DE19831710A1 - Diacylhydrazinderivate - Google Patents
DiacylhydrazinderivateInfo
- Publication number
- DE19831710A1 DE19831710A1 DE19831710A DE19831710A DE19831710A1 DE 19831710 A1 DE19831710 A1 DE 19831710A1 DE 19831710 A DE19831710 A DE 19831710A DE 19831710 A DE19831710 A DE 19831710A DE 19831710 A1 DE19831710 A1 DE 19831710A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- acid
- compounds
- compound
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 108010044426 integrins Proteins 0.000 title claims description 12
- 102000006495 integrins Human genes 0.000 title claims description 12
- 206010028980 Neoplasm Diseases 0.000 title claims description 7
- 206010061218 Inflammation Diseases 0.000 title claims description 6
- 208000015181 infectious disease Diseases 0.000 title claims description 6
- 230000004054 inflammatory process Effects 0.000 title claims description 6
- 239000003112 inhibitor Substances 0.000 title claims description 6
- 208000001132 Osteoporosis Diseases 0.000 title claims description 5
- 208000007536 Thrombosis Diseases 0.000 title claims description 5
- 125000005077 diacylhydrazine group Chemical group 0.000 title abstract 2
- 206010061216 Infarction Diseases 0.000 title 1
- 230000000747 cardiac effect Effects 0.000 title 1
- 230000007574 infarction Effects 0.000 title 1
- -1 COOA Chemical group 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 66
- 125000006239 protecting group Chemical group 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 150000007513 acids Chemical class 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- PMHRIPHAMZXZRN-QMMMGPOBSA-N (3s)-4-amino-3-[2-[[3-(diaminomethylideneamino)benzoyl]carbamoyl]hydrazinyl]-4-oxobutanoic acid Chemical compound NC(N)=NC1=CC=CC(C(=O)NC(=O)NN[C@@H](CC(O)=O)C(N)=O)=C1 PMHRIPHAMZXZRN-QMMMGPOBSA-N 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 150000007514 bases Chemical class 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 208000019622 heart disease Diseases 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 3
- 229910018828 PO3H2 Inorganic materials 0.000 abstract 1
- 229910006069 SO3H Inorganic materials 0.000 abstract 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 abstract 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 abstract 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 229920005989 resin Polymers 0.000 description 22
- 239000011347 resin Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- 239000004480 active ingredient Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000003776 cleavage reaction Methods 0.000 description 13
- 230000007017 scission Effects 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 238000000132 electrospray ionisation Methods 0.000 description 10
- 238000004949 mass spectrometry Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102000008946 Fibrinogen Human genes 0.000 description 5
- 108010049003 Fibrinogen Proteins 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229940012952 fibrinogen Drugs 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- VFXDSSUGFNVDJP-UHFFFAOYSA-N 3-(9h-fluoren-9-ylmethoxycarbonylamino)benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)OCC2C3=CC=CC=C3C3=CC=CC=C32)=C1 VFXDSSUGFNVDJP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ULLSWWGYZWBPHK-UHFFFAOYSA-N 5-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)NCCCCC(=O)O)C3=CC=CC=C3C2=C1 ULLSWWGYZWBPHK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108010012088 Fibrinogen Receptors Proteins 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- DFSRRXZHWJUCFU-UHFFFAOYSA-N 2-[3-(9h-fluoren-9-ylmethoxycarbonylamino)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(NC(=O)OCC2C3=CC=CC=C3C3=CC=CC=C32)=C1 DFSRRXZHWJUCFU-UHFFFAOYSA-N 0.000 description 2
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- NCJBFDZDBVZGED-UHFFFAOYSA-N 5-(9h-fluoren-9-ylmethoxy)-3h-1,3,4-oxadiazol-2-one Chemical compound O1C(=O)NN=C1OCC1C2=CC=CC=C2C2=CC=CC=C21 NCJBFDZDBVZGED-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- 102100022337 Integrin alpha-V Human genes 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
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- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
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- 239000012317 TBTU Substances 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 108010048673 Vitronectin Receptors Proteins 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
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- 239000005557 antagonist Substances 0.000 description 2
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- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- 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
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Medicinal Chemistry (AREA)
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- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
Priority Applications (24)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19831710A DE19831710A1 (de) | 1998-07-15 | 1998-07-15 | Diacylhydrazinderivate |
| SK41-2001A SK412001A3 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives as integrin inhibitors |
| CN99808610A CN1309633A (zh) | 1998-07-15 | 1999-07-06 | 作为整合素抑制剂的二酰基肼衍生物 |
| AU50313/99A AU753333B2 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives as integrin inhibitors |
| SI9930283T SI1097127T1 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives as integrin inhibitors |
| PT99934576T PT1097127E (pt) | 1998-07-15 | 1999-07-06 | Derivados de diacil-hidrazina como inibidores da integrina |
| BR9912072-0A BR9912072A (pt) | 1998-07-15 | 1999-07-06 | Derivados diacil-hidrazina |
| JP2000560082A JP2002520382A (ja) | 1998-07-15 | 1999-07-06 | インテグリン阻害剤としてのジアシルヒドラジン誘導体 |
| HU0102602A HUP0102602A3 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives, method for their preparation, their use and pharmaceutical compositions comprising thereof |
| AT99934576T ATE234276T1 (de) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivate als integrin-inhibitoren |
| IDW20010206A ID27168A (id) | 1998-07-15 | 1999-07-06 | Derivat-derivat diasilhidrazin |
| US09/743,605 US6326403B1 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives as integrin inhibitors |
| PL99345398A PL345398A1 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives as integrin inhibitors |
| PCT/EP1999/004673 WO2000003973A1 (de) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivate als integrin-inhibitoren |
| ES99934576T ES2194486T3 (es) | 1998-07-15 | 1999-07-06 | Derivados de diacilhidrazina como inhibidores de integrina. |
| EP99934576A EP1097127B1 (de) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivate als integrin-inhibitoren |
| DE59904547T DE59904547D1 (de) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivate als integrin-inhibitoren |
| KR1020017000359A KR20010079520A (ko) | 1998-07-15 | 1999-07-06 | 인테그린 저해제로서의 디아실히드라진 유도체 |
| DK99934576T DK1097127T3 (da) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivater som integrininhibitorer |
| CA002337305A CA2337305A1 (en) | 1998-07-15 | 1999-07-06 | Diacylhydrazine derivatives |
| TW088111860A TW448145B (en) | 1998-07-15 | 1999-07-13 | Diacylhydrazine derivatives for use as integrin inhibitors and pharmaceutical compositions containing them |
| ARP990103436A AR019777A1 (es) | 1998-07-15 | 1999-07-14 | Derivados de la diacilhidrazina, un procedimiento para su preparacion, el empleo de los mismos en la elaboracion de medicamentos, las composicionesfarmaceuticas que los contienen y un procedimiento para preparar estas composiciones farmaceuticas |
| NO20010203A NO20010203D0 (no) | 1998-07-15 | 2001-01-12 | Diacylhydrazinderivater som integrininhibitorer |
| ZA200101267A ZA200101267B (en) | 1998-07-15 | 2001-02-14 | Diacylhydrazine derivatives as intergrin inhibitors. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19831710A DE19831710A1 (de) | 1998-07-15 | 1998-07-15 | Diacylhydrazinderivate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19831710A1 true DE19831710A1 (de) | 2000-01-20 |
Family
ID=7874107
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19831710A Withdrawn DE19831710A1 (de) | 1998-07-15 | 1998-07-15 | Diacylhydrazinderivate |
| DE59904547T Expired - Fee Related DE59904547D1 (de) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivate als integrin-inhibitoren |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE59904547T Expired - Fee Related DE59904547D1 (de) | 1998-07-15 | 1999-07-06 | Diacylhydrazinderivate als integrin-inhibitoren |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6326403B1 (https=) |
| EP (1) | EP1097127B1 (https=) |
| JP (1) | JP2002520382A (https=) |
| KR (1) | KR20010079520A (https=) |
| CN (1) | CN1309633A (https=) |
| AR (1) | AR019777A1 (https=) |
| AT (1) | ATE234276T1 (https=) |
| AU (1) | AU753333B2 (https=) |
| BR (1) | BR9912072A (https=) |
| CA (1) | CA2337305A1 (https=) |
| DE (2) | DE19831710A1 (https=) |
| DK (1) | DK1097127T3 (https=) |
| ES (1) | ES2194486T3 (https=) |
| HU (1) | HUP0102602A3 (https=) |
| ID (1) | ID27168A (https=) |
| NO (1) | NO20010203D0 (https=) |
| PL (1) | PL345398A1 (https=) |
| PT (1) | PT1097127E (https=) |
| SK (1) | SK412001A3 (https=) |
| TW (1) | TW448145B (https=) |
| WO (1) | WO2000003973A1 (https=) |
| ZA (1) | ZA200101267B (https=) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001079157A1 (en) * | 2000-04-14 | 2001-10-25 | Abbott Laboratories | Hydrazide and alkoxyamide angiogenesis inhibitors |
| US6887863B2 (en) | 2000-04-14 | 2005-05-03 | Abbott Laboratories | Hydrazide and alkoxyamide angiogenesis inhibitors |
| US7276482B2 (en) | 2000-08-17 | 2007-10-02 | Biomet Deutschland Gmbh | Peptide and peptide mimetic derivatives with integrin-inhibitors properties II |
| US7655624B2 (en) | 2000-08-17 | 2010-02-02 | Biomet Deutschland Gmbh | Peptide and peptide mimetic conjugates with integrin-inhibitor properties |
| EP2281580A2 (en) | 2003-01-13 | 2011-02-09 | Bracco Imaging S.p.A | Labeled gastrin releasing peptides (GRP) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL146508A0 (en) * | 1999-06-01 | 2002-07-25 | Biogen Inc | A blocking monoclonal antibody to vla-1 and its use for the treatment of inflammatory disorders |
| DZ3415A1 (fr) * | 2000-08-31 | 2002-03-07 | Chiron Corp | Guanidinobenzamides comme mc4-r agonistes. |
| ATE348097T1 (de) | 2001-04-09 | 2007-01-15 | Chiron Corp | Guanidinoverbindungen als melanocortin-4-rezeptor (mc4-r) agonisten |
| GEP20074252B (en) | 2001-04-13 | 2007-12-10 | Biogen Idec Inc | Antibodies to vla-1 |
| WO2003099818A1 (en) | 2002-05-23 | 2003-12-04 | Chiron Corporation | Substituted quinazolinone compounds |
| US7304161B2 (en) * | 2003-02-10 | 2007-12-04 | Intrexon Corporation | Diaclhydrazine ligands for modulating the expression of exogenous genes in mammalian systems via an ecdysone receptor complex |
| US7456315B2 (en) | 2003-02-28 | 2008-11-25 | Intrexon Corporation | Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex |
| JP2007501861A (ja) | 2003-05-23 | 2007-02-01 | カイロン コーポレイション | Ｍｃ４−ｒアゴニストとしてのグアニジノ置換キナゾリノン化合物 |
| DE10325049A1 (de) * | 2003-06-02 | 2004-12-23 | Merck Patent Gmbh | Peptid- und Peptidmimetika-Derivate mit Integrin-Inhibitor-Eigenschaften III |
| WO2005051391A1 (en) | 2003-11-19 | 2005-06-09 | Chiron Corporation | Quinazolinone compounds with reduced bioaccumulation |
| ATE551060T1 (de) | 2004-06-04 | 2012-04-15 | Scripps Research Inst | Zusammensetzungen und verfahren zur behandlung von neovaskulären erkrankungen |
| JP4745175B2 (ja) * | 2005-12-28 | 2011-08-10 | 本田技研工業株式会社 | 自動二輪車 |
| MX2008014793A (es) | 2006-05-25 | 2008-12-02 | Biogen Idec Inc | Metodos para tratar la apoplejia. |
| CN104761466A (zh) * | 2007-05-29 | 2015-07-08 | 英特拉克森公司 | 通过蜕皮素受体复合物调节外源性基因表达的手性二酰基肼配体 |
| CA2864539C (en) | 2012-02-16 | 2022-06-07 | Santarus, Inc. | Antibody formulations |
| ES2683329T3 (es) | 2013-03-15 | 2018-09-26 | Intrexon Corporation | Diacilhidrazinas que contienen boro |
| SG11201609050UA (en) | 2014-05-30 | 2016-12-29 | Pfizer | Carbonitrile derivatives as selective androgen receptor modulators |
| CN104027805B (zh) * | 2014-06-18 | 2017-02-15 | 北京大学 | 抑制整合素α5的物质在制备预防内皮细胞激活和/或动脉粥样硬化的产品中的新用途 |
| WO2016044390A1 (en) | 2014-09-17 | 2016-03-24 | Intrexon Corporation | Boron-containing diacylhydrazine compounds |
| JP7445594B2 (ja) | 2017-11-01 | 2024-03-07 | アローヘッド ファーマシューティカルズ インコーポレイテッド | インテグリンリガンドおよびその使用 |
| US12486502B2 (en) | 2021-04-08 | 2025-12-02 | Arrowhead Pharmaceuticals, Inc. | RNAi agents for inhibiting expression of receptor for advanced glycation end-products, compositions thereof, and methods of use |
| WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5051405A (en) * | 1989-10-10 | 1991-09-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Anti-thrombotic peptides and pseudopeptides |
| WO1992013552A1 (en) * | 1991-02-05 | 1992-08-20 | Smithkline Beecham Corporation | Anti-aggregatory peptides containing an aromatic ester or amide |
| US5530028A (en) * | 1992-11-23 | 1996-06-25 | Rohm And Haas Company | Insecticidal N'-substituted-N,N'-diacylhydrazines |
| EP0677043A1 (en) * | 1992-12-29 | 1995-10-18 | Smithkline Beecham Corporation | Platelet aggregation inhibiting compounds |
| JPH10501222A (ja) | 1994-05-27 | 1998-02-03 | メルク エンド カンパニー インコーポレーテッド | 破骨細胞仲介骨吸収を抑制するための化合物 |
| US5482962A (en) * | 1994-07-22 | 1996-01-09 | Rohm And Haas Company | Insecticidal N,N'-disubstituted-N-N'-diacylhydrazines |
| JP2000516197A (ja) * | 1996-01-16 | 2000-12-05 | メルク エンド カンパニー インコーポレーテッド | インテグリンレセプターアンタゴニスト |
-
1998
- 1998-07-15 DE DE19831710A patent/DE19831710A1/de not_active Withdrawn
-
1999
- 1999-07-06 HU HU0102602A patent/HUP0102602A3/hu unknown
- 1999-07-06 AU AU50313/99A patent/AU753333B2/en not_active Ceased
- 1999-07-06 KR KR1020017000359A patent/KR20010079520A/ko not_active Withdrawn
- 1999-07-06 DK DK99934576T patent/DK1097127T3/da active
- 1999-07-06 PL PL99345398A patent/PL345398A1/xx unknown
- 1999-07-06 CA CA002337305A patent/CA2337305A1/en not_active Abandoned
- 1999-07-06 DE DE59904547T patent/DE59904547D1/de not_active Expired - Fee Related
- 1999-07-06 EP EP99934576A patent/EP1097127B1/de not_active Expired - Lifetime
- 1999-07-06 ES ES99934576T patent/ES2194486T3/es not_active Expired - Lifetime
- 1999-07-06 US US09/743,605 patent/US6326403B1/en not_active Expired - Fee Related
- 1999-07-06 SK SK41-2001A patent/SK412001A3/sk unknown
- 1999-07-06 JP JP2000560082A patent/JP2002520382A/ja active Pending
- 1999-07-06 PT PT99934576T patent/PT1097127E/pt unknown
- 1999-07-06 CN CN99808610A patent/CN1309633A/zh active Pending
- 1999-07-06 WO PCT/EP1999/004673 patent/WO2000003973A1/de not_active Ceased
- 1999-07-06 ID IDW20010206A patent/ID27168A/id unknown
- 1999-07-06 BR BR9912072-0A patent/BR9912072A/pt not_active IP Right Cessation
- 1999-07-06 AT AT99934576T patent/ATE234276T1/de not_active IP Right Cessation
- 1999-07-13 TW TW088111860A patent/TW448145B/zh active
- 1999-07-14 AR ARP990103436A patent/AR019777A1/es not_active Application Discontinuation
-
2001
- 2001-01-12 NO NO20010203A patent/NO20010203D0/no not_active Application Discontinuation
- 2001-02-14 ZA ZA200101267A patent/ZA200101267B/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001079157A1 (en) * | 2000-04-14 | 2001-10-25 | Abbott Laboratories | Hydrazide and alkoxyamide angiogenesis inhibitors |
| US6887863B2 (en) | 2000-04-14 | 2005-05-03 | Abbott Laboratories | Hydrazide and alkoxyamide angiogenesis inhibitors |
| US7276482B2 (en) | 2000-08-17 | 2007-10-02 | Biomet Deutschland Gmbh | Peptide and peptide mimetic derivatives with integrin-inhibitors properties II |
| US7655624B2 (en) | 2000-08-17 | 2010-02-02 | Biomet Deutschland Gmbh | Peptide and peptide mimetic conjugates with integrin-inhibitor properties |
| EP2281580A2 (en) | 2003-01-13 | 2011-02-09 | Bracco Imaging S.p.A | Labeled gastrin releasing peptides (GRP) |
| EP2500040A1 (en) | 2003-01-13 | 2012-09-19 | Bracco Imaging S.p.A | Improved Gastrin Releasing Peptide Receptor-Binding Compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1097127A1 (de) | 2001-05-09 |
| AU5031399A (en) | 2000-02-07 |
| ATE234276T1 (de) | 2003-03-15 |
| JP2002520382A (ja) | 2002-07-09 |
| AR019777A1 (es) | 2002-03-13 |
| WO2000003973A1 (de) | 2000-01-27 |
| BR9912072A (pt) | 2001-09-25 |
| TW448145B (en) | 2001-08-01 |
| DK1097127T3 (da) | 2003-06-10 |
| ES2194486T3 (es) | 2003-11-16 |
| NO20010203L (no) | 2001-01-12 |
| HUP0102602A3 (en) | 2002-02-28 |
| US6326403B1 (en) | 2001-12-04 |
| EP1097127B1 (de) | 2003-03-12 |
| CA2337305A1 (en) | 2000-01-27 |
| KR20010079520A (ko) | 2001-08-22 |
| DE59904547D1 (de) | 2003-04-17 |
| PT1097127E (pt) | 2003-07-31 |
| SK412001A3 (en) | 2001-08-06 |
| ID27168A (id) | 2001-03-08 |
| ZA200101267B (en) | 2002-10-04 |
| HUP0102602A2 (hu) | 2002-01-28 |
| NO20010203D0 (no) | 2001-01-12 |
| CN1309633A (zh) | 2001-08-22 |
| AU753333B2 (en) | 2002-10-17 |
| PL345398A1 (en) | 2001-12-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8139 | Disposal/non-payment of the annual fee |