EP0000113A1 - Dihydropyridazones, procédé pour leur préparation et médicaments les contenant, et dihydropyridazones utilisables dans le traitment médical - Google Patents
Dihydropyridazones, procédé pour leur préparation et médicaments les contenant, et dihydropyridazones utilisables dans le traitment médical Download PDFInfo
- Publication number
- EP0000113A1 EP0000113A1 EP78100001A EP78100001A EP0000113A1 EP 0000113 A1 EP0000113 A1 EP 0000113A1 EP 78100001 A EP78100001 A EP 78100001A EP 78100001 A EP78100001 A EP 78100001A EP 0000113 A1 EP0000113 A1 EP 0000113A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- methyl
- dihydropyridazone
- alkyl radical
- atoms
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 229940079593 drug Drugs 0.000 title description 2
- 238000011282 treatment Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 19
- 125000005843 halogen group Chemical group 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 5
- -1 2-Chloropropionylamino Chemical group 0.000 claims description 99
- 239000000460 chlorine Substances 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000012050 conventional carrier Substances 0.000 claims description 2
- 150000007857 hydrazones Chemical class 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 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 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000004970 halomethyl group Chemical group 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 6
- 208000001435 Thromboembolism Diseases 0.000 abstract description 2
- 229940030600 antihypertensive agent Drugs 0.000 abstract description 2
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- 238000011321 prophylaxis Methods 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000002776 aggregation Effects 0.000 description 12
- 238000004220 aggregation Methods 0.000 description 12
- 102000008186 Collagen Human genes 0.000 description 11
- 108010035532 Collagen Proteins 0.000 description 11
- 229920001436 collagen Polymers 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000003826 tablet Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000001077 hypotensive effect Effects 0.000 description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- VQKLRVZQQYVIJW-UHFFFAOYSA-N dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 description 4
- 229960002877 dihydralazine Drugs 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
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 150000003254 radicals Chemical group 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- JEQDSBVHLKBEIZ-REOHCLBHSA-N (2s)-2-chloropropanoyl chloride Chemical compound C[C@H](Cl)C(Cl)=O JEQDSBVHLKBEIZ-REOHCLBHSA-N 0.000 description 2
- 125000006083 1-bromoethyl group Chemical group 0.000 description 2
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 2
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 2
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- RGCSSAJIKFGOGS-UHFFFAOYSA-N 4-[4-[(2-chloroacetyl)amino]phenyl]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C1=CC=C(NC(=O)CCl)C=C1 RGCSSAJIKFGOGS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000035488 systolic blood pressure Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- PJIYDZWUOUJSCH-UHFFFAOYSA-N 2-iodo-n-[4-(4-methyl-6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenyl]acetamide Chemical compound CC1CC(=O)NN=C1C1=CC=C(NC(=O)CI)C=C1 PJIYDZWUOUJSCH-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- ORSUMIZRRGPJBR-UHFFFAOYSA-N 4,5-dihydro-1h-pyridazin-6-one Chemical compound O=C1CCC=NN1 ORSUMIZRRGPJBR-UHFFFAOYSA-N 0.000 description 1
- WRBOAZUDXNNWNI-UHFFFAOYSA-N 4-(4-aminophenyl)-4-oxobutanoic acid Chemical compound NC1=CC=C(C(=O)CCC(O)=O)C=C1 WRBOAZUDXNNWNI-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229940075065 polyvinyl acetate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the invention relates to 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3), its preparation and pharmaceutical preparations which contain 6- (p-acylaminophenyl) -4,5-dihydropyridazone- (3).
- R 1 is hydrogen or an alkyl radical having 1 to 3 C atoms and R 2
- R 1 is a hydrogen atom
- Alkyl radicals for R 1 are in particular methyl, ethyl and propyl.
- Halogen radicals substituted alkyl radicals for R 2 when R 1 represents a hydrogen atom, are, for example, 2-chloro-ethyl-2-bromoethyl, 2-fluoroethyl, 2-iodoethyl, 1-chloropropyl, 1-bromoropyl, 1-fluoropropyl, 1- Iodopropyl, 2-chloropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 3-iodopropyl, 1-chloroisopropyl, 1-bromoisopropyl, 1-iodoisopropyl, a-chloroisopropyl, 2-bromopropyl, 1-chlorobutyl, 1-bromobutyl, 1-fluorobutyl, 4-chlorobutyl, 4-bromobuty
- R 2 may also have, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl or 1-iodoethyl.
- R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, is an alkyl radical having 3 or 4 C atoms or a ⁇ -halogenoethyl radical substituted by a halogen atom, in particular a chlorine or bromine atom, or, if R 1 is methyl, means an alkyl radical with 1 to 4 C atoms which is substituted by a halogen atom, in particular a chlorine or bromine atom.
- the compounds of formula I can be prepared by using a compound of formula II
- Halogen radicals substituted alkyl radicals for R 2 when R 1 represents a hydrogen atom, are, for example, 2-chloroethyl, 2-bromoethyl, 2-fluoroethyl, 2-iodoethyl, 1-chloropropyl, 1-bromopropyl, 1-fluoropropyl, 1-iodopropyl , 2-chloropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 3-iodopropyl, 1-chloroisopropyl, 1-bromoisopropyl, 1-iodoisopropyl 2-chloroisopropyl, 2-bromoisopropyl, 1-chlorobutyl, 1-bromobutyl, 1- Fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4-fluorobutyl,
- R 2 may also contain, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl or 1-iodoethyl in addition to the meanings mentioned above.
- R 1 is hydrogen or methyl and R 2 , when R 1 is hydrogen, is an alkyl radical having 3 or 4 C atoms or a ⁇ -halogenoethyl radical which is substituted by a halogen atom, in particular a chlorine or bromine atom, or, if R 1 is methyl, means an alkyl radical having 1 to 4 C atoms which is substituted by a halogen atom, in particular a chlorine or bromine atom.
- the compounds of the formula I can be prepared by endowing a compound of the formula II
- the compounds of the formula I are prepared by using a compound of the formula IV, in which R has the meanings given above, with an acylating agent of the formula III in which R 2 and Y have the meanings given above, acylated under the conditions given above and the ar restroomn acyl compound V cyclized with hydrazine.
- a solvent in particular a lower alcohol, such as methanol, ethanol or propanol, a cyclic ether, such as dioxane, or a dialkylformamide, such as dimethylformamide
- R 1 is not hydrogen
- the present invention is intended to include the enantiomers.
- the new compounds of the formula I and, moreover, also compounds of the formula I in which, when R 1 is hydrogen, R 2 is a halogenomethyl or an ⁇ -halogenoethyl radical have a strong antiplatelet activity and an antihypertensive effect Award effect. They are suitable as antihypertensives and for the prophylaxis and therapy of thrombo-embolic diseases.
- Groups of 4 - 8 male spontaneously hypertensive Okamotv rats (270-340g) are administered orally.
- the systolic blood pressure is measured without blood using piezocrystal recorders.
- the ED 20% is determined taking into account the values of untreated control animals, the dose which reduces the systolic pressure by 20%.
- the effective doses or concentrations were calculated from the linear relationships between the logarithms of the doses or concentrations and the effect using the regression analysis.
- Acetylsalicylic acid served as the reference substance for inhibiting platelet aggregation, and dihydralazine for the hypotensive effect.
- Example 5 shows that the very strong inhibition of platelet aggregation can also be determined after oral administration.
- the substance also lowers the blood pressure of spontaneously hypertensive rats by 20% in the low oral dose of 1.2 mg / kg.
- the acute toxicity of Example 5 is somewhat less than that of acetylsalicylic acid and dihydralazine.
- the present invention accordingly also relates to therapeutic agents or preparations which, in addition to conventional carriers and diluents, contain the compounds mentioned as an active ingredient, and the use of these compounds for therapeutic purposes.
- the therapeutic agents or preparations are prepared in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. In humans, doses of 1 to 100 mg are possible, oral administration being preferred.
- Dosage forms that are suitable for oral administration are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions, suspensions or depot forms.
- the compounds to be used according to the invention are processed with the carriers customary in pharmaceutical pharmacy.
- the corresponding tablets can be mixed, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents, such as dextrose, sugar, sorbitol, polyvinylpyrrolidone, mannitol, calcium carbonate, calcium phosphate or lactose, disintegrants such as corn, starch, alginic acid or polyvinylpyrrolidone, binders such as starch or gelatin , Lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, can be obtained.
- the tablets can also consist of several layers.
- coated tablets can be coated by cores produced analogously to the tablets with agents commonly used in coated tablet coatings, for example Kollidon or ⁇ shellac, gum arabic, talc, titanium dioxide or sugar, ⁇ . getting produced.
- the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
- the active ingredient is moistened with polyvinylpyrrolidone in 10% strength aqueous solution, passed through a sieve with a mesh size of 1.0 mm and dried at 50.degree. These granules are mixed with polyethylene glycol (mean MW 4,000), hydroxypropylmethyl cellulose, talc and magnesium stearate and pressed into tablets of 240 mg each.
- the mixture of the active ingredient with lactose and corn starch is granulated with an 8% aqueous solution of the polyvinylpyrrolidone through a 1.5 mm sieve, dried at 50 ° C. and rubbed again through a 1.0 mm sieve.
- the granules obtained in this way are nesium stearate mixed and into coated tablets; pressed
- the Dragurk are a der that is made in the usual way with a cover and essentially consists of sugar and talc.
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772727481 DE2727481A1 (de) | 1977-06-18 | 1977-06-18 | Dihydropyridazone und dihydropyridazone enthaltende therapeutische mittel |
| DE2727481 | 1977-06-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000113A1 true EP0000113A1 (fr) | 1979-01-10 |
| EP0000113B1 EP0000113B1 (fr) | 1981-09-16 |
Family
ID=6011790
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100001A Expired EP0000113B1 (fr) | 1977-06-18 | 1978-06-01 | Dihydropyridazones, procédé pour leur préparation et médicaments les contenant, et dihydropyridazones utilisables dans le traitment médical |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4376771A (fr) |
| EP (1) | EP0000113B1 (fr) |
| JP (1) | JPS549289A (fr) |
| AT (2) | AT361494B (fr) |
| CA (1) | CA1108614A (fr) |
| DE (2) | DE2727481A1 (fr) |
| ZA (1) | ZA783464B (fr) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0012338A1 (fr) * | 1978-12-15 | 1980-06-25 | BASF Aktiengesellschaft | Dihydropyridazinones, procédé pour leur préparation et médicaments contenant ces composés |
| EP0012366A1 (fr) * | 1978-12-16 | 1980-06-25 | BASF Aktiengesellschaft | 3,4-Diaza-bicyclo(4.1.0)hepten-2-ones-5, leur procédé de préparation et compositions thérapeutiques les contenant |
| EP0089528A1 (fr) * | 1982-03-13 | 1983-09-28 | BASF Aktiengesellschaft | 6-Aryl-4,5-dihydro-3(2H)-pyridazinones, leurs préparation et usage |
| US4410529A (en) * | 1980-06-13 | 1983-10-18 | Basf Aktiengesellschaft | Novel dihydropyridazinones, their preparation and therapeutic agents containing these compounds |
| US4415571A (en) * | 1980-06-13 | 1983-11-15 | Basf Aktiengesellschaft | Carbamate dihydropyridazinones, their preparation and therapeutic agents containing these compounds |
| US4965263A (en) * | 1981-10-20 | 1990-10-23 | Mitsui Toatsu Kagaku Kabushiki Kaisha | 6-acylaminophenyl-5-alkyl-4,5-dihydro-3(2H)-pyridazinone compounds useful as blood pressure depressants, antithrombotic agents and in the treatment of heart disease |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3124699A1 (de) * | 1981-06-24 | 1983-01-13 | Basf Ag, 6700 Ludwigshafen | Neue 2-aryl-3,4-diaza-bicyclo(4.n.0.)alken-(2)-one-(5),verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3212304A1 (de) * | 1982-04-02 | 1983-10-06 | Nattermann A & Cie | Imidazolylphenyl-tetrahydropyridazine, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
| DE3328286A1 (de) * | 1982-08-07 | 1984-02-09 | Basf Ag, 6700 Ludwigshafen | Neue anilide, verfahren zu ihrer herstellung und ihre verwendung |
| DE3302021A1 (de) * | 1983-01-22 | 1984-07-26 | Basf Ag, 6700 Ludwigshafen | 6-aryl-4,5-dihydro-3(2h)-pyridazinone, ihre herstellung und verwendung |
| JPH02119064A (ja) * | 1988-10-28 | 1990-05-07 | Matsushita Electric Ind Co Ltd | 密閉形鉛蓄電池 |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| RU2008122978A (ru) | 2005-11-09 | 2009-12-20 | Комбинаторкс, Инкорпорейтед (Us) | Способы, композиции и наборы для лечения медицинских состояний |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| CA2688161C (fr) | 2007-06-04 | 2020-10-20 | Kunwar Shailubhai | Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles |
| EP2328910B1 (fr) | 2008-06-04 | 2014-08-06 | Synergy Pharmaceuticals Inc. | Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles |
| EP3241839B1 (fr) | 2008-07-16 | 2019-09-04 | Bausch Health Ireland Limited | Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| DK2681236T3 (en) | 2011-03-01 | 2018-04-16 | Synergy Pharmaceuticals Inc | PROCEDURE FOR MANUFACTURING GUANYLATE CYCLASE-C-AGONISTS |
| US20150119399A1 (en) | 2012-01-10 | 2015-04-30 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
| CA2902348C (fr) | 2013-02-25 | 2021-11-30 | Synergy Pharmaceuticals Inc. | Agonistes de la guanylate cyclase et applications associees |
| HK1220611A1 (zh) | 2013-03-15 | 2017-05-12 | Bausch Health Ireland Limited | 用於治疗胃肠道病症的组成物 |
| WO2014151206A1 (fr) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonistes de la guanylate cyclase et leurs utilisations |
| CN113388007A (zh) | 2013-06-05 | 2021-09-14 | 博士医疗爱尔兰有限公司 | 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法 |
| BR112016002789A2 (pt) | 2013-08-09 | 2017-11-21 | Ardelyx Inc | compostos e métodos para inibir transporte de fosfato |
| WO2020237096A1 (fr) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Combinaison pour baisser le phosphate sérique chez un patient |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670158A1 (de) * | 1966-01-07 | 1970-12-03 | Basf Ag | Verfahren zur Herstellung von 6-Aminophenyl-und 6-Acylaminophenyl-4,5-dihydropyridazonen (3) |
| DE2150436A1 (de) * | 1970-10-09 | 1972-04-13 | American Cyanamid Co | Neue organische Verbindungen,ihre Herstellung und ihre Verwendung |
| DE2123246A1 (de) * | 1971-05-11 | 1972-11-30 | Badische Anilin & Soda Fabrik AG, 6700 Ludwigshafen | Dihydropyndazone |
| DE2304977A1 (de) * | 1973-02-01 | 1974-08-08 | Basf Ag | Neue dihydropyridazinone |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3689652A (en) * | 1970-10-09 | 1972-09-05 | William Vincent Curran | Method of lowering blood pressure in mammals |
| US3822260A (en) * | 1970-10-09 | 1974-07-02 | American Cyanamid Co | 6-(cyanophenyl)-4,5-dihydro-3(2h)-pyridazinones |
| US3975388A (en) * | 1971-02-22 | 1976-08-17 | Bdh Pharmaceuticals Limited | Pyridazinones |
| US3746712A (en) * | 1971-06-08 | 1973-07-17 | A Ross | 6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2h)-pyridazinones |
| US3812256A (en) * | 1971-06-08 | 1974-05-21 | American Cyanamid Co | Novel method for lowering blood pressure in mammals |
| BE790106A (fr) * | 1971-10-14 | 1973-04-13 | Basf Ag | Dihydropyridazones, leur preparation et leurs utilisations therapeutiques |
| US3824271A (en) * | 1972-07-20 | 1974-07-16 | American Cyanamid Co | 3-alkyl-3-(benzoyl)propionitriles |
| US4112095A (en) * | 1976-10-07 | 1978-09-05 | American Cyanamid Company | 6-Phenyl-1,2,4-triazolo[4,3-b]pyridazine hypotensive agents |
-
1977
- 1977-06-18 DE DE19772727481 patent/DE2727481A1/de not_active Withdrawn
-
1978
- 1978-06-01 DE DE7878100001T patent/DE2861089D1/de not_active Expired
- 1978-06-01 EP EP78100001A patent/EP0000113B1/fr not_active Expired
- 1978-06-16 AT AT441178A patent/AT361494B/de not_active IP Right Cessation
- 1978-06-16 ZA ZA00783464A patent/ZA783464B/xx unknown
- 1978-06-16 JP JP7226978A patent/JPS549289A/ja active Granted
- 1978-06-16 CA CA305,625A patent/CA1108614A/fr not_active Expired
-
1980
- 1980-04-11 AT AT0198680A patent/AT363489B/de not_active IP Right Cessation
-
1981
- 1981-01-14 US US06/224,939 patent/US4376771A/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670158A1 (de) * | 1966-01-07 | 1970-12-03 | Basf Ag | Verfahren zur Herstellung von 6-Aminophenyl-und 6-Acylaminophenyl-4,5-dihydropyridazonen (3) |
| DE2150436A1 (de) * | 1970-10-09 | 1972-04-13 | American Cyanamid Co | Neue organische Verbindungen,ihre Herstellung und ihre Verwendung |
| DE2123246A1 (de) * | 1971-05-11 | 1972-11-30 | Badische Anilin & Soda Fabrik AG, 6700 Ludwigshafen | Dihydropyndazone |
| DE2304977A1 (de) * | 1973-02-01 | 1974-08-08 | Basf Ag | Neue dihydropyridazinone |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0012338A1 (fr) * | 1978-12-15 | 1980-06-25 | BASF Aktiengesellschaft | Dihydropyridazinones, procédé pour leur préparation et médicaments contenant ces composés |
| EP0012366A1 (fr) * | 1978-12-16 | 1980-06-25 | BASF Aktiengesellschaft | 3,4-Diaza-bicyclo(4.1.0)hepten-2-ones-5, leur procédé de préparation et compositions thérapeutiques les contenant |
| US4410529A (en) * | 1980-06-13 | 1983-10-18 | Basf Aktiengesellschaft | Novel dihydropyridazinones, their preparation and therapeutic agents containing these compounds |
| US4415571A (en) * | 1980-06-13 | 1983-11-15 | Basf Aktiengesellschaft | Carbamate dihydropyridazinones, their preparation and therapeutic agents containing these compounds |
| US4965263A (en) * | 1981-10-20 | 1990-10-23 | Mitsui Toatsu Kagaku Kabushiki Kaisha | 6-acylaminophenyl-5-alkyl-4,5-dihydro-3(2H)-pyridazinone compounds useful as blood pressure depressants, antithrombotic agents and in the treatment of heart disease |
| EP0089528A1 (fr) * | 1982-03-13 | 1983-09-28 | BASF Aktiengesellschaft | 6-Aryl-4,5-dihydro-3(2H)-pyridazinones, leurs préparation et usage |
Also Published As
| Publication number | Publication date |
|---|---|
| AT361494B (de) | 1981-03-10 |
| EP0000113B1 (fr) | 1981-09-16 |
| ATA198680A (de) | 1981-01-15 |
| JPS549289A (en) | 1979-01-24 |
| CA1108614A (fr) | 1981-09-08 |
| AT363489B (de) | 1981-08-10 |
| DE2861089D1 (en) | 1981-12-03 |
| JPS6231708B2 (fr) | 1987-07-09 |
| DE2727481A1 (de) | 1979-01-11 |
| US4376771A (en) | 1983-03-15 |
| ZA783464B (en) | 1979-07-25 |
| ATA441178A (de) | 1980-08-15 |
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