CH492684A - Process for the preparation of 1,2-bis (4 (N, N-bis-2-chloroethyl-amino) phenyl-carbamoyl) hydrazine - Google Patents
Process for the preparation of 1,2-bis (4 (N, N-bis-2-chloroethyl-amino) phenyl-carbamoyl) hydrazineInfo
- Publication number
- CH492684A CH492684A CH1278767A CH1278767A CH492684A CH 492684 A CH492684 A CH 492684A CH 1278767 A CH1278767 A CH 1278767A CH 1278767 A CH1278767 A CH 1278767A CH 492684 A CH492684 A CH 492684A
- Authority
- CH
- Switzerland
- Prior art keywords
- bis
- hydrazine
- chloroethyl
- amino
- phenyl
- Prior art date
Links
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 4
- -1 phenyl-carbamoyl Chemical group 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- TZMBXAYLOAYLGE-UHFFFAOYSA-N (4-nitrophenyl) N-[(4-nitrophenoxy)carbonylamino]carbamate Chemical compound N(NC(=O)OC1=CC=C(C=C1)[N+](=O)[O-])C(=O)OC1=CC=C(C=C1)[N+](=O)[O-] TZMBXAYLOAYLGE-UHFFFAOYSA-N 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JBLVXGWCHIFGNA-UHFFFAOYSA-N (4-nitrophenyl) n-aminocarbamate Chemical compound NNC(=O)OC1=CC=C([N+]([O-])=O)C=C1 JBLVXGWCHIFGNA-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UERKTBSAPLOJRQ-UHFFFAOYSA-N 1-amino-1-phenylurea Chemical compound NC(=O)N(N)C1=CC=CC=C1 UERKTBSAPLOJRQ-UHFFFAOYSA-N 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229960004793 sucrose Drugs 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung von 1,2-Bis[4(N ,N-bis-2chloräthyl-amino )phenyl carbamoyl ]hydrazin
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von
1 ,2-Bis[4(N,N-bis-2-chloräthyl-amino)- phenylcarbamoyl] hydrazin (Formel I, siehe Formelblatt) und seinen Säureadditionssalzen, dadurch gekennzeichnet, dass man
1, 2-Bis (4-nitro-phenyloxycarbonyl)-hydrazin mit 4-(N,N-Bis-2-chloräthyl)-p-phenylendiamin kondensiert und das erhaltene
1 ,2-Bis[4(N,N-bis-2-chloräthyl-amino)- phenylcarbamoyllhydrazin gegebenenfalls auf an sich bekannte Weise durch Reaktion mit organischen oder anorganischen Säuren in seine Säureadditionssalze überführt.
Das Verfahren wird vorteilhafterweise wie folgt ausgeführt: 1,2-Bis (4-nitrophenyloxycarbonyl)-hydrazin wird in einem, unter den Reaktionsbedingungen inerten Lösungsmittel, wie z. B. Methylenchlorid, Athylenchlorid, Chloroform, Tetrahydrofuran oder Aceton, gelöst, bei Zimmertemperatur mit 4-(N,N-Bis-2-chlor äthyl)-p-phenylendiamin in Gegenwart einer tertiären Base umgesetzt und während einiger Zeit stehengelassen. Das auf diese Weise erhaltene
1 ,2-Bis[4(N,N-bis-2-chloräthyl-amino)- phenylcarbamoyl]hydrazin wird hierauf nach an sich bekannten Methoden gereinigt und kann gegebenenfalls in seine therapeutisch verwertbaren Salze mit organischen und anorganischen Säuren übergeführt werden.
1 ,2-Bis[4(N,N-bis-2-chloräthyl-amino)phenyl- carbamoyl]hydrazin ist eine alkylierende Substanz und zeichnet sich durch ausgeprägte cytostatische Eigenschaften bei geringer Toxizität aus. Es eignet sich für die Behandlung von malignen Tumoren und Sarkomen. Insbesondere findet es in der Therapie von Neoplasmen der lymphatischen und myeloischen Systeme Anwendung, ferner bei anderen Krankheiten, insbesondere des immunologischen Formenkreises, die mit unerwünschter Zellvermehrung einhergehen.
1, ,2-Bis[4(N,N-bis-2-chloräthyl-amino)phenyl- carbamoylihydrazin kann als Arzneimittel allein oder in entsprechenden Arzneiformen für enterale oder parenterale Verabreichung verwendet werden. Zwecks Herstellung geeigneter Arzneiformen wird es mit anorganischen oder organischen, pharmakologisch indifferenten Hilfsstoffen verarbeitet. Als Hilfsstoffe werden verwendet z. B. für Tabletten und Dragees: Milchzucker, Stärke, Talk usw. für Sirupe: Rohrzucker-, Invertzucker-, Glucoselösungen u. a. für Injektionspräparate: Wasser, Alkohole, Glycerin, pflanzliche Öle und dergleichen für Suppositorien: natürliche oder gehärtete Öle, Wachse u. a. mehr.
Zudem können die Zubereitungen geeignete Konservierungs-, Stabilisierungs-, Netzmittel, Lösungsvermittler, Süss- und Farbstoffe, Aromantien usw. enthalten.
Die täglich zu verabreichende Dosis soll vorzugsweise 10 bis 500 mg betragen.
In dem nachfolgenden Beispiel, welches die Ausführung des Verfahrens erläutert, den Umfang der Erfindung aber in keiner Weise einschränken soll, erfolgen alle Temperaturangaben in Celsiusgraden.
EMI1.1
Beispiel
1,2-Bis [4(N,N-bis-2-chloräthyl-amino)phenyl carbamoyljhydrazin
Man löst 36 gl,2-Bis (4-nitrophenyloxycarbonyl)hydrazin in 200 ml Tetrahydrofuran, gibt 54 g 4-(N'N- Bis-2-chloräthyl)-p-phenylendiamin-hydrochlorid, 28 ml Triäthylamin und 400 ml Dimethylformamid zu, filtriert das auskristallisierte Triäthylamin-hydrochlorid ab, lässt die Lösung 24 Stunden bei 250 stehen und dampft zur Trockne ein. Man wäscht den Rückstand mit Wasser und kristallisiert aus einem Gemisch von 2000 ml Tetrahydrofuran-Diäthyläther (1: 4) um, wobei das
1 ,2-Bis[4(N,N-bis-2-chloräthyl-amino)phenyl- carbamoyl]hydrazin erhalten wird. Smp. 1350.
Process for the preparation of 1,2-bis [4 (N, N-bis-2-chloroethyl-amino) phenyl carbamoyl] hydrazine
The present invention relates to a method for producing
1, 2-bis [4 (N, N-bis-2-chloroethyl-amino) -phenylcarbamoyl] hydrazine (formula I, see formula sheet) and its acid addition salts, characterized in that one
1, 2-bis (4-nitro-phenyloxycarbonyl) -hydrazine with 4- (N, N-bis-2-chloroethyl) -p-phenylenediamine condensed and the obtained
1,2-Bis [4 (N, N-bis-2-chloroethyl-amino) - phenylcarbamoyl hydrazine optionally converted into its acid addition salts in a manner known per se by reaction with organic or inorganic acids.
The process is advantageously carried out as follows: 1,2-bis (4-nitrophenyloxycarbonyl) hydrazine is dissolved in a solvent which is inert under the reaction conditions, such as. B. methylene chloride, ethylene chloride, chloroform, tetrahydrofuran or acetone, dissolved, reacted at room temperature with 4- (N, N-bis-2-chloroethyl) -p-phenylenediamine in the presence of a tertiary base and left to stand for some time. The one obtained in this way
1,2-Bis [4 (N, N-bis-2-chloroethyl-amino) -phenylcarbamoyl] hydrazine is then purified by methods known per se and can optionally be converted into its therapeutically utilizable salts with organic and inorganic acids.
1,2-Bis [4 (N, N-bis-2-chloroethylamino) phenylcarbamoyl] hydrazine is an alkylating substance and is characterized by pronounced cytostatic properties with low toxicity. It is suitable for the treatment of malignant tumors and sarcomas. In particular, it is used in the therapy of neoplasms of the lymphatic and myeloid systems, and also in other diseases, especially of the immunological type, which are associated with undesired cell proliferation.
1,2-bis [4 (N, N-bis-2-chloroethyl-amino) phenyl-carbamoylihydrazine can be used as a medicament alone or in appropriate medicament forms for enteral or parenteral administration. In order to produce suitable dosage forms, it is processed with inorganic or organic, pharmacologically indifferent auxiliary substances. As auxiliaries are used z. B. for tablets and dragees: milk sugar, starch, talc, etc. for syrups: cane sugar, invert sugar, glucose solutions and the like. a. for injection preparations: water, alcohols, glycerine, vegetable oils and the like for suppositories: natural or hardened oils, waxes, etc. a. more.
In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorants, flavorings, etc.
The dose to be administered daily should preferably be 10 to 500 mg.
In the following example, which explains the implementation of the method but is not intended to restrict the scope of the invention in any way, all temperatures are given in degrees Celsius.
EMI1.1
example
1,2-bis [4 (N, N-bis-2-chloroethyl-amino) phenyl carbamoyl hydrazine
36 g of 2-bis (4-nitrophenyloxycarbonyl) hydrazine are dissolved in 200 ml of tetrahydrofuran, 54 g of 4- (N'N-bis-2-chloroethyl) -p-phenylenediamine hydrochloride, 28 ml of triethylamine and 400 ml of dimethylformamide are added , the crystallized triethylamine hydrochloride is filtered off, the solution is left to stand for 24 hours at 250 and evaporated to dryness. The residue is washed with water and crystallized from a mixture of 2000 ml of tetrahydrofuran diethyl ether (1: 4), the
1, 2-bis [4 (N, N-bis-2-chloroethylamino) phenylcarbamoyl] hydrazine is obtained. M.p. 1350.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1278767A CH492684A (en) | 1967-09-13 | 1967-09-13 | Process for the preparation of 1,2-bis (4 (N, N-bis-2-chloroethyl-amino) phenyl-carbamoyl) hydrazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1278767A CH492684A (en) | 1967-09-13 | 1967-09-13 | Process for the preparation of 1,2-bis (4 (N, N-bis-2-chloroethyl-amino) phenyl-carbamoyl) hydrazine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH492684A true CH492684A (en) | 1970-06-30 |
Family
ID=4386393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1278767A CH492684A (en) | 1967-09-13 | 1967-09-13 | Process for the preparation of 1,2-bis (4 (N, N-bis-2-chloroethyl-amino) phenyl-carbamoyl) hydrazine |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH492684A (en) |
-
1967
- 1967-09-13 CH CH1278767A patent/CH492684A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |