n—NH;, - (CH) n,—-NHR, = (CHz2) n—=NRgz, -0- (CHz) n—NHz, ~0- (CHz2) n—NHR, -0-(CH;) n—NR>, rR? or together by -O0- (CH2) n=0O-, or are NH,-substituted isoquinolinyl, R* is -C(=NH)-NH, which is unsubstituted or monosubstituted by -COR, -COOR, -OH or by a conventional amino protective group or -C (=NH) -NH; or -NH-C (=NH) —-NH,, -C (=0) -N=C (NH2) 2, m—{ or N= 0 CH, A is alkyl having 1-4 C atoms,
~ Hal is F, Cl, Br or I, m is 1 or 2, n is 0 or 1, and their salts and solvates.
2. Compounds according to Claim 1 a) 2-isopropyl-3-(3-amidinobenzyl)-5-(3- amidinophenyl)-3, 5-dihydrcimidazo (4, 5- clpyridin-4-one; and their salts. and their salts and solvates.
3. Process for preparing compounds of the formula I according to Claim 1, and their salts, characterized in that a) they are set free from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent, by i) liberating an amidino group from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, ii) replacing a conventional amino protective group by hydrogen by treating with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protective group, or b) in a compound of the formula I, one or more radicals R, RY, R? and/or R® are converted into one or more radicals R, RY, R? and/or R3, by, for example
* Fr PCT/EP99/10236 i) hydrolysing an ester group to a carboxyl group, ii) reducing a nitro group, iii) acylating an amino group, iv) converting a cyano group into an amidino group and/or c) a base or acid of the formula I is converted into one of its salts.
4. Process for producing producing pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary.
5. Pharmaceutical preparation, characterized in that it comprises at least one compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts.
6. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates as pharmaceutically active compounds. AMENDED SHEET
7. Use of a compound of the formula I according to Claim 1 or its physiologically acceptable salts in the manufacture of a preparation for controlling thromboses, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
8. Use of a compound of the formula I according to Claim 1 or its physiologically acceptable salts in the manufacture of a preparation for use as an inhibitor of the coagulation factor Xa.
9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for producing a medicament.
10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts in control of thromboses, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
11. A substance or composition for use in a method for controlling thromboses, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication, said substance or composition comprising a compound as claimed in Claim 1 or its physiologically acceptable salts, and said method comprising administering said substance or AMENDED SHEET o PCT/EP99/10236 - 3 6 - composition.
12. A substance or composition for use as an inhibitor of the coagulation factor Xa, said substance or composition comprising a compound of the formula I and said method comprising administering said substance or composition.
13. A compound according to Claim 1, substantially as herein described and illustrated.
14. A process according to Claim 3, substantially as herein described and illustrated.
A process according to Claim 4, substantially as herein described and illustrated.
16. A preparation according to Claim 5, substantially as herein described and illustrated.
17. Use according to any one of Claims 7 to 10, substantially as herein described and illustrated.
18. A substance or composition for use in a method of treatment according to Claim 11 or Claim 12, substantially as herein described and illustrated.
19. A new compound, a new process for preparing a compound, a new process for producing a preparation, a new preparation, new use of a compound as claimed in Claim 1, or a physiologically acceptable salt or AMENDED SHEET é PCT/EP99/10236 solute thereof, or a substance or composition for a new use in a method of treatment, substantially as herein described.
AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19900471A DE19900471A1 (en) | 1999-01-08 | 1999-01-08 | Imidazo [4,5c] pyridin-4-one derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200106454B true ZA200106454B (en) | 2002-11-06 |
Family
ID=7893790
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200106454A ZA200106454B (en) | 1999-01-08 | 2001-08-06 | Imidazo[4,5-c]-pyridine-4-on-derivatives. |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP1149099A2 (en) |
| JP (1) | JP2002534429A (en) |
| KR (1) | KR20010086085A (en) |
| CN (1) | CN1333772A (en) |
| AR (1) | AR022220A1 (en) |
| AU (1) | AU3041700A (en) |
| BR (1) | BR9916774A (en) |
| CA (1) | CA2357771A1 (en) |
| CZ (1) | CZ20012407A3 (en) |
| DE (1) | DE19900471A1 (en) |
| HU (1) | HUP0105054A3 (en) |
| NO (1) | NO20013384L (en) |
| PL (1) | PL349341A1 (en) |
| SK (1) | SK9442001A3 (en) |
| WO (1) | WO2000040583A2 (en) |
| ZA (1) | ZA200106454B (en) |
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| BR9917080A (en) | 1998-12-23 | 2002-03-12 | Du Pont Pharm Co | Compound, pharmaceutical composition, use of the compound and method of treatment or prevention of thromboembolic dysfunction |
| JP2004501918A (en) | 2000-06-23 | 2004-01-22 | ブリストル−マイヤーズ スクイブ ファーマ カンパニー | 1- (Heteroaryl-phenyl) -fused pyrazole derivatives as factor Xa inhibitors |
| CA2447488A1 (en) | 2001-05-22 | 2002-11-28 | Irina Jacobson | Bicyclic inhibitors of factor xa |
| GB0215293D0 (en) | 2002-07-03 | 2002-08-14 | Rega Foundation | Viral inhibitors |
| GB0225399D0 (en) * | 2002-10-31 | 2002-12-11 | Merck Sharp & Dohme | Therapeutic agents |
| AU2003302238A1 (en) | 2002-12-03 | 2004-06-23 | Axys Pharmaceuticals, Inc. | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors |
| EP1706403B9 (en) | 2003-12-22 | 2012-07-25 | K.U.Leuven Research & Development | Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment |
| SI1841765T1 (en) | 2004-12-21 | 2009-08-31 | Gilead Sciences Inc | IMIDAZO?á4,5-C?åPYRIDINE COMPOUND AND METHOD OF ANTIVIRAL TREATMENT |
| BRPI0613045A2 (en) | 2005-07-15 | 2010-12-14 | Hoffmann La Roche | heteroaryl fused cyclic amines |
| PT1942898E (en) | 2005-09-14 | 2011-12-20 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetes |
| JP5122462B2 (en) | 2005-09-16 | 2013-01-16 | 武田薬品工業株式会社 | Dipeptidyl peptidase inhibitor |
| WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| PL2038275T3 (en) | 2006-07-07 | 2010-08-31 | Gilead Sciences Inc | Novel pyridazine compound and use thereof |
| TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| UA99466C2 (en) | 2007-07-06 | 2012-08-27 | Гилиад Сайенсиз, Инк. | Crystalline pyridazine compound |
| BR112017002598B1 (en) * | 2014-08-12 | 2022-03-03 | Syngenta Participations Ag | Pesticide-active heterocyclic derivatives with sulfur-containing substituents |
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| EP1039907A4 (en) * | 1997-12-01 | 2001-09-19 | Merck & Co Inc | Thrombin inhibitors |
-
1999
- 1999-01-08 DE DE19900471A patent/DE19900471A1/en not_active Withdrawn
- 1999-12-21 CA CA002357771A patent/CA2357771A1/en not_active Abandoned
- 1999-12-21 HU HU0105054A patent/HUP0105054A3/en unknown
- 1999-12-21 CN CN99815465A patent/CN1333772A/en active Pending
- 1999-12-21 WO PCT/EP1999/010236 patent/WO2000040583A2/en not_active Application Discontinuation
- 1999-12-21 AU AU30417/00A patent/AU3041700A/en not_active Abandoned
- 1999-12-21 SK SK944-2001A patent/SK9442001A3/en unknown
- 1999-12-21 KR KR1020017007074A patent/KR20010086085A/en not_active Application Discontinuation
- 1999-12-21 CZ CZ20012407A patent/CZ20012407A3/en unknown
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- 1999-12-21 BR BR9916774-3A patent/BR9916774A/en not_active Application Discontinuation
- 1999-12-21 EP EP99964639A patent/EP1149099A2/en not_active Withdrawn
- 1999-12-21 JP JP2000592291A patent/JP2002534429A/en active Pending
-
2000
- 2000-01-07 AR ARP000100062A patent/AR022220A1/en unknown
-
2001
- 2001-07-06 NO NO20013384A patent/NO20013384L/en not_active Application Discontinuation
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| Publication number | Publication date |
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| NO20013384D0 (en) | 2001-07-06 |
| PL349341A1 (en) | 2002-07-15 |
| AU3041700A (en) | 2000-07-24 |
| CN1333772A (en) | 2002-01-30 |
| CA2357771A1 (en) | 2000-07-13 |
| NO20013384L (en) | 2001-07-06 |
| JP2002534429A (en) | 2002-10-15 |
| KR20010086085A (en) | 2001-09-07 |
| BR9916774A (en) | 2001-10-30 |
| AR022220A1 (en) | 2002-09-04 |
| HUP0105054A3 (en) | 2002-12-28 |
| WO2000040583A3 (en) | 2000-09-21 |
| WO2000040583A2 (en) | 2000-07-13 |
| EP1149099A2 (en) | 2001-10-31 |
| CZ20012407A3 (en) | 2001-12-12 |
| HUP0105054A2 (en) | 2002-05-29 |
| DE19900471A1 (en) | 2000-07-13 |
| SK9442001A3 (en) | 2002-05-09 |
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