ZA200202287B - Novel integrin alphavbeta3 inhibitors. - Google Patents
Novel integrin alphavbeta3 inhibitors. Download PDFInfo
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- ZA200202287B ZA200202287B ZA200202287A ZA200202287A ZA200202287B ZA 200202287 B ZA200202287 B ZA 200202287B ZA 200202287 A ZA200202287 A ZA 200202287A ZA 200202287 A ZA200202287 A ZA 200202287A ZA 200202287 B ZA200202287 B ZA 200202287B
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- South Africa
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- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 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
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal 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
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000002997 osteoclast Anatomy 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
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 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
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000007017 scission Effects 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960002415 trichloroethylene Drugs 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Description
hE ES TCE. YI CY - i 2 ¥ ® : 400 20 - 1 - *
Novel inhibitors of the integrin o.fs
The invention relates to novel compounds of the formula I
X-Y-Z-R!-CH,-R? (R*) -CH,-CO-R’ I in which
X is HyN-C(=NH)-, HN-C(=NH)-NH-, A-C(=NH) -NH-, Het'- or Het!-NH-, where the primary amino groups can also be provided with conventional amino protective groups, ; :
Y is - ~(CHa)a-, (CHy)7 (CHpo
R3 in which one, two, three or four methylene groups can be replaced by N, O and/or S,
A is absent, =-0-, -NH-, -NA-, -CH(OH)-, -CH (QA) -, : -CHA-, -CA,- or -S-, rR? is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF3 or CN,
Rr? is N, CH or CA,
R? is H, F, Cl, Br, A, OA or OCFs,
R? is phenyl, naphthyl or Het?, mono- or poly- substituted by F, Cl, Br, A, aryl, OA, SA, CO-A,
CN, COOA, CONH,, CONHA, CONA; or NO,
RS is OH, OA, NH,, NHA or NA,
A
® LL
Het' is a mono- or binuclear heterocycle having 1 to 4
N atoms, which can be unsubstituted or mono- OI disubstituted by NHj,
Het? is an aromatic mono- or binuclear heterocycle having 1 to 3 N, O and/or S atoms, which can be unsubstituted or mono- or disubstituted by F, Cl,
Br, A, OA, SA, OCF3;, -CO-A, CN, COOA, CONH;, CONHA,
CONA; or NOg, aryl is phenyl or naphthyl, unsubstituted or mono- or polysubstituted by Hal, A, OA, OH, CO-A, CN, COCA,
COOH, CONH,, CONHA, CONA; or NO,
A is alkyl having 1-12 C atoms, n is 1, 2, 3, 4, 5 or 6, m, o in each case independently of one another are 0, 1, 2, 3, 4, 5 or ob, with the proviso that R* # a phenyl or naphthyl radical monosubstituted by A or aryl, and their physiologically acceptable salts and solvates. :
The invention was based on the object of discovering novel compounds having valuable 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 valuable pharmacological properties, together with good tolerability. They act especially as integrin inhibitors, in particular inhibiting the interactions of the Oly integrin receptors with ligands. The compounds exhibit particular activity in the case of the integrins af; oo
Lb 4002/2704 ® a and a.Bs. The compounds are very particularly active as adhesion receptor antagonists for the receptor oP.
This action can be demonstrated by the method which is described by J.W. Smith et al., in J. Biol. Chem. 263, 11008-11013 and 12267-12271 (1990).
The inhibition of vitronectin binding to the receptor o.Bs was confirmed experimentally for 3-(4-flucro- phenyl) -4-{4-[3-(pyridin-2-ylamino)propoxy}phenyl}- butyric acid.
In Curr. Opin. Cell. Biol. 5, 864 (1993),
B. Felding-Habermann and D.A. Cheresh describe the ; importance of the integrins as adhesion receptors for a wide variety of phenomena and syndromes, especially ; with respect to the receptor a.fs.
Other inhibitors of the integrin a.f3; are described in :
EP 0820988. Vitronectin receptor antagonists are also : described in WO 97/24124 and in EP 0820991.
The dependence of the origin of angiogenesis on the : interaction between vascular integrins and extracellular matrix proteins is described by
P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).
The possibility of the inhibition of this interaction and thus for the initiation of apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P.C. Brooks, A.M. Montgomery,
M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and
D.A. Cheresh in Cell 79, 1157-64 (1994).
The experimental proof that the compounds according to the invention also prevent the adhesion of living cells to the corresponding matrix proteins and accordingly also the adhesion of tumour cells to matrix proteins can be furnished in a cell adhesion test which is carried out analogously to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995). oT
{oe @0Q0° ® Ca
In J. Clin. Invest. 96, 1815-1822 (1995), P.C. Brooks et al. describe o,f; antagonists for the control of cancer and for the treatment of tumour-induced angiogenic diseases.
The compounds of the formula I according to the invention can therefore be employed as pharmaceutical active compounds, in particular for the treatment of oncoses, osteoporosis, osteolytic disorders and for the suppression of angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, of fibrinogen, on the fibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the spread of tumour cells by metastasis.
This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the vascular system takes place through the formation of nmicroaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are screened by the protection in the microaggregate and are not recognized by the cells of the immune system.
The microaggregates can attach to vessel walls, owing to which further penetration of tumour cells into the tissue is facilitated. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on the activated blood platelets, the GPIIb/IIIa antagonists can be regarded as effective metastasis inhibitors.
In addition to the binding of fibrinogen, fibronectin and of the von Willebrand factor to the fibrinogen receptor of the blood platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the formation of blood platelet thrombi and can therefore be employed oo
® — 5 - for the treatment of thromboses, apoplexy, cardiac infarct, inflammation and arteriosclerosis.
The properties of the compounds can also be demonstrated by methods which are described in
EP-A1-0 462 960. The inhibition of fibrinogen binding to the fibminogen receptor can be demonstrated by the method which is given in EP-A1-0 381 033.
The platelet aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature : 4832, 927-929, 1962). The inhibition of bone resorption by the compounds of the invention can be confirmed with the aid of a osteoclast resorption test analogously to
WO 95/32710.
The invention accordingly relates to the compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the production of a medicament for use as an integrin inhibitor. The invention relates in particular to compounds of the formula I according to Claim 1 and/or their acceptable salts for the production of a medicament for the control of pathologically angiogenic disorders, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, oncoses, osteolytic diseases such as osteoporosis, hypercalcaemia, pathologically angiogenic diseases such as, for example, inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis,
Crohn’s disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial TT
Ce - infection, fungal infection, in acute kidney failure and in wound healing for assisting the healing processes.
The compounds of the formula I can be employed as antimicrobially active substances in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic action here. The efficacy of the antimicrobial activity can be demonstrated by the process described by
P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention also relates to the hydrates and solvates, e.g. alcoholates, of these compounds.
The invention further relates to a process for the preparation of compounds of the formula I according to
Claim 1, and their salts, characterized in that a) a compound of the formula I is set free from its functional derivatives by treating with a solvolysing, reducing or hydrogenolysing agent, or : b) a radical X and/or R® is converted into another radical X and/or R®, by, for example, i) converting an amino group into a guanidino group by reaction with an amidinating agent, ii) hydrolysing an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation, and/or converting a base or acid of the formula I into one of its salts. oo
’ » ® - 7 =
The compounds of the formula I can have a chiral centre and can therefore occur in a number of stereoisomeric forms. All these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in the formula I.
So-called prodrug derivatives are also included in the compounds according to the invention, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body to the active compounds according to the invention.
The abbreviations mentioned above and below stand for: :
Ac acetyl
BOC tert-butoxycarbonyl
CBZ or Z benzyloxycarbonyl
DCCI dicyclohexylcarbodiimide
DMF dimethylformamide
EDCI N-ethyl-N,N’-(dimethylaminopropyl)carbo- diimide
Et ethyl
Fmoc 9-fluorenylmethoxycarbonyl
HOBt l-hydroxybenzotriazole
Me methyl
Mtr 4-methoxy-2, 3, 6-trimethylphenylsulfonyl
HONSu N-hydroxysuccinimide
OBut tert-butyl ester
Oct octanoyl
OMe methyl ester
OEt ethyl ester
POA phenoxyacetyl
TFA trifluoroacetic acid
Trt trityl (triphenylmethyl).
It applies to the whole invention that all radicals which occur a number of times, such as, for example, A,
® Ca can be identical or different, i.e. are independent of one another.
A is alkyl and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, l-ethyl- l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl, undecyl or docecyl. A is also alkyl substituted by : halogen, preferably CFj.
X is preferably, for example, pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1l-yl, imidazol-2-ylamino, I benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazol-5-ylamino, 2-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl.
Y is preferably, for example, ethylene, propylene or butylene.
Zz is preferably, for example, O.
R! is preferably, for example, 1,4-phenylene.
R? is preferably, for example, CH or N, very particularly CH.
R* is preferably, for example, phenyl mono- or polysubstituted by F.
R® is preferably, for example, OH.
Het! is preferably 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, unsubstituted or mono- or disubstituted by A, NHA and/or NH, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or =5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or T-benzopyrazolyl, 2-, 3-, 4-, 5-, 6-, 7- To
® Cs or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, I1- or 8-quinazolinyl, 1H-imidazo[4,5-b]pyridin-2-yl Or 1,8-naphthyridin-7-yl.
The heterocyclic radicals can also be partially or completely hydrogenated.
Het! can thus, for example, also be 2,3-dihydro-l-, -2-, =-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -=3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetra- hydro-1-, -2- or -4-imidazolyl, 4,5-dihydroimidazol- 2-yl, 2,3-dihydro-1-, -2-, =-3-, -4- or -5-pyrazolyl, tetrahydro-1-, =-3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, =-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, : -3-, -4-, -5- or =—6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, hexahydro-1-, =-3- or -4-pyridazinyl, hexahydro-1-, -2-, =-4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, =3-, -4-, -5-, -6-, =-7- or -8-quinolyl, 1,2,3,4-tetrahydro-l-, -2-, =-3-, =-4-, =5-, -6-, -7- or -8-isoquinolyl or 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl.
Hydrogenated or partially hydrogenated Het! radicals can additionally be substituted by =NH or carbonyl oxygen.
Het? is preferably 2,3-, 2,4-, 2,5- or 3,4-thienyl, 2,3-, 2,4-, 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2,4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl, unsubstituted or monosubstituted by F, Cl, Br, A, OA or OCFj. n is preferably 2, 3, 4, 5 or 6, very particularly preferably n is 3, 4 or 5. m and o are preferably, in each case independently of one another, 0, 1 or 2, very particularly preferably they are 0.
Substituted "one or more times" means mono-, di-, tri- or tetrasubstituted.
® - 10 -
Aryl is phenyl which is unsubstituted, preferably - as indicated - monosubstituted, specifically preferably phenyl, 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-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonyl- phenyl, o-, m- or p-aminophenyl, o-, m- or p-methyl- aminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m~- or p-acetylphenyl, o-, m- Or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonyl- phenyl, further 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-chloro-3-methyl-, 2-chloro- 4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl- 5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo- 3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo- 4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichloro- phenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-di- methylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro- 4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo- 6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy- 5-methylphenyl, 2,4,6-triisopropylphenyl.
Amino protective group is preferably formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy- oo
® Ca carbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbo- benzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl. 5S Accordingly, the present 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 Im, 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 a) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-l-yl, imidazol-2-yl- amino, benzimidazol-2-ylamino, 4,5-di- hydroimidazol-2-ylamino, 2-amino- 5 imidazol-5-ylamino, 2-aminopyridin- 6-ylamino, 2-aminoimidazol-5-yl or : 2-aminopyridin-6-yl; in b) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-y1, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- - hydroimidazol-2-ylamino,
Y is =-(CH2)n—, n is 2, 3 or 4; in c¢) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-yl1, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is -(CHz2)n-, n is 2, 3 or 4; in d) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-y1, imidazol-2-yl- = EE —
® S12 - amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is = (CH2) na, n is 2, 3 or 4,
Z is O; in e) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-yl1, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is = (CHz2)n-, n is 2, 3 or 4, z is 0,
R? is N or CH; : in f) X is pyrimidin-2-ylamino, pyridin-2-yl- : amino, imidazol-1-v1, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is =(CHz)n—, n is 2, 3 or 4,
Z is O,
R? is N or CH, rR? is phenyl which is mono- or poly- substituted by F, Cl, Br, OA, OCF, . -CO-A, CN, COOA, CONH; or NO; in g) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-yl, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is -(CHz)n—, n is 2, 3 or 4,
Z is O,
R? is N or CH,
Rr is phenyl which is mono- or poly- substituted by F, Cl, Br, OA or OCFj3;
R® is OA or OH; hn
® C13 - in h) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-y1, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is -(CHjz)n—, n is 2, 3 or 4,
Z is O,
Rr? is N or CH,
R* is phenyl which is mono- or poly- substituted by F,
R® is OA or OH; : in 1) X is pyrimidin-2-ylamino, pyridin-2-yl- E amino, imidazol-1-yl, imidazol-2-yl- - amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is -(CHz2)a—, n is 2, 3 or 4,
Z is O,
R? is N or CH, rR? is phenyl which is mono- or poly- substituted by Hal, A or aryl,
R® is OA or OH with the proviso that R' is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl; in k) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-yl, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino, p4 is -(CHz2)n—, n is 2, 3 or 4, yA is 0,
R? is N or CH,
R* is phenyl which is substituted by Hal and aryl,
R® is OA or OH
J Cw with the proviso that R* is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl; in 1) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1l-yl1, imidazol-2-yl- amino, benzimidazol-2-ylamino or 4,5-di- hydroimidazol-2-ylamino,
Y is -(CHz)n—, n is 2, 3 or 4, g z is O,
R? is N or CH,
R* is phenyl which is substituted by Hal and aryl,
R® is OA or OH, aryl is phenyl which is mono-, di- or trisubstituted by Hal, A, OA, CF;3;, CN or
NO» with the proviso that R* is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl; in m) X is pyrimidin-2-ylamino, pyridin-2-yl- amino, imidazol-1-yl, imidazol-2-yl- amino, benzimidazol-2-ylamino, 4,5-di- - hydroimidazol-2-ylamino, 2-amino- imidazol-5-ylamino, 2-aminopyridin-6-yl- amino, 2-aminoimidazol-5-yl or 2-amino- pyridin-6-yl,
Y is -(CHz)n—, n is 2, 3 or 4,
Z is O,
R? is N or CH,
R* is phenyl which is mono- or poly- substituted by Hal, A or aryl,
R’ is OA or OH with the proviso that R* is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl. oo
® - 15 -
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.
If desired, the starting substances can 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 liberating compounds of the formula I from one of : their functional derivatives by treating with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably those which, instead of an H atom which is linked to an N atom, carry an amino protective group, in particular those which, instead of an HN group, carry an R’ N group in which R’ is an amino protective group, and/or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR”, in which R” is a hydroxyl protective group.
It is also possible for a number of - identical or different - protected amino and/or hydroxyl groups to oo be present in the molecule of the starting substances.
If the protective groups present are different from one another, in many cases they can be removed selectively.
The expression “amino protective group” is generally known and relates to groups which are suitable for protecting (or blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired : reaction (or reaction sequence), their nature and size : is otherwise not critical; however, those having 1-20, : in particular 1-8, C atoms are preferred. The expression “acyl group” is to be interpreted in the : widest sense in connection with the present process. It : includes acyl groups derived from aliphatic, . araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, : aryloxycarbonyl and especially aralkoxycarbonyl groups.
Examples of acyl groups of this type are formyl or alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy- carbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (“carbobenzoxy”), 4-methoxybenzyloxy- carbonyl, Fmoc; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, additionally
CBZ, Fmoc, benzyl, formyl and acetyl.
The removal of the amino protective group takes place - depending on the protective group used - e.g. using strong acids, expediently using TFA or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or oo
® - 17 - sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DME’, halogenated hydrocarbons such as dichloromethane, additionally also alcohols such as methanol, ethanol or isopropanol, and also water. Mixtures of the above- mentioned solvents are additionally suitable. TFA 1is preferably used in an excess without addition of a : further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the i ratio 9:1. The reaction temperatures for the cleavage are expediently between approximately 0 and approximately 50°; the reaction is preferably carried out at between 15 and 30° (room temperature).
The groups BOC, OBut and Mtr can preferably be removed, ’ for example, using TFA in dichloromethane or using : approximately 3 to 5N HCl in dioxane at 15-30°, the
Fmoc group using an approximately 5 to 50% strength solution of secondary amines such as dimethylamine, diethylamine or piperidine in DMF at 15-30°.
Hydrogenolytiecally removable protective groups (e.g.
CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as
DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100° and pressures between approximately 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group takes place well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°. oT
® C18 -
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloro- ethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane: alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, : dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds ~ such as nitromethane or nitrobenzene; esters such as ethyl acetate, water or mixtures of the solvents mentioned.
It is furthermore possible to hydrolyse an ester of the formula I. Expediently, this is carried out by e solvolysis or hydrogenolysis, as indicated above, e.g. using LiOH in methanol, NaOH or KOH in dioxane/water at temperatures between 0 and 60°C, preferably between 10 and 40°C.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxyl- amine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd/C.
It is furthermore possible to replace a conventional amino protective group by hydrogen by removing the protective group, as described above, solvolytically or hydrogenolytically or by liberating an amino group protected by a conventional protective group by solvolysis or hydrogenolysis. oo
® - 19 -
For the preparation of compounds of the formula I in which X is HyN-C(=NH)-NH-, an appropriate amino compound can be treated with an amidinating agent. A preferred amidinating agent is l-amidino-3,5-di- methylpyrazole (DPFN), which is particularly employed in the form of its nitrate. The reaction is expediently carried out with addition of a base such as tri- ethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. water/dioxane at temperatures ) between 0 and 120°C, preferably between 60 and 120°C. :
For the preparation of an amidine of the formula I ; (X = -C(=NH)~-NH,), ammonia can be added to a nitrile of the formula I (X = CN). The addition is preferably carried out in a number of stages by a) converting the nitrile in a manner known per se using HS into a thiocoamide, which is converted using an alkylating agent, e.g. CH3I, into the corresponding S-alkyl- imidothiocester, which for its part reacts with NH3 to give the amidine, b) converting the nitrile using an alcohol, e.g. ethanol in the presence of HCl, into the corresponding imidoester and treating this with ammonia, or c) reacting the nitrile with lithium bis- (trimethylsilyl)amide and then hydrolysing the product.
The release of the compounds of the formula I from an oxidized precursor, by, for example, reducing an oxy- heterocycle using a reducing agent such as, for example, phosphorus trichloride in an inert solvent, is furthermore preferred.
Furthermore, free amino groups can be acylated in the customary manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, expediently in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and +30°.
® - 20 -
A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition : organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the : formula I.
On the other hand, an acid of the formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base.
Possible salts here are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, in addition substituted ammonium salts, e.g. the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl-, dicyclohexylammonium salts, dibenzyl- ethylenediammonium salts, furthermore, for example, salts with arginine or lysine. oo
® - 21 -
The compounds of the formula I contain one or more chiral centres and can therefore be present in racemic or in optically active form. Racemates obtained can be separated into the enantiomers mechanically or chemically by methods known per se. Preferably, diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent.
Suitable resolving agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, : mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as
B-camphorsulfonic acid. Resolution of enantiomers with the aid of a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine) is also advantageous; a suitable eluent is, for example, a mixture of hexane/isopropanol/acetonitrile, e.g. in the volume ratio 82:15:3.
Of course, it is also possible to obtain optically active compounds of the formula I according to the methods described above, by using starting substances which are already optically active.
The invention- includes not only the compounds mentioned but also mixtures and preparations which, in addition to these compounds according to the invention, also contain other pharmacological active compounds or adjuvants which can influence the primary pharmacological action of the compounds according to the invention in the desired manner. These can be used as therapeutics, diagnostics or as reagents. They can be given to man or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally, or iontophoretically, which includes formulations in suspensions, emulsions or solutions, liposomes, ointments, pastes, biodegradable polymers or oo
® - 22 - as nanoparticles, tablets, capsules or pills, granules or powders, as an aerosol for inhaling, as intranasal drops or sprays. A combination of the novel products with other techniques, such as surgery, irradiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy, as well as with other medicaments is also possible. Such medicaments can originate, for example, from the cardiovascular, central nervous system Or oncology fields. They can be tumour agents, such as angiogenesis inhibitors or cytostatics, chemotherapeutics of the groups alkylating agents, antibiotics, antimetabolites, biologicals and immunomodulators, hormones and their antagonists, mustard gas derivatives, alkaloids and others, where . these substances can be of low molecular weight or high : molecular weight. They can be lipids, carbohydrates or proteins. Also included amongst these are cytokines, toxins, fusion proteins, monoclonal antibodies and vaccines.
The invention accordingly relates to compounds of the formulae defined above and below and also in the claims, including their physiologically acceptable salts, as medicaments, diagnostics or reagents.
The invention relates in particular to corresponding medicaments as inhibitors for the control of disorders which are based indirectly or directly on expression of the a.f3 integrin receptor, thus in particular in the case of pathologically angiogenic disorders, thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and also for influencing wound-healing processes.
The invention also relates to corresponding pharmaceutical preparations which contain at least one medicament of the formula I and, if appropriate, vehicles and/or excipients. oT
® C23 -
The invention furthermore relates to the use of the compounds and/or their physiologically acceptable salts according to the claims and the description for the production of a medicament for the control of disorders which are based indirectly or directly on expression of the o.Bfs integrin receptor, thus in particular in the case of pathologically angiogenic disorders, thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and for influencing wound-healing processes. :
The medicaments according to the invention or pharmaceutical preparations comprising them can be used as medicaments in human or veterinary medicine. E
Suitable vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application or for application in the form of an inhalation spray and do : not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used, in particular, for rectal administration, solutions, preferably oily or aqueous solutions, in addition suspensions, emulsions or implants, are used for parenteral administration and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain excipients such as glidants, preservatives, stabilizing and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
Claims (20)
1. Compounds of the formula I X-Y-Z-R'-CH,-R? (R*) -~CH;-CO-R® I in which X is HyN-C(=NH)-, HN-C(=NH)-NH-, A-C(=NH)-NH-, Het!- or Het!'-NH-, where the primary amino groups can also be provided with conventional amino protective groups, Y is ~«(CH2)n- ’ <{CH,)5 (CH,),- ’ R3 in which one, two, three or four methylene groups can be replaced by N, O and/or S, Z is absent, -0-, -NH-, -NA-, -CH (CH) -, -CH(OA)~-, -CHA-, -CA;- or -S-, R! is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF3; or CN, R? is N, CH or CA, R’ is H, F, Cl, Br, A, OA or OCFj, R* is phenyl, naphthyl or Het?, mono- or poly- substituted by F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH,, CONHA, CONA; or NOz, X R®> is OH, OA, NH, NHA or NA, _
® Cas Het! is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NH, Het? is an aromatic mono- or binuclear heterocycle having 1 to 3 N, O and/or S atoms, which can be unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONH,, CONHA, CONA; or NO, aryl is phenyl or naphthyl, unsubstituted or mono- or polysubstituted by Hal, A, OA, OH, COC-A, CN, COOA, COOH, CONH;, CONHA, CONA; or NO, E A is alkyl having 1-12 C atoms, n is 1, 2, 3, 4, 5 or 6, m, o in each case independently of one another are 0, 1, 2, 3, 4, 5 or 6, : with the proviso that R* is not equal to a phenyl or naphthyl radical monosubstituted by A or aryl, and their physiologically acceptable salts and solvates.
2. Compounds according to Claim 1 a) 3-(4-fluorophenyl)-4-{4-([3-(pyridin-2-ylamino)- propoxylphenyl}butyric acid, b) 3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridin- 6-ylamino)propoxylphenyllbutyric acid, c) 3-(4-fluorophenyl)-4-{4-[3-(2-aminoimidazol- 5-ylamino)propoxylphenyllbutyric acid,
® C36 - and their physiologically acceptable salts and solvates.
3. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) a compound of the formula I is set free from its functional derivatives by treating with a solvolysing, reducing or hydrogenolysing agent, or ; b) a radical X and/or R’ is converted into another : radical X and/or R®, by, for example, i) converting an amino group into a guanidino 2 group by reaction with an amidinating agent, ii) hydrolysing an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation, and/or converting a base or acid of the formula I into one of its salts.
4. Compounds of the formula I according to Claim 1 and the compounds according to Claim 2, and their physiologically acceptable salts and solvates as medicaments.
5. Medicament according to Claim 4 as an inhibitor for the control of disorders which are based on expression and pathological function of auf; integrin receptors.
® co &8002/:287
6. Medicament according to Claim 5 for the control of thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, fibroses, inflammation, infections, psoriasis and also for influencing wound-healing processes.
7. Pharmaceutical preparation, comprising at least one medicament according to one of Claims 5 and 6 and, if appropriate, vehicles and/or excipients and, if appropriate, other active compounds.
8. Use of compounds according to Claims 1 and 2 and/or their physiologically acceptable salts for the production of a medicament for the control of disorders which are based on expression and pathological function of a.f3 integrin receptors.
9. Use according to Claim 8 for the production of a medicament for the control of pathological processes which are supported or propagated by angiogenesis.
10. Use according to Claim 8 for the production of a medicament for the control of thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, fibroses, inflammation, infections, psoriasis and for influencing wound-healing processes.
ff : PCT/EP00/07591
11. A substance or composition for use in a method for the control of disorders which are based on expression and pathological function of o,f; integrin receptors, said substance or composition comprising a compound according to Claim 1 or Claim 2 or a physiologically acceptable salt thereof, and said method comprising administering said substance or composition
12. A substance or composition for use in a method of treatment according to Claim 11 for the control of pathological processes which are supported or propagated by angiogenesis.
13. A substance or composition for use in a method of treatment according to Claim 11, for the control of thromboses, cardiac infarcts, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, fibroses, inflammation, infections, psoriasis and for influencing wound-healing processes.
14. A compound according to Claim 1 or Claim 4, substantially as herein described and illustrated.
15. A process according to Claim 3, substantially as ’ herein described and illustrated.
16. A medicament according to Claim 5, substantially as herein described and illustrated.
17. A preparation according to Claim 7, substantially as herein described and illustrated.
18. Use according to Claim 8 or Claim 9 or Claim 10, substantially as herein described and illustrated. AMENDED SHEET —
PCT/EP00/07591
19. A substance or composition for use in a method of treatment according to Claim 11 or Claim 12 or Claim 13, substantially as herein described and illustrated.
20. A new compound, a new medicament, a new preparation, a new process for the preparation of a compound, a new use of a compound according to Claim 1 or Claim ) 2 or of a physiologically acceptable salt 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 |
---|---|---|---|
DE19939981A DE19939981A1 (en) | 1999-08-24 | 1999-08-24 | New inhibitors of the integrin alphavß3 |
Publications (1)
Publication Number | Publication Date |
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ZA200202287B true ZA200202287B (en) | 2003-08-27 |
Family
ID=7919343
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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ZA200202287A ZA200202287B (en) | 1999-08-24 | 2002-03-20 | Novel integrin alphavbeta3 inhibitors. |
Country Status (17)
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EP (1) | EP1206454A1 (en) |
JP (1) | JP2003507458A (en) |
KR (1) | KR20020016651A (en) |
CN (1) | CN1370147A (en) |
AU (1) | AU6570500A (en) |
BR (1) | BR0013504A (en) |
CA (1) | CA2382850A1 (en) |
CZ (1) | CZ2002523A3 (en) |
DE (1) | DE19939981A1 (en) |
HK (1) | HK1049666A1 (en) |
HU (1) | HUP0203697A3 (en) |
MX (1) | MXPA02001861A (en) |
NO (1) | NO20020886D0 (en) |
PL (1) | PL352989A1 (en) |
SK (1) | SK2282002A3 (en) |
WO (1) | WO2001014338A1 (en) |
ZA (1) | ZA200202287B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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PE20020665A1 (en) | 2000-06-15 | 2002-08-14 | Pharmacia Corp | CYCLOALKYL PHENYL ALCANOIC ACID AS ANTAGONIST OF INTEGRINS OVß3 |
US6531494B1 (en) | 2001-08-29 | 2003-03-11 | Pharmacia Corporation | Gem-substituted αvβ3 antagonists |
ES2436170T3 (en) * | 2003-12-03 | 2013-12-27 | The Scripps Research Institute | Antibodies and peptides specific for integrin alfa II beta3 |
EP1802618A1 (en) * | 2004-10-14 | 2007-07-04 | Pharmacia Corporation | Biphenyl integrin antagonists |
US10717736B2 (en) * | 2016-11-08 | 2020-07-21 | Bristol-Myers Squibb Company | Pyrrole amides as alpha V integrin inhibitors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH08325264A (en) * | 1995-05-31 | 1996-12-10 | Sumitomo Metal Ind Ltd | New 2-aromatic ring-substituted-3-phenylpropionic acid or acrylic acid derivative |
AU717283B2 (en) * | 1996-10-30 | 2000-03-23 | Merck & Co., Inc. | Integrin antagonists |
EP1061921A4 (en) * | 1998-03-10 | 2005-03-30 | Smithkline Beecham Corp | Vitronectin receptor antagonists |
-
1999
- 1999-08-24 DE DE19939981A patent/DE19939981A1/en not_active Withdrawn
-
2000
- 2000-08-04 WO PCT/EP2000/007591 patent/WO2001014338A1/en not_active Application Discontinuation
- 2000-08-04 CZ CZ2002523A patent/CZ2002523A3/en unknown
- 2000-08-04 EP EP00953158A patent/EP1206454A1/en not_active Withdrawn
- 2000-08-04 CN CN00811950A patent/CN1370147A/en active Pending
- 2000-08-04 PL PL00352989A patent/PL352989A1/en unknown
- 2000-08-04 MX MXPA02001861A patent/MXPA02001861A/en unknown
- 2000-08-04 SK SK228-2002A patent/SK2282002A3/en unknown
- 2000-08-04 CA CA002382850A patent/CA2382850A1/en not_active Abandoned
- 2000-08-04 AU AU65705/00A patent/AU6570500A/en not_active Abandoned
- 2000-08-04 JP JP2001518427A patent/JP2003507458A/en active Pending
- 2000-08-04 HU HU0203697A patent/HUP0203697A3/en unknown
- 2000-08-04 KR KR1020027001419A patent/KR20020016651A/en not_active Application Discontinuation
- 2000-08-04 BR BR0013504-6A patent/BR0013504A/en not_active IP Right Cessation
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2002
- 2002-02-22 NO NO20020886A patent/NO20020886D0/en not_active Application Discontinuation
- 2002-03-20 ZA ZA200202287A patent/ZA200202287B/en unknown
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2003
- 2003-03-12 HK HK03101785.4A patent/HK1049666A1/en unknown
Also Published As
Publication number | Publication date |
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NO20020886L (en) | 2002-02-22 |
EP1206454A1 (en) | 2002-05-22 |
KR20020016651A (en) | 2002-03-04 |
CZ2002523A3 (en) | 2002-05-15 |
HUP0203697A3 (en) | 2004-04-28 |
HUP0203697A2 (en) | 2003-03-28 |
WO2001014338A1 (en) | 2001-03-01 |
DE19939981A1 (en) | 2001-03-01 |
SK2282002A3 (en) | 2002-06-04 |
BR0013504A (en) | 2002-05-07 |
CN1370147A (en) | 2002-09-18 |
JP2003507458A (en) | 2003-02-25 |
NO20020886D0 (en) | 2002-02-22 |
AU6570500A (en) | 2001-03-19 |
PL352989A1 (en) | 2003-09-22 |
MXPA02001861A (en) | 2004-09-06 |
HK1049666A1 (en) | 2003-05-23 |
CA2382850A1 (en) | 2001-03-01 |
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