DE2511891A1 - Anti-thrombotic dioxo-piperazine derivs - prepd. e.g. by cyclising N,N,N',N'-1,2-alkylene-diamine-tetraacetic acids with amines - Google Patents
Anti-thrombotic dioxo-piperazine derivs - prepd. e.g. by cyclising N,N,N',N'-1,2-alkylene-diamine-tetraacetic acids with aminesInfo
- Publication number
- DE2511891A1 DE2511891A1 DE19752511891 DE2511891A DE2511891A1 DE 2511891 A1 DE2511891 A1 DE 2511891A1 DE 19752511891 DE19752511891 DE 19752511891 DE 2511891 A DE2511891 A DE 2511891A DE 2511891 A1 DE2511891 A1 DE 2511891A1
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- radical
- carbon atoms
- general formula
- alkyl
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- 239000002253 acid Substances 0.000 title claims abstract description 16
- 150000007513 acids Chemical class 0.000 title claims abstract description 9
- 150000001412 amines Chemical class 0.000 title claims description 13
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 title abstract 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 title 1
- 230000002785 anti-thrombosis Effects 0.000 title 1
- 239000003146 anticoagulant agent Substances 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- -1 alkyl radical Chemical group 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 20
- 150000005840 aryl radicals Chemical class 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical class O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 6
- 238000011321 prophylaxis Methods 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 206010014523 Embolism and thrombosis Diseases 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 238000011282 treatment Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- ACSAKRLPJQIBFB-UHFFFAOYSA-N 2-phenyl-n-(2-phenylethyl)ethanamine Chemical class C=1C=CC=CC=1CCNCCC1=CC=CC=C1 ACSAKRLPJQIBFB-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000005189 Embolism Diseases 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
- 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 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
E 591 Neue Derivate des 2,6-Dioxopiperazins, Verfahren zu ihrer Herstellung, diese Verhindungen enthaltende Arzneimittel sowie Verfahren zu deren Herstellung.E 591 New derivatives of 2,6-dioxopiperazine, process for their preparation, Medicines containing these preventions and processes for their production.
Die vorliegende Erfindung betrifft neue Derivate des 2,6-Dioxopiperazins mit wertvollen therapeutischen Eigenschaften sowie Verfahren zur Elerstellung dieser Verbindungen. Weiter sind Gegenstand der vorliegenden Erfindung pharmazeutische Darreichungsformen, die diese Verbindungen enthalten, sowie Verfahren zur Herstellung solcher Darreichungsformen. The present invention relates to new derivatives of 2,6-dioxopiperazine with valuable therapeutic properties as well as processes for creating them Links. The present invention also relates to pharmaceuticals Dosage forms containing these compounds and processes for their production such dosage forms.
Die erfindungsgemäßen Verbindungen entsprechen der allgemeinen Formel worin R1 für einen Alkylrest mit 1 bis 6 Kohlenstoffatomen, einen 5- bis 7-gliedrigen Cycloalkylrest, einen Arylrest oder für einen alkylrest steht, R2 und H 3 gleich oder verschieden sind und für Wasserstoff oder für Alkylreste mit 1 bis 4 Kohlenstoffatomen oder zusammengenommen mit der Äthylenbrücke für einen Cycloalkylrest stehen, wobei die Blume der in den Resten R1, R2 und R3 enthaltenen Kohlenstoffatome größer als 2 ist.The compounds according to the invention correspond to the general formula where R1 is an alkyl radical having 1 to 6 carbon atoms, a 5- to 7-membered cycloalkyl radical, an aryl radical or an alkyl radical, R2 and H 3 are identical or different and are hydrogen or alkyl radicals having 1 to 4 carbon atoms or taken together with of the ethylene bridge stand for a cycloalkyl radical, the flower of the carbon atoms contained in the radicals R1, R2 and R3 being greater than 2.
Steht R1 für einen Arylrest, so ist dieser vorzugsweise ein Phenyl-, olyl- oder Xylylrest. Bedeutet R1 einen Aralkylrest, so ist dieser vorzagsweise ein Benzyl- oder Phenyläthylrest.If R1 stands for an aryl radical, this is preferably a phenyl, olyl or xylyl radical. If R1 is an aralkyl radical, this is preferably a benzyl or phenylethyl radical.
Enthalten die Verbindungen der allgemeinen Formel I ein optisch aktives Kohlenstoffatom, so sind Gegenstand der Erfindung sowohl die Razemate als auch die optisch aktiven Isomeren. walze der Verbindungen der allgemeinen Formel I mit pharmazeutisch anwendbaren Säuren gehören ebenfalls zum Gegenstand der Erfindung.If the compounds of general formula I contain an optically active one Carbon atom, the invention relates to both the racemates and the optically active isomers. roll the compounds of general formula I with pharmaceutical Applicable acids also belong to the subject of the invention.
Die Verbindungen der allgemeinen Formel I werden hergestellt, indem man eine Säure der allgemeinen Formel worin R2 und R3 die vorgenannte Bedeutung haben oder eines ihrer funktionellen Derivate mit einem Amin der allgemeinen Formel H2N - R1 III worin R1 die vorgenannte Bedeutung hat, umsetzt. Als funktionelle Derivate der Säuren der allgemeinen Formel II kommen insbesondere deren Anhydride in Frage. Es sind jedoch auch ihre Halogenide, vorzugsweise ihre Chloride oder Bromide, sowie Ester mit niederen aliphatischen Alkoholen oder Phenolen verwendbar.The compounds of the general formula I are prepared by adding an acid of the general formula in which R2 and R3 have the aforementioned meaning or one of their functional derivatives is reacted with an amine of the general formula H2N - R1 III in which R1 has the aforementioned meaning. Functional derivatives of the acids of the general formula II are, in particular, their anhydrides. However, their halides, preferably their chlorides or bromides, and esters with lower aliphatic alcohols or phenols can also be used.
Geht man zur Herstellung von Verbindungen der allgemeinen Formel I von Anhydriden von sauren der allgemeinen Formel II aus, so ist es zweckmäßig, das Reaktionsgemisch zur Vervollständigung der Reaktion zu erhitzen und/oder die Reaktion in Anwesenheit eines die Ringschlußreaktion fördernden Mittels durchzuführen. Man kann insbesondere das bei der Reaktion entstehende Wasser abdestillieren bzw. durch azeotrope Destillation entfernen. Man kann das Verfahren auch zweistufig durchführen, indem man zunächst ein Bis-mono- oder Bis-diamid dei rietrc äure der allgemeinen Formel II mit einem Amin der allgemeinen Formel III umsetzt und dieses nach Isolieren in der zweiten Stufe cyclisiert. Hierbei kann die Rinsclußreaktion allein durch Erhitzen bewirkt werden. Man kann auch in diesem Fall den Ringschluß fördernde Kondensationsmittel, wie z.B. Essigsäureanhydrid, Thionylchlorid, Acetylchlorid und ähnliche saure, wasserabspaltend wirkende Mittel zusetzen.If one goes to the preparation of compounds of the general formula I. of anhydrides of acids of the general formula II, it is expedient to use that Heat the reaction mixture to complete the reaction and / or the reaction to be carried out in the presence of an agent promoting the ring closure reaction. Man can in particular distill off or through the water formed during the reaction Remove azeotropic distillation. The process can also be carried out in two stages, by first adding a bis-mono- or bis-diamide dei rietrc acid of the general Formula II is reacted with an amine of the general formula III and this after isolation cyclized in the second stage. Here, the Rinsclußreaktion can by itself Heating can be effected. In this case, too, condensation agents that promote ring closure can be used, such as acetic anhydride, thionyl chloride, acetyl chloride and similar acidic, dehydrating add effective means.
Eine bevorzugte Verfahrensvariante ist die Herstellung und Isolierung des Bis-monomaides einer Säure der allgemeinen Formel II mit einem Amin der Formel III und dessen anschließende Cyclisierung. Rei der Herstellung des Bis-monoam-ides, ausgehend von einem Anhydrid der Säure der Formel II ist es zur Vermeidung der Entstehung von Bis-diamiden empfehlenswert, eine äquivalente Menge eines tertiären Amines, wie z.B.A preferred variant of the process is production and isolation of the bis-monomaides of an acid of the general formula II with an amine of the formula III and its subsequent cyclization. Rei the production of the bis-monoam-ides, starting from an anhydride of the acid of formula II, it is to avoid the formation of bis-diamides recommended, an equivalent amount of a tertiary amine, such as.
Griäthylamin, als Säurefänger zuzusetzen. Man kann jedoch für diesen Zweck auch einen Überschuß des Amins der allgemeinen Formel III verwenden.Griethylamine to be added as an acid scavenger. However, you can go for this Purpose also use an excess of the amine of general formula III.
Es ist für den Erfolg des erfindungsgemäßen Verfahrens bedeutungslos, ob das Amin der Formel III als solches eingesetzt wird, oder ob eine Verbindung benutzt wird, die unter den Reaktionsbedingungen ein Amin der Formel III liefert. Solche Verbindungen sind beispielsweise Salze, wie Carbonate usw. des Amins der Formel III.It is meaningless for the success of the method according to the invention, whether the amine of the formula III is used as such, or whether a compound is used, which gives an amine of the formula III under the reaction conditions. Such compounds are, for example, salts such as carbonates etc. of the amine Formula III.
Weiterhin können als ein Amin der Formel lII liefernde Verbindungen die von einem solchen Amin abgeleiteten Harnstoffe, '2hioharnstoffe, Carbonsäureamide usw. eingesetzt werden.Furthermore, compounds which provide an amine of the formula III can be used the ureas, '2hioureas, carboxamides derived from such an amine etc. can be used.
Die nach dem vorstehend beschriebenen Verfahren erhaltenen Verbindungen der allgemeinen Formel I können zur Herstellung von Arzneimitteln in entsprechend dosierten Arzneiformen verwendet werden. Gewünschtenfalls können sie auch mit anderen Wirkstoffen kombiniert werden. Zur Herstellung geeigneter Arzneiforrllen werden die Wirkstoffe mit anorganischen oder organischen pharmakologisch indifferenten Hilfsstoffen verarbeitet, die auch so ausgewahlt sein können, daß eine verzögerte Freisetzung der Wirkstoffe erfolgt. Als Hilf sstoffe werden z. B. verwendet: Für Tabletten und Dragees: Milchzucker, Stärke, Talk, Stearinsäure, Magnesiumstearat, tiberzugslacke usw.The compounds obtained by the method described above of the general formula I can be used for the preparation of drugs in accordingly dosed dosage forms are used. If you wish, you can also talk to others Active ingredients are combined. For the production of suitable medicament forms the active ingredients with inorganic or organic pharmacologically indifferent Processed auxiliaries, which can also be selected so that a delayed The active ingredients are released. As auxiliaries are z. B. used: For Tablets and dragees: lactose, starch, talc, stearic acid, magnesium stearate, coating varnishes, etc.
Für Sirupe, Tropfen u. dergl.: Rohrzucker, Invertzucker, Glucoselösung und anderes.For syrups, drops, etc.: cane sugar, invert sugar, glucose solution and other things.
Für Injektionspräparate; Wasser, ein- oder mehrwertige Alkohole, pflanzliche Öle u. dergl.For injectables; Water, monohydric or polyhydric alcohols, vegetable Oils and the like
Für Suppositorien: natürliche oder gehärtete Öle und Wachse u. a.For suppositories: natural or hydrogenated oils and waxes, among others.
Für Cremes, Salben und Gele: Vaselinum album, Vaselinum flavum, Lanolin, Adeps Lanae, Ungentum molle, Tragant, Agar u. ä.For creams, ointments and gels: Vaselinum album, Vaselinum flavum, lanolin, Adeps Lanae, Ungentum molle, tragacanth, agar, etc.
Zudem können die Zubereitungen geeignete Konservierungs-, Stabilisierungs-, Netzmittel, Lösungsvermittler, Süß-und Farbstoffe sowie Aromastoffe enthalten.In addition, the preparations can contain suitable preservation, stabilization, Contains wetting agents, solubilizers, sweeteners, colorings and flavorings.
Die so erhaltenen Arzneimittel eignen sich u. a. zur Prophylaxe und Therapie von Thrombenbildung und Embolien.The medicaments thus obtained are suitable, inter alia. for prophylaxis and Therapy of thrombus formation and embolism.
Die Tagesdosis beträgt 10 bis 3000 mg 1 bis mehrmals täglich.The daily dose is 10 to 3000 mg 1 to several times a day.
Die folgenden Beispiele dienen zur weiteren Erläuterung der Erfindung. Die Temperaturangaben sind durchweg unkorrigiert. Bei der Durchführung der Beispiele wurden maximale Ausbeuten nicht angestrebt.The following examples serve to further illustrate the invention. The temperature data are uncorrected throughout. When performing the examples maximum yields were not aimed for.
Beispiel 1 22,8 g (0,1 Mol) des Bis-anhydrides der Athylendiamin-N,N,N',N'-tetraessigsäure werden in 200 ml absolutem Dimethylformamid aufgeschlammt und mit 20,2 g (0,2 ol) Triäthylamin versetzt. Unter starkem Rühren läßt man 9,02 g (0,2 Mol) Äthylamin, gelöst in 25 ml absolutem Dimethylformamid, zutropfen. Die klare Reaktionslösung wird im Vakuum zur Trockne eingeengt. Der Destillationsrückstand wird aus Alkohol umkristallisiert. Man erhält so das Bis-(monoäthyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 161 - 162°C in einer Ausbeute von 83 % der Theorie.Example 1 22.8 g (0.1 mol) of the bis-anhydride of ethylenediamine-N, N, N ', N'-tetraacetic acid are suspended in 200 ml of absolute dimethylformamide and mixed with 20.2 g (0.2 ol) Triethylamine added. While stirring vigorously, 9.02 g (0.2 mol) of ethylamine, dissolved in 25 ml of absolute dimethylformamide, add dropwise. The clear reaction solution is concentrated to dryness in vacuo. The distillation residue becomes alcohol recrystallized. The bis (monoethyl) amide of ethylenediamine-N, N, N ', N'-tetraacetic acid is obtained in this way with a melting point of 161-162 ° C. in a yield of 83% of theory.
Beispiel 2 Man verfährt wie in Beispiel 1 und erhält unter Verwendung von (n)-Propylamin das Bis-(mono-(n)-propyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 144 - 1450C nach Umkristallisation aus Isopropanol in einer Ausbeute von 88 % der Theorie.Example 2 The procedure is as in Example 1 and using of (n) -propylamine the bis- (mono- (n) -propyl) -amide of ethylenediamine-N, N, N ', N'-tetraacetic acid from melting point 144-1450C after recrystallization from isopropanol in a yield of 88% of theory.
Beispiel 3 Man verfährt wie in Beispiel 1 und erhält unter Verwendung von (i)-Propylamin das Bis-(mono-(i)-propyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 174 - 1770 nach Umkristallisation aus Isopropanol in einer Ausbeute von 81 % der Theorie.Example 3 The procedure is as in Example 1 and using of (i) -propylamine the bis- (mono- (i) -propyl) -amide of ethylenediamine-N, N, N ', N'-tetraacetic acid from melting point 174-1770 after recrystallization from isopropanol in one yield of 81% of theory.
Beispiel 4 Man verfährt wie in Beispiel 1 und erhält unter Verwendung von (n)-Butylamin.das Bis-(mono-(n)-but.yl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 148 - 1490G nach Umkristallisation aus Isopropanol in einer Ausbeute von 94 %o der Theorie.Example 4 The procedure is as in Example 1 and using of (n) -butylamine. the bis- (mono- (n) -but.yl) -amide of ethylenediamine-N, N, N ', N'-tetraacetic acid of melting point 148-1490G after recrystallization from isopropanol in a yield of 94% o of theory.
Beispiel 5 Man verfährt wie in Beispiel 1 und erhält unter Verwendung von Anilin das Bis-(mono-phenyl)-ainid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 192 - 1930 nach Umkristallisation aus Äthanol in einer Ausbeute von 89 % der Theorie.Example 5 The procedure is as in Example 1 and using of aniline the bis (mono-phenyl) -ainide of ethylenediamine-N, N, N ', N'-tetraacetic acid from melting point 192 - 1930 after recrystallization from ethanol in one yield of 89% of theory.
Beispiel 6 Man verfährt wie in Beispiel 1 und erhält unter Verwendung von Benzylamin das Bis-(mono-benzyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 162 - 1650C: nach Umkristallisation aus Äthanol in einerAusbeute von 95 % der Theorie.Example 6 The procedure is as in Example 1 and using of benzylamine the bis (mono-benzyl) amide of ethylenediamine-N, N, N ', N'-tetraacetic acid from melting point 162 - 1650C: after recrystallization from ethanol in a yield of 95% of theory.
Beispiel 7 Man verfährt wie in Beispiel 1 und erhält unter Verwendung von Phenyläthylamin das Bis-(mono-phenyläthyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure vom Schmelzpunkt 159 bis 160°C nach Umkristallisation aus Äthanol in einer Ausbeute von 91 /o der Theorie.Example 7 The procedure is as in Example 1 and using of phenylethylamine bis (mono-phenylethyl) amide of ethylenediamine-N, N, N ', N'-tetraacetic acid from melting point 159 to 160 ° C after recrystallization from ethanol in one yield of 91 / o of theory.
Beispiel 8 34,6 g (0,1 Mol) Bis-(mono-äthyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure werden im Wasserstrahlvakuum auf 165 - 1700C erhitzt und bis zur Beendigung der Gasentwicklung bei diesel Temperatur gehalten. Nackl Abkühlen wird die Schmelze aus Äthanol umkristallisiert. Man erhält so das Äthylendiamin-N,N,N',N'-tetraessigsäure-di-N-äthylimid vom Schmelzpunkt 150 - 15200 in einer Ausbeute von 78 Vo der Theorie.Example 8 34.6 g (0.1 mol) of bis (mono-ethyl) amide of ethylenediamine-N, N, N ', N'-tetraacetic acid are heated in a water jet vacuum to 165 - 1700C and until the end of the Gas evolution kept at diesel temperature. Nackl cooling down is the melt recrystallized from ethanol. The ethylenediamine-N, N, N ', N'-tetraacetic acid-di-N-ethylimide is obtained in this way with a melting point of 150-15200 in a yield of 78 Vo of theory.
Beispiel 9 Man verfährt wie in Beispiel 8 und erhält unter Verwendung des Bis-(mono-(n)-propyl)-amides der Athylendiamin-N,N,N' ,N'-tetraessigsäure das Äthylendiamin-N,N,N',N'-tetraessigsäure-di-N-(n)-propylimid vom Schmelzpunkt 149 - 15000 in einer Ausbeute von 73 % der Theorie.Example 9 The procedure is as in Example 8 and using of the bis (mono- (n) -propyl) amides of ethylenediamine-N, N, N ', N'-tetraacetic acid Ethylenediamine-N, N, N ', N'-tetraacetic acid-di-N- (n) -propylimide of melting point 149 - 15,000 in a yield of 73% of theory.
Beispiel 10 Man verfährt wie in Beispiel 8 und erhält unter Verwendung des Bis-(mono-(i)-propyl)-amides der Äthylendiamin-N,N,N',N'-tetraessigsäure das Äthylendiamin-N,N,N',N'-tetraessigsäuredi-(N-(i)-propylimid in einer Ausbeute von 68 % der Theorie.Example 10 The procedure is as in Example 8 and using of bis (mono- (i) -propyl) amides of ethylenediamine-N, N, N ', N'-tetraacetic acid Ethylenediamine-N, N, N ', N'-tetraacetic acid di (N- (i) -propylimide in a yield of 68% of theory.
Beispiel 11 Man verfährt wie in Beispiel 8 und erhält unter Verwendung des Bis-(mono-(n)-butyl)-amides der Xthylendiamin-N,N,N',N'-tetraessigsäure das Xthylendiamin-N,N,N',N'-tetraessigsäuredi-N-(n)-butylimid vom Schmelzpunkt 116 - 1180C nach Umkristallisation aus Äthanol in einer Ausbeute von 68 % der Theorie.Example 11 The procedure is as in Example 8 and using of bis (mono- (n) -butyl) amides of xthylenediamine-N, N, N ', N'-tetraacetic acid Xthylenediamine-N, N, N ', N'-tetraacetic acid di-N- (n) -butylimide with a melting point of 116 - 1180C after recrystallization from ethanol in a yield of 68% of theory.
Beispiel 12 Man verfährt wie in Beispiel 8 und erhält unter Verwendung des Bis-(mono-phenyl)-amides der Äthylendiamin-N,N,N',N'-tetraessigsäure das Äthylendiamin-N , N , i ,N'-tetraessigsäuredi -N-phenylimid vom bchmelzpunkt 264 - 27000 noch Umkristallisation aus Acetanhydrid in einer Ausbeute von 78 % der Theorie.Example 12 The procedure is as in Example 8 and using of bis (mono-phenyl) amides of ethylenediamine-N, N, N ', N'-tetraacetic acid, ethylenediamine-N , N, i, N'-tetraacetic acid di -N-phenylimide with a melting point of 264-27000 still recrystallized from acetic anhydride in a yield of 78% of theory.
Beispiel 13 Man verfährt wie in Beispiel 8 und erhält unter Verwendung des Bis-(mono-benzyl)-amides der Athylendiamin-N,N,N',N'-tetraessigsäure das Äthylendiamin-N,N,N',N'-tetraessigsäuredi-N-benzylimid in einer Ausbeute von 81 % der Theorie.Example 13 The procedure is as in Example 8 and using of bis (mono-benzyl) amides of ethylenediamine-N, N, N ', N'-tetraacetic acid, ethylenediamine-N, N, N', N'-tetraacetic acid di-N-benzylimide in a yield of 81% of theory.
Beispiel 14 Man verfährt wie in Beispiel 8 und erhält unter Verwendung des Bis-(mono-phenyläthyl)-amides der Äthylendiamin-N,N,N',N'-tetraessigsäure das Äthylendiamin-N,N,N',N'-tetraessigsäure-di-N-phenyl-äthylimid in einer Ausbeute von 82 % der Theorie.Example 14 The procedure is as in Example 8 and using of bis (mono-phenylethyl) amides of ethylenediamine-N, N, N ', N'-tetraacetic acid Ethylenediamine-N, N, N ', N'-tetraacetic acid-di-N-phenyl-ethylimide in one yield of 82% of theory.
Beispiel 15 22,8 (0,1 Mol) des Bis-anhydrides der Äthylendiamin-N,N,N',N'-tetraessigsäure werden in 200 ml absolutem Dimethylformamid aufgeschlämmt und tropfenweise mit 18,04 g (0,4 Mol) Äthylamin, gelöst in 50 ml Dimethylformamid,versetzt. Man läßt eine Stunde bei 1000C nachreagieren und entfernt das Lösungsmittel durch Destillation im Vakuum. Der Rückstand wird 30 Minuten mit Acetanhydrid zum Rückfluß erhitzt. Nach Abdestillation des Lösungsmittels und Umkristallisation aus Äthanol erhält man das Äthylendiamin-N,N,N',N'-tetraessigsäure-di-N-äthylimid in einer Ausbeute von 58 % der Theorie, identisch mit der nach Beispiel 8 erhaltenen Verbindung.Example 15 22.8 (0.1 mol) of the bis-anhydride of ethylenediamine-N, N, N ', N'-tetraacetic acid are slurried in 200 ml of absolute dimethylformamide and added dropwise with 18.04 g (0.4 mol) of ethylamine, dissolved in 50 ml of dimethylformamide, are added. One leaves one React at 1000C for an hour and remove the solvent by distillation in a vacuum. The residue is refluxed with acetic anhydride for 30 minutes. Obtained after distilling off the solvent and recrystallization from ethanol one the ethylenediamine-N, N, N ', N'-tetraacetic acid-di-N-ethylimide in one yield of 58% of theory, identical to the compound obtained according to Example 8.
Beispiel 16 34,6 g (0,1 Mol) Bis-(mono-äthyl)-amid der Äthylendiamin-N,N,N',N'-tetraessigsäure werden in einem Gemisch von 250 ml Acetanhydrid und 25 ml Thionylchlorid 24 Stunden bei Raumteperatur gerührt. Der Niederschlag wird abfiltriert und aus Äthanol umkristallisiert. Man erhält so das Äthylendiamin-N,N,N',N'-tetraessigsäure-di-N-äthylamid in einer Ausbeute von 52 % der Theorie, identisch mit der nach Beispiel 8 erhaltenen Verbindung.Example 16 34.6 g (0.1 mol) of bis (mono-ethyl) amide of ethylenediamine-N, N, N ', N'-tetraacetic acid are in a mixture of 250 ml of acetic anhydride and 25 ml of thionyl chloride for 24 hours stirred at room temperature. The precipitate is filtered off and recrystallized from ethanol. The ethylenediamine-N, N, N ', N'-tetraacetic acid-di-N-ethylamide is thus obtained in one Yield of 52% of theory, identical to the compound obtained according to Example 8.
Beispiel 17 Man verfährt wie in den vorstehenden Beispielen beschrieben und erhält so die folgenden Verbindungen: R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C2H5 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C3H7 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C4H9 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C5H11 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H13 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C5H9 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H11 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C7H13 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H5 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H CH3-C6H4 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H 1,2-(CH3)-C6H3 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H5-CH2 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H5-(CH2)2 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C2H5 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C3H7 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C4H9 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C5H11 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H13 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C5H9 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H11 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C7H13 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H5 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 CH3-C6H4 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 1,2-(CH3)-C6H3 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H5-CH2 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H5-(CH2)2 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C2H5 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C3H7 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C4H9 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C5H11 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H13 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C5H9 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H11 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C7H13 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H5 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 CH3-C6H4 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 1,2-(CH3)-C6H3 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H5-CH2 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H5-(CH2)2 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C2H5 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C3H7 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C4H9 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C5H11 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C6H13 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C5H9 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C6H11 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C7H13 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C6H5 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 CH3-C6H4 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 1,2-(CH3)-C6H3 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C6H5-CH2 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 C6H5-(CH2)2 C4H9 C3H7 C4H9 C4H9 (CH2)3 (CH2)4 R1 R2 R3 CH3 (CH2)5 C2H5 (CH2)5 C3H7 (CH2)5 C4H9 (CH2)5 C5H11 (CH2)5 C6H13 (CH2)5 C5H9 (CH2)5 C6H11 (CH2)5 C7H13 (CH2)5 C6H5 (CH2)5 CH3-C6H4 (CH2)5 1,2-(CH3)-C6H3 (CH2)5 C6H5-CH2 (CH2)5 C6H5-(CH2)2 (CH2)5 PatentansprücheExample 17 The procedure described in the preceding examples is repeated and thus has the following connections: R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C2H5 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C3H7 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C4H9 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C5H11 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H13 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C5H9 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H11 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C7H13 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H5 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H CH3-C6H4 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H 1,2- (CH3) -C6H3 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H5-CH2 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H C6H5- (CH2) 2 CH3 CH3 CH3 H C2H5 C2H5 C2H5 H R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C2H5 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C3H7 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C4H9 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C5H11 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H13 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C5H9 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H11 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C7H13 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H5 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 CH3-C6H4 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 1,2- (CH3) -C6H3 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H5-CH2 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 C6H5- (CH2) 2 C2H5 CH3 C3H7 H C3H7 CH3 C3H7 C2H5 R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C2H5 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C3H7 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C4H9 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C5H11 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H13 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C5H9 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H11 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C7H13 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H5 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 CH3-C6H4 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 1,2- (CH3) -C6H3 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H5-CH2 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 C6H5- (CH2) 2 C3H7 C3H7 C4H9 H C4H9 CH3 C4H9 C2H5 R1 R2 R3 R2 R3 R2 R3 R2 R3 CH3 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C2H5 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C3H7 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C4H9 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C5H11 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C6H13 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C5H9 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C6H11 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C7H13 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C6H5 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 CH3-C6H4 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 1,2- (CH3) -C6H3 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C6H5-CH2 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 C6H5- (CH2) 2 C4H9 C3H7 C4H9 C4H9 (CH2) 3 (CH2) 4 R1 R2 R3 CH3 (CH2) 5 C2H5 (CH2) 5 C3H7 (CH2) 5 C4H9 (CH2) 5 C5H11 (CH2) 5 C6H13 (CH2) 5 C5H9 (CH2) 5 C6H11 (CH2) 5 C7H13 (CH2) 5 C6H5 (CH2) 5 CH3-C6H4 (CH2) 5 1,2- (CH3) -C6H3 (CH2) 5 C6H5-CH2 (CH2) 5 C6H5- (CH2) 2 (CH2) 5 claims
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0125475A1 (en) * | 1983-04-12 | 1984-11-21 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives, process for their preparation, antitumor agents comprising them and compositions containing them |
| EP0140327A3 (en) * | 1983-10-31 | 1986-07-23 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives, process for their preparation, antitumor agents comprising them and compositions containing them |
| FR2601364A1 (en) * | 1986-07-09 | 1988-01-15 | Adir | NOVEL DERIVATIVES OF 2,6-DIONE PIPERAZINE, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US4868303A (en) * | 1986-02-07 | 1989-09-19 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives |
| EP0409499A3 (en) * | 1989-07-13 | 1991-03-27 | National Research Development Corporation | Pharmaceutical compositions |
| WO1992011232A1 (en) * | 1990-12-21 | 1992-07-09 | Nycomed Imaging As | Chelating agents |
| GB2257430A (en) * | 1991-07-12 | 1993-01-13 | British Tech Group | Piperazine derivatives |
| WO1993010104A1 (en) * | 1991-11-18 | 1993-05-27 | Windleshaw Enterprises Ltd | Bis(3,5-dioxoalkylpiperazine) derivatives for use in preventing or treating conditions that involve iron metabolism |
| EP0598837A4 (en) * | 1991-08-09 | 1994-07-13 | Univ California | Amino acid, ester and/or catechol contrast agents for mri. |
| GB2292943A (en) * | 1994-08-09 | 1996-03-13 | Univ Surrey | Metal ion ligating materials |
| US5562894A (en) * | 1991-08-09 | 1996-10-08 | Regents Of The University Of California | Amino-acyl-type and catecholamine-type contrast agents for MRI |
| EP0603403B2 (en) † | 1992-07-03 | 2001-06-27 | Welfide Corporation | Novel chelating agent, complex compound composed of said agent and metallic atom, and diagnostic agent containing said compound |
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1975
- 1975-03-19 DE DE19752511891 patent/DE2511891A1/en active Pending
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0125475A1 (en) * | 1983-04-12 | 1984-11-21 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives, process for their preparation, antitumor agents comprising them and compositions containing them |
| EP0140327A3 (en) * | 1983-10-31 | 1986-07-23 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives, process for their preparation, antitumor agents comprising them and compositions containing them |
| US4650799A (en) * | 1983-10-31 | 1987-03-17 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives, process for their preparation, antitumor agents comprising them and compositions containing them |
| US4868303A (en) * | 1986-02-07 | 1989-09-19 | Zenyaku Kogyo Kabushiki Kaisha | Bis-dioxopiperazine derivatives |
| FR2601364A1 (en) * | 1986-07-09 | 1988-01-15 | Adir | NOVEL DERIVATIVES OF 2,6-DIONE PIPERAZINE, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| EP0262993A1 (en) * | 1986-07-09 | 1988-04-06 | Adir Et Compagnie | 2,6-Piperazine-dione derivatives, processes for their preparation and pharmaceutical compositions containing them |
| EP0409499A3 (en) * | 1989-07-13 | 1991-03-27 | National Research Development Corporation | Pharmaceutical compositions |
| WO1992011232A1 (en) * | 1990-12-21 | 1992-07-09 | Nycomed Imaging As | Chelating agents |
| GB2257430A (en) * | 1991-07-12 | 1993-01-13 | British Tech Group | Piperazine derivatives |
| WO1993000901A1 (en) * | 1991-07-12 | 1993-01-21 | British Technology Group Ltd. | Pharmaceutical compositions |
| GB2257430B (en) * | 1991-07-12 | 1995-05-31 | British Tech Group | Piperazine derivatives |
| US5438057A (en) * | 1991-07-12 | 1995-08-01 | British Technology Group Limited | Pharmaceutical compositions |
| EP0598837A4 (en) * | 1991-08-09 | 1994-07-13 | Univ California | Amino acid, ester and/or catechol contrast agents for mri. |
| US5562894A (en) * | 1991-08-09 | 1996-10-08 | Regents Of The University Of California | Amino-acyl-type and catecholamine-type contrast agents for MRI |
| WO1993010104A1 (en) * | 1991-11-18 | 1993-05-27 | Windleshaw Enterprises Ltd | Bis(3,5-dioxoalkylpiperazine) derivatives for use in preventing or treating conditions that involve iron metabolism |
| EP0603403B2 (en) † | 1992-07-03 | 2001-06-27 | Welfide Corporation | Novel chelating agent, complex compound composed of said agent and metallic atom, and diagnostic agent containing said compound |
| GB2292943A (en) * | 1994-08-09 | 1996-03-13 | Univ Surrey | Metal ion ligating materials |
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